{"paper_id":"42fe435c-40f2-4b8a-a4e6-87dc41541af8","body_text":"Treatment of hypothyroidism with levothyroxine plus slow-release liothyronine; A Study Protocol for a Randomized Controlled Double-Blinded Clinical Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Treatment of hypothyroidism with levothyroxine plus slow-release liothyronine; A Study Protocol for a Randomized Controlled Double-Blinded Clinical Trial Fereidoun Azizi, Atieh Amouzegar, Hengameh ABDI, Maryam Tohidi, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4851538/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Jul, 2025 Read the published version in Trials → Version 1 posted 6 You are reading this latest preprint version Abstract Background There are emerging controversies regarding the priority of T4 + T3 combination therapy over standard care with LT4 monotherapy in the management of hypothyroid subjects. Combination therapy with a slow-release form of liothyronine (SRT3) and levothyroxine may restore T3 concentrations and provide better outcomes, especially in individuals with persistent complaints despite having normal serum TSH levels. Methods 100 patients with hypothyroidism ≥ 20 years old., who achieve euthyroidism under LT4 monotherapy for at least three months will be randomized to two groups of LT4 + SRT3 combined therapy (75 µg LT4 + 25 µg SRT3) and LT4 monotherapy for 48 weeks. Participants will be evaluated at baseline and three subsequent follow-ups, 12, 24, and 48 weeks after treatment allocation. Before and after the intervention, body weight, heart rate, blood pressure, ECG, quality of life ( by Thypro-39 and SF-12), resting energy expenditure, and body composition will be evaluated. Also, serum TSH, total T3, total T4, free T4, free T3, total cholesterol, LDL, HDL, triglycerides, FBS, insulin, HbA1C, HOMA-IR, SHBG, Enolase, LDH and CK, Ferritin and metabolomics will be assessed at baseline and compared with their corresponding values at 24 and 48 weeks. Epigenetic-related markers will be measured and compared between the responders and non-responders. Conclusion It is expected that LT4 + SRT3 combined therapy more closely mimics the serum levels of T3, T4, and the T3/T4 ratio of euthyroid subjects than LT4 monotherapy, and improves health outcomes and quality of life, especially in hypothyroid patients with persistent symptoms under LT4 monotherapy. Genetic polymorphism sequencing may identify hypothyroid patients who are not responding well to levothyroxine alone. Hypothyroidism Levothyroxine Slow-release Liothyronine Combination therapy Clinical trial Patient-reported outcomes Patient satisfaction Background and rationale Hypothyroidism is a common endocrine disorder that significantly impacts human health ( 2 – 4 ). The most common cause of primary hypothyroidism is iodine deficiency, followed by an autoimmune condition known as Hashimoto's thyroiditis ( 5 ). Overt hypothyroidism affects 0.2–5.3% of people in Europe( 6 ) and 0.3–3.7% of people in the United States ( 7 ) in the general population. In Iran, the prevalence of overt hypothyroidism is 2%, resulting in a total of 1,600,000 individuals in the general population ( 8 ). In normal subjects, 80% of T3 is generated from the conversion of T4 in kidney and liver cells, while the thyroid gland secretes the remaining 20%. This process is lacking in those who suffer from thyroid failure and undergo LT4 monotherapy ( 3 ). Many animal and human studies suggest that LT4 monotherapy may not be sufficient to restore euthyroidism in all tissues, as evidenced by a decreased T3 to T4 ratio, lower quality of life, and reduced resting energy expenditure ( 9 – 12 ). About 10–20% of treated patients do not achieve well-being and complain of unresolved signs and symptoms of thyroid hypo-function despite achieving normal thyroid hormone concentration( 13 ), which accounts for 320,000 in Iran and 29,200,000 globally. In the periphery, T4 is converted to T3 by deiodinases ( 14 ). Deiodinase genes have been shown to include numerous single-nucleotide polymorphisms. Two polymorphisms in the deiodinase type 2 (D2) gene, D2-Thr92Ala ( 15 ) and D2-ORFa-Gly3Asp ( 16 ), have been linked to thyroid hormone levels. Theoretically, polymorphisms could result in lower enzyme activity and, therefore, less conversion of T4 to T3 in the periphery, with even small changes in hormone levels having significant long-term consequences( 15 ). Individuals with such polymorphisms potentially would require LT3 replacement to attain euthyroidism. Therefore, dysfunctional deiodinase in a subset of hypothyroid patients could be an important rationale for including active FT3 to improve symptoms in those patients. A subset of patients with hypothyroidism who continue to be symptomatic on LT4 therapy with normal TSH and FT4 or with normal or subnormal FT3 might benefit from the addition of FT3 therapy. Many patients do not feel well on standard LT4 ( 17 – 20 ) and may benefit from experimental treatment with combined LT3 + LT4 preparations ( 13 ); however, combination therapy with LT4/LT3 did not show any significant improvement in related parameters compared to LT4 monotherapy ( 21 ). An analysis of five cross-over studies ( 21 – 26 ) by Wiersinga et al. ( 13 ) revealed that 48% of all hypothyroid patients chose LT3 + LT4 combination therapy, 27% preferred LT4 monotherapy, and 25% had no preference. No study has ever explained why so many patients prefer LT3. In the Grozinsky-Glasberg et al. meta-analysis ( 21 ), no difference was observed in symptom scores or serum lipid profiles in those treated with combination therapy versus those treated with LT4 alone. In a systematic review of nine controlled trials (N = 1056), no benefit in mood, quality of life (QOL), or psychometric performance was found with LT4/LT3 combination therapy compared with LT4 monotherapy ( 27 ). A meta-analysis of 11 randomized trials (N = 1216) found no differences in pain, depression, anxiety, fatigue, cognitive function, or QOL outcomes in patients treated with LT4/LT3 combination therapy versus LT4 monotherapy ( 21 ). These reviews conclude that no reproducible clinical evidence supports the efficacy of LT4/LT3 over LT4 alone ( 28 ). Lack of success was due to: 1. Using higher amounts of T3; 2. High variations in T3 serum concentration due to low half-life and rapid absorption of T3, and 3. Lack of attention to T3 surge after TSH surge during midnight ( 29 ). The only human study using a combination of LT4 and slow-release LT3 reported an increased T3/T4 ratio; however, this ratio did not return to normal values. The study period was short, and it did not assess other outcomes or the effects of applying different combinations ( 30 ). In 2019, the consortium of the American Thyroid Association (ATA), British Thyroid Association (BTA), and European Thyroid Association (ETA), headed by J. Jonklaas, released a Consensus Statement to guide the development of future clinical trials of LT4/LT3 combination therapy ( 31 ). There were 13 statements with 100% agreement among the 28 consensus statements with at least 75% agreement. Those with 100% agreement included studies powered to investigate the effect of genetic polymorphisms on study outcomes, the inclusion of patients dissatisfied with their current therapy and requiring at least 1.2 µg/kg of LT4 daily, the use of twice daily LT3 or, if available, a slow-release preparation, the use of patient-reported outcomes as a primary outcome (measured by a valid and reliable tool). The reforms proposed to the previous studies' designs may be a significant step toward adequately evaluating the potential benefits of \"physiological thyroid hormone replacement\" using combination LT4 + LT3 therapy. Based on the consensus mentioned above, we developed a slow-release preparation to maintain serum T3 concentration and the T3/T4 ratio within normal ranges for 12–24 hours. We designed a parallel randomized clinical trial to characterize the PK and PD of the three combined preparations of LT4 + SR-T3 in hypothyroid patients. We found that combined treatment with a single dose of SR-T3 plus LT4 is associated with an increased serum T3/T4 ratio and minimal fluctuations in serum T3 concentration over 24 hours ( 32 ). We suggested that the best formulation for combination therapy should incorporate a higher ratio of SR-T3 to LT4 than that of the previously recommended by international organizations. In this study, We aim to conduct a parallel randomized clinical trial, based on the suggestion proposed in the consortium, to compare the efficacy and safety of the new combination of SRT3 plus LT4 with LT4 monotherapy. Objectives To compare treatment efficacy and safety with LT4 + SR-T3 with LT4 monotherapy Trial design Double-blind, randomized control clinical trial Methods: Participants, interventions, and outcomes Study setting The Tehran Thyroid Study (TTS), a prospective population-based cohort study, is being conducted within the framework of the Tehran Lipid and Glucose Study (TLGS). Of the 15,005 TLGS participants aged 20 years or older, 5,786 were randomly selected between March 1997 and December 1999 and followed at three-year intervals for ten years to investigate the epidemiology of thyroid diseases and their long-term consequences in the iodine-sufficient population of Tehran ( 33 ). Eligibility criteria Who will take informed consent? The responsible person will recall these patients to the TTS research unit and explain the project's aim and details. If a patient is willing to participate, the informed written consent will be completed by the patient. Five participants are evaluated each day. Additional consent provisions for the collection and use of participant data and biological specimens Not Applicable Interventions The explanation for the choice of comparators One hundred patients will be selected from the group of hypothyroid patients who participated in the TTS. Patients will be randomly assigned to one of the following groups using simple randomization with stratification by age. The group with a daily intake of 75 µg LT4 + 15 µg SR-T3 The group with LT4 monotherapy Intervention description Drug Formulation and Dosing The formulation of liothyronine sodium sustained-release tablets was developed by Dorsa Pharmaceutical Company and Noor Research & Educational Institute (TAVAN). Using Avicel PH-102 and HPMC in the formulation of tablets sustained the drug release of T3 for 24 hours. The in vitro dissolution study was conducted in 500 mL of pH 6.8 phosphate buffer using a United States Pharmacopeia Apparatus I, employing the basket method, at a speed of 100 rpm and a temperature of 37°C. The combination of 75 µg LT4 and 15 µg SR-t3 is considered a preferred combination based on the results of our two previous studies. The drug dosage will be administered on the last dosage, levothyroxine, which was at a weight-based dose of ~ 1.6 mcg/kg to retain euthyroidism in both intervention groups. After six weeks, serum TSH will be measured to adjust drug dosage, and the measurements will be repeated until euthyroidism is achieved. After achieving the ideal dosage, the drug will be continued for 12 months. Participants take their medicine at least 30 minutes before breakfast. Adherence to therapy and adverse effects will be monitored at three follow-up visits and monthly via telephone calls. Criteria for discontinuing or modifying allocated interventions During each visit, signs and symptoms of hypo and hyperthyroidism will be evaluated using standard anamnesis, related questionnaires, and physical examination. Any new clinical signs, symptoms, or illnesses will be recorded and managed. If any critical symptoms become apparent during the treatment, it is permissible to either change the dosage or discontinue the new combination therapy. Individuals who adjust their medication dosage within the initial eight weeks of the study will be considered adherent to the protocol and, therefore, will not be included in the intention-to-treat analysis. The participants who discontinue the trial will be excluded. Strategies to improve adherence to interventions The date and quantity of medicine distribution and return will be recorded. Participants must return the finished medicine package and any unused medicine at all scheduled visits (at 12, 24, and 48 weeks). Furthermore, free healthcare education consultations at baseline followed by monthly telephone monitoring calls will improve intervention adherence. Additionally, failure to comply with the study's requirements, as evidenced by abnormal TSH levels during scheduled visits, is grounds for exclusion. We will closely monitor the study population to minimize follow-up loss and maintain the statistical power and validity of our findings. Relevant concomitant care permitted or prohibited during the trial Other thyroid or anti-thyroid medications, as well as estrogen-containing products, are not allowed for patients. Any increase or decrease in medication dosage administered is also prohibited. Patients are recommended to inform any new disease, drug intake, or medical event to the principal investigator (PI) during the trial. Provisions for post-trial care In the event of adverse events or reactions, the PI will determine whether they are related to the intervention and follow the participants until the symptoms have ceased or become stable. If the insurance does not cover the participants, the RIES will cover the cost corresponding economic compensation for any damage related to the trial. If a subject is excluded at any time after entering the study, the investigator will ensure this does not affect the patient’s standard of care. The reasons for withdrawal will be recorded on the case report form (CRF) and included in the final report. After the end of the trial, all patients will be back to standard care with LT4 monotherapy and followed until euthyroidism is achieved. All remaining biological samples (blood) will be destroyed at the patient's request. Outcomes Primary outcome Quality of life via Thyroid-specific Patient-Reported Outcome short-form (ThyPRO-39) modeled for hypothyroid subjects to quantify dissatisfaction and SF-12 The change in the QOL score from baseline to the end of the 48-week treatment will be evaluated. The recent Consensus Statements to guide the development of future clinical trials of LT4/LT3 combination therapy suggest using patient-reported outcomes as the primary outcome in the redesigned trials, primarily the thyroid-specific quality of life, measured by a valid and reliable tool. The newly-translated thyroid-specific Patient-Reported Outcome short-form (ThyPRO-39) instrument was designed for ethnic-Iranian patients suffering from benign thyroid diseases. Although the ThyPRO has been recommended for use in patients with thyroid dysfunction and its cross-cultural validity has been confirmed, evaluating the applicability of the psychometric properties of the ThyPRO and its short form in Iranian patients with thyroid dysfunction is necessary. Therefore, the translation, cultural adaptation, validity, and reliability of the ThyPRO-39 instrument have been previously assessed in Iranian patients with benign thyroid disease. The between-group change at baseline compared to 24 and 48 weeks of treatment will be assessed for the primary outcome. Secondary outcomes For the following secondary outcomes, the between-group change at baseline compared to 12, 24, and 48 weeks of treatment will be assessed: Serum TSH, FT4, FT3, and TT3 values were used to determine whether combination therapy improved the T3/T4 ratio to levels near normal values and statistically different from those on LT4 monotherapy. Normal ranges of TSH, TT4, TT3, and TT4/TT3 ratio are as follows: TSH (0.3–5.1 mU/L), TT4 (4.5–11.5 µg/dl), TT3 (70–220 ng/dl), Free T3 (230–420 pg /dl), FT4 (0/8–1/5 ng/dl). Achieving physiological values of TSH and the T3/T4 ratio is one of the primary goals in managing hypothyroidism; serum thyroid hormone levels serve as a surrogate marker and may not accurately reflect cellular activities. Patient Preference Patient preference will be assessed at multiple time points during the study, including 12 and 24 weeks of therapy, as well as at study completion (48 weeks), to evaluate both early and sustained responses. Additionally, patients will be asked whether they believe they are receiving combination therapy or standard levothyroxine (LT4) therapy. They will also be asked to document the reason for their preference. Qualitative interviews might be considered in a subset of patients to gain further insight into individual patient preferences. Tertiary outcome Physiologically measurable parameters provide the most accurate reflection of thyroid hormone activity in cells, enabling a more precise assessment of euthyroid status. Therefore, tertiary efficacy outcomes in the following domains are considered for inclusion in the trials: metabolic, cardiovascular, and musculoskeletal. Tertiary outcomes include metabolic efficacy outcomes, musculoskeletal efficacy outcomes, cardiac efficacy outcomes, ferritin, and metabolomics. The changes in these outcomes from baseline to the end of the study, at 48 weeks of treatment, will be evaluated. Metabolic efficacy outcomes include body weight, waist circumference, and Resting Energy Expenditure) REE(Body composition, lipid profile, FBS, insulin sensitivity (HbA1C, HOMA-IR), and sex hormone-binding globulin (SHBG). Musculoskeletal efficacy outcomes include muscular biomarkers (E.g., Enolase, LDH, and CK) and bone biomarkers (e.g., C-telopeptide or N-telopeptide). Cardiac efficacy outcomes include resting heart rate and BP. Genetic polymorphisms (rs225014, rs225015, rs12885300, rs17606253) are also assessed and compared between the responders and non-responders. Metabolic efficacy outcomes Lipid profiles (total cholesterol, LDL, HDL, triglyceride) FBS, Insulin sensitivity (HbA1C, HOMA-IR) Peripheral thyroid status (Sex hormone binding globulin: SHBG) Resting Energy Expenditure (REE) and body composition Musculoskeletal efficacy outcomes muscular biomarkers (Enolase, lactate dehydrogenase: LDH, and creatine kinase: CK) bone biomarkers (C-telopeptide or N-telopeptide) Cardiac efficacy outcomes Resting heart rate BP • Ferritin • Metabolomics Genetic polymorphisms Thr92Ala polymorphism of the type 2 deiodinase gene (DIO2) (Thr92Ala-DIO2) and polymorphisms in thyroid hormone transporters (e.g. MCT8, MCT10, OATP1C1) Safety monitoring Safety monitoring involves assessing thyrotoxic symptoms, hypothyroid symptoms, and any other adverse events. These signs and symptoms include dyspnea on exertion, palpitations, tiredness, preference for heat, preference for cold, excessive sweating, diminished sweating, dry skin, cold intolerance, nervousness, increased appetite, decreased appetite, decreased weight, increased weight, headache, diarrhea, constipation, hoarseness, and deafness. Signs: periorbital puffiness, palpable thyroid, bruit over the thyroid, exophthalmos, lid retraction, lid lag, hyperkinesia, hands hot and moist, pulse rate > 90/min, atrial fibrillation, delayed ankle reflex, coarse and cold skin. Biochemical measurements of thyroid hormones are also considered for safety monitoring. Cardiac monitoring, including ECG and blood pressure (BP) measurement, at baseline and after 12, 24, and 48 weeks, is also considered a safety monitoring tool. Participant timeline Table 1 Schedule of enrolment, interventions, and assessments STUDY PERIOD Randomization Follow-up Follow-up last Follow-up VISIT NUMBER Visit 1 Visits 2 Visits 3 Visits 4 Month # 0 3 6 12 Informed consent X Confirm eligibility X Randomization X Demographic Information X Medical History X Height measurement X Weight measurement X X X X Physical Examination X X X X Vital Sign Measurements X X X X ECG X X X REE & Body Composition X X X Blood Collection X X X X CBC, and serum levels of 25(OH) Vit D, Vit B12 and TPOAb X Metabolic measurements total cholesterol, LDL, HDL, triglycerides, FBS, insulin, HbA1C, SHBG, Enolase, LDH and CK, Ferritin, and metabolomics X X X Serum TSH, total T3, total T4, free T4 and free T3 X X X X Polymorphism X Metabolomics X X X Demographic and Past Medical History Questionnaire X X X QOL questionnaire SF-12 X X X QOL questionnaire Thypro-39 X X X Study drug dispensing X X Compliance check X X X Adverse Event Check X X X Concomitant medication Check X Sample size The sample size was calculated based on the primary outcome of quality of life (THYPRO-39, SF-12) improvement over 48 weeks in the daily intake of the LT4 + SR-T3 group versus the LT4 monotherapy group. We assumed an anticipated effect size of 0.50, a type I error of 0.05, a test power of 90%, and a correlation coefficient of 0.5 for repeated measurements. A total sample size of n = 32 was calculated using G*Power 3.1 (University of Kiel, Germany) for repeated measures analysis of variance (ANOVA), considering a 20% loss to follow-up in each group. A total of 2*20 = 40 individuals will be sufficient. The effect size in this formula was derived from the consensus document on the evidence-based Use of levothyroxine/ liothyronine combinations in treating hypothyroidism ( 31 ): Output G*Power 3.1: F tests - ANOVA: Repeated measures between factors Analysis: A priori: Compute required sample size Input: Effect size f = 0.50 α err prob = 0.05 Power (1-β err prob) = 0.90 Number of groups = 2 Number of measurements = 3 Corr among rep measures = 0.5 Output: Noncentrality parameter λ = 12.0000000 Critical F = 4.1708768 Numerator df = 1.0000000 Denominator df = 30.0000000 Total sample size = 32 Recruitment Since hypothyroid patients with 18 years of follow-up in TTS will be recruited by trained social workers in the TTS Unit, enrollment and obtaining written consent will be easily facilitated. Assignment of interventions: allocation Sequence generation Subject inclusion/exclusion criteria will be determined at the baseline visit, and subjects who do not meet all the requirements will be excluded from the study. Using simple stratified randomization, two hundred patients will be randomly allocated to two treatment groups. The groups with a daily intake of LT4 + SR-T3 (Group A) The groups with LT4 monotherapy (Group B) Participants will be randomized with equal probability (1:1) to receive one of the two treatments. As the size of each group is predicted to be 50, the allocation sequence is generated with sample randomization and stratification by gender. The allocation sequences will be generated by the software and in Excel format. The patients were sequentially enrolled in the study according to this random sequence. Concealment mechanism Before the study begins, the computer will generate a series of random numbers. The allocation sequence will be generated by a statistician who will not be involved in participant enrollment. The allocation is concealed in a password-protected computer file, accessible only to the data manager. The randomization list is sent to the trained social worker in the TTS unit, who is not directly involved in the trial, and the medicine is labeled with blinding codes according to this list. The trained social worker keeps the random numbers in plain, closed envelopes marked with patient numbers. This staff will be instructed to keep the list private and to only reveal a treatment allocation after receiving information demonstrating that the patient is eligible and has provided consent for the trial. The envelopes will not be accessible to individuals directly involved in the study. After proper randomization implementation, the subjects will be assigned to the groups using allocation concealment, which helps to keep clinicians, participants, and investigators unaware of upcoming assignments. The trial participants and the investigators are kept from knowing who is assigned to which treatment (double-blind). To fulfill this, both groups will receive identical tablets in terms of physical appearance, taste, and smell. To ensure a double-blind design, all tablets will be distributed in identical packages of the same size and color, keeping patients and physicians blinded to the treatment allocation. Implementation A physician and a trained social worker are involved in enrolling participants under the supervision of the principal investigators. After signing the informed consent form, each participant is allocated a sequential number that randomizes them to one of the two groups. Participants will be randomly assigned and allocated a unique number. Assignment of interventions: Blinding Who will be blinded The trial participants, investigators, outcome assessors, and data analysts will be blinded to the group assignment until the trial is completed. Procedure for unblinding if needed The blinding code will not be broken during the trial period except in the case of a severe adverse event that requires an urgent breaking of the blinding code, e.g., any new cardiovascular or cerebral events, atrial fibrillation, myxedema coma, or severe psychiatric disorders. Finally, the trial steering committee will take a terminal decision. Data collection and management Plans for assessment and collection of outcomes Medical History and Clinical Examination Confidentiality To protect participants' privacy, all participant's data will be collected in a specific reception room rather than in public areas. Every participant's information throughout the trial is recorded in the Case report form (CRF). On the CRF, the initials of patient names will be used, and all documents will be stored confidentially in a secure location. All data collected from enrolled participants will be stored in a secure database, and only anonymized data will be shared. Subjects have their own independent codes for uploading test results. A third party will manage the final statistical process. Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use Blood for a research biobank will be collected at baseline and after 12,24 and 48 weeks of treatment. The biobank aims to measure and compare potential changes in biomarkers related to metabolic efficacy, musculoskeletal efficacy, ferritin, and metabolomics from baseline to the end of the study, at 48 weeks, in two trial groups and the control group. Any excess blood will be stored for a period of ten years. Informed consent is obtained from all participants to enable the analysis for other research purposes. Genetic polymorphisms (rs225014, rs225015, rs12885300, rs17606253) are also assessed and compared between the responders and non-responders. Laboratory measurements At baseline blood sampling, a complete blood count (CBC) will be performed using a KX-21 hematology analyzer (Sysmex, Japan). At the follow-up visits, 20 cc fasting blood samples will be collected from all participants between 7:00 and 9:00 am into vacutainer tubes at each reassessment. After standard centrifugation, serum samples will be stored at -70° C until analysis. Measurements of serum TSH, 25(OH) Vit D, and Vit B12 at baseline sample and serum total tri-iodothyronine(TT3), total thyroxine (TT4), free T4 (FT4), TSH, ferritin, SHBG, and insulin at baseline and follow-ups will be performed by electrochemiluminescence immunoassay (ECLIA) method, using Roche Diagnostics kits and the Roche/Hitachi Cobas e-411 analyzer (GmbH, Mannheim, Germany). Thyroid peroxidase antibody (TPO Ab) will be assayed by immunoenzymometric assay (IEMA) using a commercial kit (Monobind, USA) and the Sunrise ELISA reader (Tecan Co., Austria). To monitor the accuracy of immunoassays, lyophilized quality control materials Lyphochek Immunoassay plus Control (Bio-Rad Laboratories, USA) and PreciControl (Roche, GmbH, Germany) will be used. In our institute's endocrine laboratory, the intra- and inter-assay coefficients of variation (CVs) for all tests performed by the ECLIA and IEMA methods have been less than 4.7% and 5.7%, respectively. Serum total cholesterol (TC) and triglycerides (TG) will be measured using enzymatic calorimetric methods. High-density lipoprotein cholesterol (HDL-C) will be measured after precipitation of apolipoprotein B-containing lipoproteins with phosphotungstic acid. Low-density lipoprotein cholesterol (LDL-C) will be calculated using the modified Friedwald formula ( 34 ). CK and LDH will be measured using the NAC kinetic UV test and the DGKC photometric method, respectively. All these simple biochemical tests will be performed using commercial kits (Pars Azmon Inc., Iran) and the Pictus 700 clinical chemistry analyzer (Diatron MI Plc, Hungary). Assay performance for simple biochemical tests will be monitored using quality control materials in two concentrations, TruLab N and TruLab P (Pars Azmon Inc., Iran). Inter- and intra-assay CVs for all the mentioned biochemical tests, i.e., FBS, lipid profile, and enzymes, have been less than 3.0% in the biochemical laboratory of our institute. HbA1C will be determined by enzymatic method using a commercial kit (Pishtaz Teb, Iran) and Hitachi 911 chemistry analyzer (Roche Diagnostics, GmbH, Germany) with intra- and inter-assay CVs of less than 1.7%. The Homeostatic Model Assessment (HOMA) will be used as a surrogate marker of insulin resistance (IR) and calculated as HOMA-IR = fasting insulin (IU/mL) × fasting glucose (mM/L) / 22.5. Measurement of body composition and resting energy expenditure Body Composition will be assessed using a portable multi-frequency bioimpedance analysis (BIA) device (brand: InBody 570, InBody Co., Ltd.). The InBody 570 is renowned for its reliability and consistency across various groups; however, its precision may be influenced by factors such as hydration, body temperature, and population-specific characteristics. The BIA technique involves utilizing a portable multi-frequency BIA device with an eight-electrode arrangement. Participants must follow specific preparation guidelines, including fasting for 2 hours, abstaining from caffeine for 2 hours, refraining from physical activity for 4–6 hours, and dressing in light, comfortable clothing without shoes or socks. The BIA device conducted a safe electrical current through the body at low levels, measuring impedance at various frequencies. It uses predictive formulas to determine different BC parameters. It is essential to note that BIA should not be used in individuals with heart pacemakers, platinum or metal prostheses, or a Holter device implanted in their bodies. Individuals should remove any metal or jewelry before undergoing BIA measurements. This step is taken to minimize the potential interference and improve the reliability of the BIA results. After cleaning the palm and sole with an electrolyte tissue, individuals place their soles on the foot electrodes and hold the hand-held paddle electrodes with their hands. Additional information, such as gender, height, weight, and age, is also documented. FM (fat mass, kg), PBF (percentage of body fat), and FFM (fat-free mass, kg) will be measured. The FMI, FFMI, and SMMI will be calculated by dividing their values by the square of the height, measured in kg/m². The ratio of fat mass to skeletal muscle mass will be determined by dividing the fat mass by the skeletal muscle mass. BMR values will be estimated using the BIA software, which employs prediction equations based on age, weight, height, and sex. These values represent calculated estimates and should not be interpreted as direct measurements of BMR( 35 ). Statistical methods Statistical methods for primary and secondary outcomes All study practices and statistical methods are based on the International Conference on Harmonization (IHC) document “Statistical Principles for Clinical Trials.” Descriptive statistics will be computed for each treatment group, with medians and percentiles reported for continuous variables that exhibit skewness. Descriptive statistics and 95% confidence intervals will be used to summarize the differences between groups for both primary and secondary outcomes. The intervention arms will be compared against the control for all preliminary analyses. We will use the chi-squared test for binary outcomes and ANCOVA for continuous outcomes. For subgroup analyses, we will use regression methods. Multivariable analyses will be based on logistic regression for binary outcomes and linear regression for continuous outcomes. For analyzing repeated measurements, repeated measures ANOVA and, if needed, the Generalized Estimation Equation will be used. Relative Risk (RR) with corresponding 95% confidence intervals will be estimated by logistic regression to compare dichotomous variables. SPSS (Chicago, IL) will be used for data analysis. For all tests, we will use two-sided p-values with an alpha level of significance of less than 0.05. For data analysis, the intention-to-treat approach and the superiority hypothesis will be considered. Interim analyses The Trial Steering Committee comprises five investigators, including the PI, who supervise and monitor the project. The investigators review the data every two months, and in the event of unexpected findings, an interim analysis will be conducted to inform a pertinent decision. The Trial Steering Committee may decide to terminate the project under specific circumstances. Methods for additional analyses (e.g., subgroup analyses) The subgroup analysis will be performed in different sex groups and respondents and non-respondents groups regarding the quality of life and patient preference, Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data Participants with poor adherence or those who are no longer undergoing testing and receiving medication during the study will be included in the intention-to-treat analysis and excluded from the per-protocol analysis. In cases of missing data, single or multiple imputation methods will be employed, depending on the nature and extent of the missing data. Plans to give access to the complete protocol, participant-level data, and statistical code The protocol and the statistical analysis plan (SAP) will be accessible at www.clinicaltrials.gov , identifier: IRCT20100922004794N12 . The corresponding author makes the participant-level data and statistical code available upon reasonable request. Oversight and monitoring Composition of the coordinating Center and trial steering committee The coordinating center is the Endocrine Research Center, Research Institute for Endocrine Sciences, at Shahid Beheshti University of Medical Sciences, which will assist in recruiting participants and obtaining their consent. The trial steering committee comprises five investigators who will supervise the trial and review its progress. Composition of the data monitoring committee, its role, and reporting structure The Data Monitoring Committee (DMC) is an independent group of individuals selected from the Endocrine Research Council who work closely with investigators and sponsors to monitor data collection, trial conduct, patient safety, and efficacy, as well as to ensure the trial's validity and integrity, and to make a benefit-risk assessment. DMC has no relationship with a sponsor organization. Adverse event reporting and harms Any unintended adverse effects, including clinical or biochemical symptoms of hyperthyroidism or hypothyroidism, as measured by thyroid hormones and other unexpected events, will be reported to the steering committee for final decision. Symptoms: Dyspnea, palpitations, tiredness, preference for heat, preference for cold, excessive sweating, nervousness, increased appetite, decreased appetite, decreased weight, increased weight, hair loss Signs: Palpable thyroid, bruit over the thyroid, exophthalmos, lid retraction, lid lag, hyperkinesia, hands hot, hands moist, casual pulse rate: >80/min, > 90/min, atrial fibrillation Frequency and plans for auditing trial conduct The trial will be supervised by the steering committee and data monitoring committee, which will be independent of the sponsor organization. Plans for communicating necessary protocol amendments to relevant parties (e.g., trial participants, ethical committees) Any changes and modifications made to each part of the protocol, such as updates to eligibility criteria, outcomes, and analyses, will be reported in trial registries as well as to the Ethics Approval Committee of the Research Institute for Endocrine Sciences. Dissemination plans Before enrolling the first patient, information about the trial is published on ClinicalTrials.gov. The protocol and study findings will be published in peer-reviewed international journals. Positive, negative, and inconclusive results will all be made public. Following publication, the trial results will be disseminated to trial participants, healthcare professionals, and other relevant groups via email, scientific webinars, conferences, and other data-sharing arrangements as needed, and to the general public through written and online media. Consistency of the current trial with the recently published consensus document to guide well-designed trials on lt4/lt3 combination therapy ATA, BTA, and ETA jointly held a conference to review the new evidence on combination therapy ( 31 ). Out of 10 area topics identified by the Joint Association, 34 summary Consensus Statements were developed regarding the appropriate design of future clinical trials of combination therapy, incorporating features that may increase the likelihood of demonstrating efficacy. Of 28 statements with at least 75% agreement, 22 items are considered in the current trial, including 11 items out of 13 statements for which 100% consensus has been achieved. The most important items included in the design of the current trial are as follows: the use of a slow-release preparation, the use of patient-reported outcomes as a primary outcome (measured by a valid and responsive tool) and patient preference as a secondary outcome, applying a randomized placebo-controlled adequately powered with double-blinded design although not being parallel, inclusion of patients dissatisfied with their LT4 monotherapy with at least 1.2 µg/kg of LT4 daily and studying the effect of deiodinase and thyroid hormone transporter polymorphisms on study outcomes (might not be powered sufficiently for this aim). The combination therapy used in the current study, consisting of 75 µg LT4 plus 5 µg SRT3, was based on the results of our two clinical trials. We found that SRT3 monotherapy in patients with hypothyroidism, administered at an equivalent dose to L-T4, maintained normal serum T3 levels and decreased serum TSH levels. In another clinical trial, combined treatment with a single dose of SR-T3 plus LT4 at a 1:5-7.5 ratio was associated with a more favorable serum T3/T4 ratio and minimal fluctuations in serum T3 concentration over 24 hours. Table 2 presents a detailed comparison of the consistency between the recommended suggestions in the consensus documents and the current trial. Table 2 Important considerations based on the Consensus Document developed by the American Thyroid Association (ATA), British Thyroid Association (BTA), and European Thyroid Association (ETA) for guiding well-designed clinical trials of LT4/SRT3 combination therapy Consensus statement under each topic area Degree of agreement RCT inclusion Topi. Local control of thyroid hormone action, type 2 deiodinase polymorphisms, and the effects of LT4 monotherapy versus combination therapy CS. Future trials of combination therapy in humans should consider including genotyping for the Thr92AlaD2 polymorphism and should be adequately powered to study the effect of this polymorphism on study outcomes. 100 √ Study power? Topic. Non-classical actions of thyroid hormone CS. Consideration should be given to assessing the effects of thyroid hormones that may manifest via non-canonical as well as canonical pathways (e.g., triglyceride levels and cardiac function) in future trials of combination therapy. 83 √ Topic. Thyroid Hormone Transporters and CNS Levels of Thyroid Hormone CS. A consideration for future trials of combination therapy in humans is that they could be adequately powered to study the effect of polymorphisms in thyroid hormone transporters (e.g. MCT8, MCT10, OATP1C1) on study outcomes. 100 √ Study power? Topic. Selection of participants for combination therapy trials CS. Following the exclusion of other causes of these symptoms, patients who do not experience relief of their symptoms with LT4 therapy should be specifically recruited for combination therapy trials. 75 √ in subgroup analysis CS. One or more of several previously validated thyroid-related quality of life questionnaires should be used to assess baseline dissatisfaction, which can be used as an inclusion criterion. 100 √ CS. Patients should be treated with at least 1.2 mcg/kg/day of LT4 to be eligible for treatment. 100 √ Topic. T3/T4 Dose Equivalence – Clinical and Trial Data CS. Future combination therapy trials should incorporate measurement of trough levels of both serum FT4 and total T3 (for example, as a nested pharmacokinetic study in a representative small sub-group). 92 √ CS. Future combination therapy trials should incorporate measurement of peak levels of serum total T3 (approximately 1.8–2.5 hours after LT3 administration) as a nested pharmacokinetic study in a representative small sub-group. 83 √ Topic. Target T3 and TSH levels and Slow Release T3 CS. The goal of future LT4/LT3 combination studies should be to achieve a physiological ratio of FT3 to FT4. 67 √ CS. If non-slow-release LT3 therapy is used, it should be given at least twice daily. 100 NA CS. The use of slow-release T3 preparations is desirable in future trials of combination LT4/ LT3 to achieve physiological levels of thyroid function. However, no approved slow-release T3 therapies are currently available. 100 √ Topic. Psychological and Quality of Life Measures CS. If a PRO is used as a primary outcome in clinical trials, the measure should have well-documented content and validity for thyroid-related QoL as well as responsiveness to change. 100 √ CS. Future studies need to be appropriately powered for PROs as primary outcomes based on the primary endpoint on an effect size of at least 0.5, and preferably 0.3. 100 √ CS.ThyPRO-39 is considered the primary quality of life (QoL) endpoint for the study. 100 √ CS. Patient preference should be included as a secondary outcome in the trial. 100 √ CS. A qualitative study should be considered to explain patient preferences for thyroid hormone formulations. 75 √ Topic. Biological Outcomes, Biomarkers, and Safety Measures CS. Metabolic efficacy outcomes in future trials should include body weight and lipid panel. Resting energy expenditure should be considered for study in a nested subgroup. 92 √ CS. Cardiac efficacy outcomes in future trials should include resting heart rate. 100 √ CS. Cognition efficacy outcomes should include fluid cognition testing. The NIH Toolbox cognitive battery is a viable option. 92 × CS. Musculoskeletal efficacy outcomes in future trials should include a bone biomarker (e.g., C-telopeptide) and consider measuring bone density using a DXA scan if the trial is 12 months or longer in duration. 92 √ CS. Safety monitoring should incorporate measurement of thyrotoxic symptoms, hypothyroid symptoms, and adverse events. 92 √ CS. Safety monitoring should incorporate cardiac monitoring with ECG at baseline and 3-month intervals. Cardiac rhythm monitoring of longer duration could be considered in a nested sub-group. 83 √ Topic. Trial Design Considerations CS. A future combination therapy trial should be randomized, placebo-controlled, and double-blinded. 100 √ CS. A future combination therapy trial should be at least a year in duration, with interim outcome assessments at 3 and 6 months. 80 √ CS. A future combination therapy trial should incorporate a parallel design. 100 × CS. Future trials should be pragmatic and include patients with managed, stable comorbidities to ensure the results are generalizable to the broader hypothyroid patient population. 90 × Topic. Incorporation of patient experiences CS. The level of interaction between patient and physician should be considered as a factor affecting satisfaction with therapy in future trials and should, therefore, be carefully standardized. 92 × CS. Fatigue/tiredness measures can be assessed in future trials using the composite scale of ThyPRO39 or the full Tiredness scale from the 85-item ThyPRO 92 × CS. Neurocognitive testing instruments selected for future trials should be tested to determine if they are responsive to changes in “brain fog.” 92 × CS refers to the consensus statement. Among the remaining statements presented as potential additional considerations with less than 75% agreement, the goal to achieve a physiological FT3/FT4 ratio is considered in the current study. Table .. summarizes the inclusion status of the Consensus Statements with higher than 75% agreement under each topic area. We did not include the following potential additional considerations: 1. assessment for the effects of thyroid hormones that may operate by non-thyroid hormone receptor-mediated pathways (e.g., cancer progression); 2. Including Patients who have low baseline serum total T3 levels while taking LT4 monotherapy; 3. Pilot trials to explore additional outcomes of secondary importance as well as relationships between variables; 4. Incorporating an arm treated with DTE, in addition to the LT4 and LT4/LT3 arms; and 5. Randomizing patients to either LT4 or combination therapy and to either a lifestyle intervention (e.g., education, diet, exercise, or a combination) or no lifestyle intervention for finding the effects of pharmacologic and nonpharmacologic interventions on patient experiences of their therapy. Limitations Formulating a slow-release preparation to maintain serum T3 levels for an extended period can be technically challenging due to the short half-life of T3 (approximately 16 hours). Nevertheless, the new slow-release preparation demonstrated a 24-hour drug release in in-vitro studies. Moreover, we were unable to formulate a single tablet containing SR-T3 and LT4 to improve patient adherence due to the complexity of mixing a delayed-release medication with one that is normally absorbed. Innovation This upcoming trial will be the initial substantial effort in the management of hypothyroidism to evaluate the impact of combining LT4 with SR-T3 versus LT4 monotherapy alone in terms of quality of life, thyroid hormone levels, and metabolic efficacy outcomes to address the limitations of T4 monotherapy. Furthermore, creating new global products has the potential to boost research and innovation while also enhancing employment opportunities in Iran. Discussion Abnormal findings in clinical and biochemical indices of patients on T4 monotherapy and residual symptoms of hypothyroidism in a substantial minority of hypothyroid patients treated with LT4 monotherapy emerged the need for a new approach using levothyroxine plus slow-release liothyronine preparations to mimic the normal physiological serum values of T4, T3, TSH, and T3/T4 ratio. Randomized controlled trials have failed to demonstrate superiority for the new approach, mostly due to the non-physiological T3 doses used in these studies and the existing barriers to co-administration of LT4 plus T3, resulting from their different pharmacokinetics, especially in the slow-release form of T3. Additionally, individual heterogeneity in set points for optimal thyroid homeostasis, residual thyroid function, and deiodinase polymorphisms in tissues that regulate the activation and deactivation of circulating thyroid hormones may lead to varied responses to combination therapy. Future clinical trials using combined preparation of LT4 plus SRT3 with more appropriate doses, which provide a more extended period of relatively stable serum T3 concentrations and support a more individualized approach, are warranted. The results of these studies might help to resolve the shortcomings of levothyroxine monotherapy, especially in patients with persistent symptoms or metabolic abnormalities. Trial status Trial Id: 44220 IRCT Id: IRCT20100922004794N12 Trial registration ID: IRCT20100922004794N12 Registration date: 2020-02-27 First revision : 2023-07-09 Second revision: 2024-07-01 Expected recruitment start date: 2024-10-06 Expected recruitment end date: 2025-10-23 Abbreviations LT4 Levothyroxine LT3 Liothyronine FT3 Free tri-iodothyronine FT4 Free thyroxine TT4 Total thyroxine TT3 Total tri-iodothyronine LT3 + LT4 Levothyroxine plus Liothyronine QOL quality of life ThyPRO-39 Thyroid-specific Patient-Reported Outcome short-form TTS Tehran thyroid study TLGS Tehran lipid and glucose study PTU Polytuiuracil REE Resting Energy Expenditure SHBG sex hormone-binding globulin TC total cholesterol TG triglycerides HDL-C High-density lipoprotein cholesterol LDL-C Low-density lipoprotein cholesterol CK Creatine kinase LDH Lactate dehydrogenase HOMA Homeostasis model assessment ANCOVA Analysis of covariance RR Relative Risk DMC Data Monitoring Committee SAP statistical analysis plan ATA American Thyroid Association BTA British Thyroid Association ETA and European Thyroid Association Declarations Acknowledgments We sincerely acknowledge the participants in the Tehran Thyroid study for their cooperation and commitment. Authors’ contributions FA; principal investigator; Concept and idea generation, AA: Administrative Support; Ensured regulatory compliance and IRB approval; HA; Clinical expertise; MT: Laboratory manager; SM: Data Management and analysis; KhD: Technical support; Mehrabi Y: Biostatistical expertise and sample size calculations; ZA: Genetic consultant; HA: Paraclinical expertise; AAM: Acquisition of Data; LM: Co-principal investigator, supervision, design, protocol writing; All authors contributed to the writing and editing of the proposal, including drafting, revising, and proofreading. Funding This trial is financially supported by the Research Institute for Endocrine Sciences and Dorsa Pharmaceutical Company. Dorsa Pharmaceutical Company played no role in the design, collection, analysis, or interpretation of the study's data, nor in the writing of the manuscript. Availability of data and materials The data supporting the findings of this study are available from the corresponding author upon reasonable request. Ethics approval and consent to participate The study design was registered by the Iranian Registry of Clinical Trials, IRCT20100922004794N12. This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki, and all procedures involving the study participants were approved by the National Research Council of the Islamic Republic of Iran (IR.SBMU.ENDOCRINE.REC.1403.061), the Human Research Review Committee of the Endocrine Research Center, Shahid Beheshti University, Tehran, Iran. Trial participants sign informed consent forms at baseline, and their personal information remains strictly confidential. Consent for publication “Not applicable.” Competing interests \"The authors declare that they have no competing interests.\" References Davies TF. The pathogenesis of Graves’ disease. 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Cross-calibration of eight-polar bioelectrical impedance analysis versus dual-energy X-ray absorptiometry for the assessment of total and appendicular body composition in healthy subjects aged 21-82 years. Annals of human biology. 2003;30(4):380-91. Supplementary Files SPIRITchecklist.docx Cite Share Download PDF Status: Published Journal Publication published 01 Jul, 2025 Read the published version in Trials → Version 1 posted Editorial decision: Minor revision 05 May, 2025 Reviewers agreed at journal 28 Apr, 2025 Reviewers invited by journal 28 Apr, 2025 Editor invited by journal 28 Apr, 2025 Editor assigned by journal 06 Apr, 2025 First submitted to journal 05 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Mehran\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5ElEQVRIiWNgGAWjYBACPgYGNhAtB8QGQCwBFTfArYUNqsWYdC2JDXiVoWgRO3zscUXNnfR+6eaND37uscjjZ2B++IGh4B5uLdJp6YZnjj3LnTnnWLFhzzOJYskGNmMJBoNiPFpyzICKDuduuJFjJs1wQCJxwwEGM6AjE/Boyf8m2fDvcLo9TMv+A+zfCGjJYZNsbDucYCABs4WBh5AtaWaSjX2HDWfcSAP6BahlxmGeYokEPFr4pZOfSTZ8OyzPPyN544MfB+oS+9vbN3748Ae3FiyAGYhJ0jAKRsEoGAWjAAMAAEzAS+4w3WIEAAAAAElFTkSuQmCC\",\"orcid\":\"https://orcid.org/0000-0001-8568-7419\",\"institution\":\"Shahid Beheshti University of Medical Sciences Research Institute for Endocrine Sciences\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Ladan\",\"middleName\":\"\",\"lastName\":\"Mehran\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2024-08-03 05:49:37\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-4851538/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-4851538/v1\",\"draftVersion\":[],\"editorialEvents\":[{\"content\":\"https://doi.org/10.1186/s13063-025-08940-5\",\"type\":\"published\",\"date\":\"2025-07-01T15:57:47+00:00\"}],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":86179759,\"identity\":\"f3170ec5-342c-4fa6-9d6d-43b4f86fa36d\",\"added_by\":\"auto\",\"created_at\":\"2025-07-07 16:19:24\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":2395433,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4851538/v1/fe83dffc-bc1f-4549-acac-d3078f45ba06.pdf\"},{\"id\":81678474,\"identity\":\"7502428c-07ca-49ce-b161-ce3765591768\",\"added_by\":\"auto\",\"created_at\":\"2025-04-30 08:20:40\",\"extension\":\"docx\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":34138,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"SPIRITchecklist.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4851538/v1/c43916775f123b38fc37bcad.docx\"}],\"financialInterests\":\"\",\"formattedTitle\":\"Treatment of hypothyroidism with levothyroxine plus slow-release liothyronine; A Study Protocol for a Randomized Controlled Double-Blinded Clinical Trial\",\"fulltext\":[{\"header\":\"Background and rationale\",\"content\":\"\\u003cp\\u003eHypothyroidism is a common endocrine disorder that significantly impacts human health (\\u003cspan additionalcitationids=\\\"CR3\\\" citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e). The most common cause of primary hypothyroidism is iodine deficiency, followed by an autoimmune condition known as Hashimoto's thyroiditis (\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e). Overt hypothyroidism affects 0.2\\u0026ndash;5.3% of people in Europe(\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e) and 0.3\\u0026ndash;3.7% of people in the United States (\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e) in the general population. In Iran, the prevalence of overt hypothyroidism is 2%, resulting in a total of 1,600,000 individuals in the general population (\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e). In normal subjects, 80% of T3 is generated from the conversion of T4 in kidney and liver cells, while the thyroid gland secretes the remaining 20%. This process is lacking in those who suffer from thyroid failure and undergo LT4 monotherapy (\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e). Many animal and human studies suggest that LT4 monotherapy may not be sufficient to restore euthyroidism in all tissues, as evidenced by a decreased T3 to T4 ratio, lower quality of life, and reduced resting energy expenditure (\\u003cspan additionalcitationids=\\\"CR10 CR11\\\" citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e). About 10\\u0026ndash;20% of treated patients do not achieve well-being and complain of unresolved signs and symptoms of thyroid hypo-function despite achieving normal thyroid hormone concentration(\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e), which accounts for 320,000 in Iran and 29,200,000 globally.\\u003c/p\\u003e \\u003cp\\u003eIn the periphery, T4 is converted to T3 by deiodinases (\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e). Deiodinase genes have been shown to include numerous single-nucleotide polymorphisms. Two polymorphisms in the deiodinase type 2 (D2) gene, D2-Thr92Ala (\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e) and D2-ORFa-Gly3Asp (\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e), have been linked to thyroid hormone levels. Theoretically, polymorphisms could result in lower enzyme activity and, therefore, less conversion of T4 to T3 in the periphery, with even small changes in hormone levels having significant long-term consequences(\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e). Individuals with such polymorphisms potentially would require LT3 replacement to attain euthyroidism. Therefore, dysfunctional deiodinase in a subset of hypothyroid patients could be an important rationale for including active FT3 to improve symptoms in those patients. A subset of patients with hypothyroidism who continue to be symptomatic on LT4 therapy with normal TSH and FT4 or with normal or subnormal FT3 might benefit from the addition of FT3 therapy.\\u003c/p\\u003e \\u003cp\\u003eMany patients do not feel well on standard LT4 (\\u003cspan additionalcitationids=\\\"CR18 CR19\\\" citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e) and may benefit from experimental treatment with combined LT3\\u0026thinsp;+\\u0026thinsp;LT4 preparations (\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e); however, combination therapy with LT4/LT3 did not show any significant improvement in related parameters compared to LT4 monotherapy (\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e). An analysis of five cross-over studies (\\u003cspan additionalcitationids=\\\"CR22 CR23 CR24 CR25\\\" citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e) by Wiersinga et al. (\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e) revealed that 48% of all hypothyroid patients chose LT3\\u0026thinsp;+\\u0026thinsp;LT4 combination therapy, 27% preferred LT4 monotherapy, and 25% had no preference. No study has ever explained why so many patients prefer LT3. In the Grozinsky-Glasberg et al. meta-analysis (\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e), no difference was observed in symptom scores or serum lipid profiles in those treated with combination therapy versus those treated with LT4 alone. In a systematic review of nine controlled trials (N\\u0026thinsp;=\\u0026thinsp;1056), no benefit in mood, quality of life (QOL), or psychometric performance was found with LT4/LT3 combination therapy compared with LT4 monotherapy (\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e). A meta-analysis of 11 randomized trials (N\\u0026thinsp;=\\u0026thinsp;1216) found no differences in pain, depression, anxiety, fatigue, cognitive function, or QOL outcomes in patients treated with LT4/LT3 combination therapy versus LT4 monotherapy (\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eThese reviews conclude that no reproducible clinical evidence supports the efficacy of LT4/LT3 over LT4 alone (\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e). Lack of success was due to: 1. Using higher amounts of T3; 2. High variations in T3 serum concentration due to low half-life and rapid absorption of T3, and 3. Lack of attention to T3 surge after TSH surge during midnight (\\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e). The only human study using a combination of LT4 and slow-release LT3 reported an increased T3/T4 ratio; however, this ratio did not return to normal values. The study period was short, and it did not assess other outcomes or the effects of applying different combinations (\\u003cspan citationid=\\\"CR30\\\" class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eIn 2019, the consortium of the American Thyroid Association (ATA), British Thyroid Association (BTA), and European Thyroid Association (ETA), headed by J. Jonklaas, released a Consensus Statement to guide the development of future clinical trials of LT4/LT3 combination therapy (\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e). There were 13 statements with 100% agreement among the 28 consensus statements with at least 75% agreement. Those with 100% agreement included studies powered to investigate the effect of genetic polymorphisms on study outcomes, the inclusion of patients dissatisfied with their current therapy and requiring at least 1.2 \\u0026micro;g/kg of LT4 daily, the use of twice daily LT3 or, if available, a slow-release preparation, the use of patient-reported outcomes as a primary outcome (measured by a valid and reliable tool). The reforms proposed to the previous studies' designs may be a significant step toward adequately evaluating the potential benefits of \\\"physiological thyroid hormone replacement\\\" using combination LT4\\u0026thinsp;+\\u0026thinsp;LT3 therapy.\\u003c/p\\u003e \\u003cp\\u003eBased on the consensus mentioned above, we developed a slow-release preparation to maintain serum T3 concentration and the T3/T4 ratio within normal ranges for 12\\u0026ndash;24 hours. We designed a parallel randomized clinical trial to characterize the PK and PD of the three combined preparations of LT4\\u0026thinsp;+\\u0026thinsp;SR-T3 in hypothyroid patients. We found that combined treatment with a single dose of SR-T3 plus LT4 is associated with an increased serum T3/T4 ratio and minimal fluctuations in serum T3 concentration over 24 hours (\\u003cspan citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e). We suggested that the best formulation for combination therapy should incorporate a higher ratio of SR-T3 to LT4 than that of the previously recommended by international organizations. In this study, We aim to conduct a parallel randomized clinical trial, based on the suggestion proposed in the consortium, to compare the efficacy and safety of the new combination of SRT3 plus LT4 with LT4 monotherapy.\\u003c/p\\u003e\\n\\u003ch3\\u003eObjectives\\u003c/h3\\u003e\\n\\u003cp\\u003eTo compare treatment efficacy and safety with LT4\\u0026thinsp;+\\u0026thinsp;SR-T3 with LT4 monotherapy\\u003c/p\\u003e \\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eTrial design\\u003c/h2\\u003e \\u003cp\\u003eDouble-blind, randomized control clinical trial\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Methods: Participants, interventions, and outcomes\",\"content\":\"\\u003cdiv id=\\\"Sec5\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStudy setting\\u003c/h2\\u003e \\u003cp\\u003eThe Tehran Thyroid Study (TTS), a prospective population-based cohort study, is being conducted within the framework of the Tehran Lipid and Glucose Study (TLGS). Of the 15,005 TLGS participants aged 20 years or older, 5,786 were randomly selected between March 1997 and December 1999 and followed at three-year intervals for ten years to investigate the epidemiology of thyroid diseases and their long-term consequences in the iodine-sufficient population of Tehran (\\u003cspan citationid=\\\"CR33\\\" class=\\\"CitationRef\\\"\\u003e33\\u003c/span\\u003e).\\u003c/p\\u003e \\u003c/div\\u003e\\n\\u003ch3\\u003eEligibility criteria\\u003c/h3\\u003e\\n\\n\\u003ch3\\u003eWho will take informed consent?\\u003c/h3\\u003e\\n\\u003cp\\u003eThe responsible person will recall these patients to the TTS research unit and explain the project's aim and details. If a patient is willing to participate, the informed written consent will be completed by the patient. Five participants are evaluated each day.\\u003c/p\\u003e \\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eAdditional consent provisions for the collection and use of participant data and biological specimens\\u003c/h2\\u003e \\u003cp\\u003eNot Applicable\\u003c/p\\u003e \\u003c/div\\u003e\\n\\u003ch3\\u003eInterventions\\u003c/h3\\u003e\\n\\u003cdiv id=\\\"Sec10\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eThe explanation for the choice of comparators\\u003c/h2\\u003e \\u003cp\\u003eOne hundred patients will be selected from the group of hypothyroid patients who participated in the TTS. Patients will be randomly assigned to one of the following groups using simple randomization with stratification by age.\\u003c/p\\u003e \\u003cp\\u003e \\u003col\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003eThe group with a daily intake of 75 \\u0026micro;g LT4\\u0026thinsp;+\\u0026thinsp;15 \\u0026micro;g SR-T3\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003eThe group with LT4 monotherapy\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003c/ol\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec11\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eIntervention description\\u003c/h2\\u003e \\u003cdiv id=\\\"Sec12\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003eDrug Formulation and Dosing\\u003c/h2\\u003e \\u003cp\\u003eThe formulation of liothyronine sodium sustained-release tablets was developed by Dorsa Pharmaceutical Company and Noor Research \\u0026amp; Educational Institute (TAVAN). Using Avicel PH-102 and HPMC in the formulation of tablets sustained the drug release of T3 for 24 hours. The in vitro dissolution study was conducted in 500 mL of pH 6.8 phosphate buffer using a United States Pharmacopeia Apparatus I, employing the basket method, at a speed of 100 rpm and a temperature of 37\\u0026deg;C.\\u003c/p\\u003e \\u003cp\\u003eThe combination of 75 \\u0026micro;g LT4 and 15 \\u0026micro;g SR-t3 is considered a preferred combination based on the results of our two previous studies. The drug dosage will be administered on the last dosage, levothyroxine, which was at a weight-based dose of ~\\u0026thinsp;1.6 mcg/kg to retain euthyroidism in both intervention groups.\\u003c/p\\u003e \\u003cp\\u003eAfter six weeks, serum TSH will be measured to adjust drug dosage, and the measurements will be repeated until euthyroidism is achieved. After achieving the ideal dosage, the drug will be continued for 12 months. Participants take their medicine at least 30 minutes before breakfast. Adherence to therapy and adverse effects will be monitored at three follow-up visits and monthly via telephone calls.\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec13\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eCriteria for discontinuing or modifying allocated interventions\\u003c/h2\\u003e \\u003cp\\u003eDuring each visit, signs and symptoms of hypo and hyperthyroidism will be evaluated using standard anamnesis, related questionnaires, and physical examination. Any new clinical signs, symptoms, or illnesses will be recorded and managed.\\u003c/p\\u003e \\u003cp\\u003eIf any critical symptoms become apparent during the treatment, it is permissible to either change the dosage or discontinue the new combination therapy. Individuals who adjust their medication dosage within the initial eight weeks of the study will be considered adherent to the protocol and, therefore, will not be included in the intention-to-treat analysis. The participants who discontinue the trial will be excluded.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec14\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStrategies to improve adherence to interventions\\u003c/h2\\u003e \\u003cp\\u003eThe date and quantity of medicine distribution and return will be recorded. Participants must return the finished medicine package and any unused medicine at all scheduled visits (at 12, 24, and 48 weeks). Furthermore, free healthcare education consultations at baseline followed by monthly telephone monitoring calls will improve intervention adherence. Additionally, failure to comply with the study's requirements, as evidenced by abnormal TSH levels during scheduled visits, is grounds for exclusion. We will closely monitor the study population to minimize follow-up loss and maintain the statistical power and validity of our findings.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec15\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eRelevant concomitant care permitted or prohibited during the trial\\u003c/h2\\u003e \\u003cp\\u003eOther thyroid or anti-thyroid medications, as well as estrogen-containing products, are not allowed for patients. Any increase or decrease in medication dosage administered is also prohibited. Patients are recommended to inform any new disease, drug intake, or medical event to the principal investigator (PI) during the trial.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec16\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eProvisions for post-trial care\\u003c/h2\\u003e \\u003cp\\u003eIn the event of adverse events or reactions, the PI will determine whether they are related to the intervention and follow the participants until the symptoms have ceased or become stable. If the insurance does not cover the participants, the RIES will cover the cost corresponding economic compensation for any damage related to the trial. If a subject is excluded at any time after entering the study, the investigator will ensure this does not affect the patient\\u0026rsquo;s standard of care. The reasons for withdrawal will be recorded on the case report form (CRF) and included in the final report. After the end of the trial, all patients will be back to standard care with LT4 monotherapy and followed until euthyroidism is achieved. All remaining biological samples (blood) will be destroyed at the patient's request.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec17\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eOutcomes\\u003c/h2\\u003e \\u003cdiv id=\\\"Sec18\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003ePrimary outcome\\u003c/h2\\u003e \\u003cp\\u003e \\u003cul\\u003e \\u003cli\\u003e \\u003cp\\u003e \\u003cb\\u003eQuality of life via Thyroid-specific Patient-Reported Outcome short-form (ThyPRO-39) modeled for hypothyroid subjects to quantify dissatisfaction and SF-12\\u003c/b\\u003e \\u003c/p\\u003e \\u003c/li\\u003e \\u003c/ul\\u003e \\u003c/p\\u003e \\u003cp\\u003eThe change in the QOL score from baseline to the end of the 48-week treatment will be evaluated. The recent Consensus Statements to guide the development of future clinical trials of LT4/LT3 combination therapy suggest using patient-reported outcomes as the primary outcome in the redesigned trials, primarily the thyroid-specific quality of life, measured by a valid and reliable tool. The newly-translated thyroid-specific Patient-Reported Outcome short-form (ThyPRO-39) instrument was designed for ethnic-Iranian patients suffering from benign thyroid diseases. Although the ThyPRO has been recommended for use in patients with thyroid dysfunction and its cross-cultural validity has been confirmed, evaluating the applicability of the psychometric properties of the ThyPRO and its short form in Iranian patients with thyroid dysfunction is necessary. Therefore, the translation, cultural adaptation, validity, and reliability of the ThyPRO-39 instrument have been previously assessed in Iranian patients with benign thyroid disease.\\u003c/p\\u003e \\u003cp\\u003eThe between-group change at baseline compared to 24 and 48 weeks of treatment will be assessed for the primary outcome.\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec19\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eSecondary outcomes\\u003c/h2\\u003e \\u003cp\\u003eFor the following secondary outcomes, the between-group change at baseline compared to 12, 24, and 48 weeks of treatment will be assessed:\\u003c/p\\u003e \\u003cp\\u003e \\u003col\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003eSerum TSH, FT4, FT3, and TT3 values were used to determine whether combination therapy improved the T3/T4 ratio to levels near normal values and statistically different from those on LT4 monotherapy. Normal ranges of TSH, TT4, TT3, and TT4/TT3 ratio are as follows: TSH (0.3\\u0026ndash;5.1 mU/L), TT4 (4.5\\u0026ndash;11.5 \\u0026micro;g/dl), TT3 (70\\u0026ndash;220 ng/dl), Free T3 (230\\u0026ndash;420 pg /dl), FT4 (0/8\\u0026ndash;1/5 ng/dl).\\u003c/p\\u003e \\u003cp\\u003eAchieving physiological values of TSH and the T3/T4 ratio is one of the primary goals in managing hypothyroidism; serum thyroid hormone levels serve as a surrogate marker and may not accurately reflect cellular activities.\\u003c/p\\u003e \\u003cli\\u003e \\u003cp\\u003ePatient Preference\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003c/ol\\u003e \\u003c/p\\u003e \\u003cp\\u003ePatient preference will be assessed at multiple time points during the study, including 12 and 24 weeks of therapy, as well as at study completion (48 weeks), to evaluate both early and sustained responses. Additionally, patients will be asked whether they believe they are receiving combination therapy or standard levothyroxine (LT4) therapy. They will also be asked to document the reason for their preference. Qualitative interviews might be considered in a subset of patients to gain further insight into individual patient preferences.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec20\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eTertiary outcome\\u003c/h2\\u003e \\u003cp\\u003ePhysiologically measurable parameters provide the most accurate reflection of thyroid hormone activity in cells, enabling a more precise assessment of euthyroid status. Therefore, tertiary efficacy outcomes in the following domains are considered for inclusion in the trials: metabolic, cardiovascular, and musculoskeletal. Tertiary outcomes include metabolic efficacy outcomes, musculoskeletal efficacy outcomes, cardiac efficacy outcomes, ferritin, and metabolomics. The changes in these outcomes from baseline to the end of the study, at 48 weeks of treatment, will be evaluated.\\u003c/p\\u003e \\u003cp\\u003eMetabolic efficacy outcomes include body weight, waist circumference, and Resting Energy Expenditure) REE(Body composition, lipid profile, FBS, insulin sensitivity (HbA1C, HOMA-IR), and sex hormone-binding globulin (SHBG). Musculoskeletal efficacy outcomes include muscular biomarkers (E.g., Enolase, LDH, and CK) and bone biomarkers (e.g., C-telopeptide or N-telopeptide). Cardiac efficacy outcomes include resting heart rate and BP. Genetic polymorphisms (rs225014, rs225015, rs12885300, rs17606253) are also assessed and compared between the responders and non-responders.\\u003c/p\\u003e \\u003cp\\u003e \\u003cul\\u003e \\u003cli\\u003e \\u003cp\\u003e \\u003cb\\u003eMetabolic efficacy outcomes\\u003c/b\\u003e \\u003c/p\\u003e \\u003c/li\\u003e \\u003c/ul\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003col\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003eLipid profiles (total cholesterol, LDL, HDL, triglyceride)\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003eFBS, Insulin sensitivity (HbA1C, HOMA-IR)\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003ePeripheral thyroid status (Sex hormone binding globulin: SHBG)\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003eResting Energy Expenditure (REE) and body composition\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003c/ol\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cul\\u003e \\u003cli\\u003e \\u003cp\\u003e \\u003cb\\u003eMusculoskeletal efficacy outcomes\\u003c/b\\u003e \\u003c/p\\u003e \\u003c/li\\u003e \\u003c/ul\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003col\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003emuscular biomarkers (Enolase, lactate dehydrogenase: LDH, and creatine kinase: CK)\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003ebone biomarkers (C-telopeptide or N-telopeptide)\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003c/ol\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cul\\u003e \\u003cli\\u003e \\u003cp\\u003e \\u003cb\\u003eCardiac efficacy outcomes\\u003c/b\\u003e \\u003c/p\\u003e \\u003c/li\\u003e \\u003c/ul\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003col\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003eResting heart rate\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e\\u003cp\\u003eBP\\u003c/p\\u003e\\u003c/li\\u003e \\u003c/ol\\u003e \\u003c/p\\u003e \\u003cdiv id=\\\"Sec22\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003e\\u0026bull; Ferritin\\u003c/h2\\u003e \\u003cdiv id=\\\"Sec23\\\" class=\\\"Section4\\\"\\u003e \\u003ch2\\u003e\\u0026bull; Metabolomics\\u003c/h2\\u003e \\u003cp\\u003e \\u003cul\\u003e \\u003cli\\u003e \\u003cp\\u003e \\u003cb\\u003eGenetic polymorphisms\\u003c/b\\u003e \\u003c/p\\u003e \\u003c/li\\u003e \\u003c/ul\\u003e \\u003c/p\\u003e \\u003cp\\u003eThr92Ala polymorphism of the type 2 deiodinase gene (DIO2) (Thr92Ala-DIO2) and polymorphisms in thyroid hormone transporters (e.g. MCT8, MCT10, OATP1C1)\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec24\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003eSafety monitoring\\u003c/h2\\u003e \\u003cp\\u003eSafety monitoring involves assessing thyrotoxic symptoms, hypothyroid symptoms, and any other adverse events. These signs and symptoms include dyspnea on exertion, palpitations, tiredness, preference for heat, preference for cold, excessive sweating, diminished sweating, dry skin, cold intolerance, nervousness, increased appetite, decreased appetite, decreased weight, increased weight, headache, diarrhea, constipation, hoarseness, and deafness. Signs: periorbital puffiness, palpable thyroid, bruit over the thyroid, exophthalmos, lid retraction, lid lag, hyperkinesia, hands hot and moist, pulse rate\\u0026thinsp;\\u0026gt;\\u0026thinsp;90/min, atrial fibrillation, delayed ankle reflex, coarse and cold skin. Biochemical measurements of thyroid hormones are also considered for safety monitoring. Cardiac monitoring, including ECG and blood pressure (BP) measurement, at baseline and after 12, 24, and 48 weeks, is also considered a safety monitoring tool.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec25\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003eParticipant timeline\\u003c/h2\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eSchedule of enrolment, interventions, and assessments\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"5\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eSTUDY PERIOD\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eRandomization\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eFollow-up\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eFollow-up\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003elast Follow-up\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eVISIT NUMBER\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eVisit 1\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eVisits 2\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eVisits 3\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eVisits 4\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eMonth\\u003c/b\\u003e\\u003csup\\u003e\\u003cb\\u003e#\\u003c/b\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003e0\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e6\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e12\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eInformed consent\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eConfirm eligibility\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eRandomization\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eDemographic Information\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eMedical History\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eHeight measurement\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eWeight measurement\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003ePhysical Examination\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eVital Sign Measurements\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eECG\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eREE \\u0026amp; Body Composition\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eBlood Collection\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eCBC, and serum levels of 25(OH) Vit D, Vit B12 and TPOAb\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eMetabolic measurements\\u003c/em\\u003e\\u003c/p\\u003e \\u003cp\\u003e\\u003cem\\u003etotal cholesterol, LDL, HDL, triglycerides, FBS, insulin, HbA1C, SHBG, Enolase, LDH and CK, Ferritin, and metabolomics\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eSerum TSH, total T3, total T4, free T4 and free T3\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003ePolymorphism\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eMetabolomics\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eDemographic and Past Medical History Questionnaire\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eQOL questionnaire SF-12\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eQOL questionnaire Thypro-39\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eStudy drug dispensing\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eCompliance check\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eAdverse Event Check\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eConcomitant medication Check\\u003c/em\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eX\\u003c/b\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec26\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003eSample size\\u003c/h2\\u003e \\u003cp\\u003eThe sample size was calculated based on the primary outcome of quality of life (THYPRO-39, SF-12) improvement over 48 weeks in the daily intake of the LT4\\u0026thinsp;+\\u0026thinsp;SR-T3 group versus the LT4 monotherapy group. We assumed an anticipated effect size of 0.50, a type I error of 0.05, a test power of 90%, and a correlation coefficient of 0.5 for repeated measurements. A total sample size of n\\u0026thinsp;=\\u0026thinsp;32 was calculated using G*Power 3.1 (University of Kiel, Germany) for repeated measures analysis of variance (ANOVA), considering a 20% loss to follow-up in each group. A total of 2*20\\u0026thinsp;=\\u0026thinsp;40 individuals will be sufficient. The effect size in this formula was derived from the consensus document on the evidence-based Use of levothyroxine/ liothyronine combinations in treating hypothyroidism (\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e):\\u003c/p\\u003e \\u003cp\\u003eOutput G*Power 3.1:\\u003c/p\\u003e \\u003cp\\u003eF tests - ANOVA: Repeated measures between factors\\u003c/p\\u003e \\u003cp\\u003eAnalysis: A priori: Compute required sample size\\u003c/p\\u003e \\u003cp\\u003eInput: Effect size f\\u0026thinsp;=\\u0026thinsp;0.50\\u003c/p\\u003e \\u003cp\\u003eα err prob\\u0026thinsp;=\\u0026thinsp;0.05\\u003c/p\\u003e \\u003cp\\u003ePower (1-β err prob)\\u0026thinsp;=\\u0026thinsp;0.90\\u003c/p\\u003e \\u003cp\\u003eNumber of groups\\u0026thinsp;=\\u0026thinsp;2\\u003c/p\\u003e \\u003cp\\u003eNumber of measurements\\u0026thinsp;=\\u0026thinsp;3\\u003c/p\\u003e \\u003cp\\u003eCorr among rep measures\\u0026thinsp;=\\u0026thinsp;0.5\\u003c/p\\u003e \\u003cp\\u003eOutput: Noncentrality parameter λ\\u0026thinsp;=\\u0026thinsp;12.0000000\\u003c/p\\u003e \\u003cp\\u003eCritical F\\u0026thinsp;=\\u0026thinsp;4.1708768\\u003c/p\\u003e \\u003cp\\u003eNumerator df\\u0026thinsp;=\\u0026thinsp;1.0000000\\u003c/p\\u003e \\u003cp\\u003eDenominator df\\u0026thinsp;=\\u0026thinsp;30.0000000\\u003c/p\\u003e \\u003cp\\u003eTotal sample size\\u0026thinsp;=\\u0026thinsp;32\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec27\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eRecruitment\\u003c/h2\\u003e \\u003cp\\u003eSince hypothyroid patients with 18 years of follow-up in TTS will be recruited by trained social workers in the TTS Unit, enrollment and obtaining written consent will be easily facilitated.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec28\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eAssignment of interventions: allocation\\u003c/h2\\u003e \\u003cdiv id=\\\"Sec29\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003eSequence generation\\u003c/h2\\u003e \\u003cp\\u003eSubject inclusion/exclusion criteria will be determined at the baseline visit, and subjects who do not meet all the requirements will be excluded from the study. Using simple stratified randomization, two hundred patients will be randomly allocated to two treatment groups.\\u003c/p\\u003e \\u003cp\\u003e \\u003col\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003eThe groups with a daily intake of LT4\\u0026thinsp;+\\u0026thinsp;SR-T3 (Group A)\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003cspan\\u003e \\u003cli\\u003e \\u003cp\\u003eThe groups with LT4 monotherapy (Group B)\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/span\\u003e \\u003c/ol\\u003e \\u003c/p\\u003e \\u003cp\\u003eParticipants will be randomized with equal probability (1:1) to receive one of the two treatments. As the size of each group is predicted to be 50, the allocation sequence is generated with sample randomization and stratification by gender. The allocation sequences will be generated by the software and in Excel format. The patients were sequentially enrolled in the study according to this random sequence.\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec30\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eConcealment mechanism\\u003c/h2\\u003e \\u003cp\\u003eBefore the study begins, the computer will generate a series of random numbers. The allocation sequence will be generated by a statistician who will not be involved in participant enrollment. The allocation is concealed in a password-protected computer file, accessible only to the data manager. The randomization list is sent to the trained social worker in the TTS unit, who is not directly involved in the trial, and the medicine is labeled with blinding codes according to this list. The trained social worker keeps the random numbers in plain, closed envelopes marked with patient numbers. This staff will be instructed to keep the list private and to only reveal a treatment allocation after receiving information demonstrating that the patient is eligible and has provided consent for the trial. The envelopes will not be accessible to individuals directly involved in the study. After proper randomization implementation, the subjects will be assigned to the groups using allocation concealment, which helps to keep clinicians, participants, and investigators unaware of upcoming assignments. The trial participants and the investigators are kept from knowing who is assigned to which treatment (double-blind). To fulfill this, both groups will receive identical tablets in terms of physical appearance, taste, and smell. To ensure a double-blind design, all tablets will be distributed in identical packages of the same size and color, keeping patients and physicians blinded to the treatment allocation.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec31\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eImplementation\\u003c/h2\\u003e \\u003cp\\u003eA physician and a trained social worker are involved in enrolling participants under the supervision of the principal investigators. After signing the informed consent form, each participant is allocated a sequential number that randomizes them to one of the two groups. Participants will be randomly assigned and allocated a unique number.\\u003c/p\\u003e \\u003cdiv id=\\\"Sec32\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003eAssignment of interventions: Blinding\\u003c/h2\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec33\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003eWho will be blinded\\u003c/h2\\u003e \\u003cp\\u003eThe trial participants, investigators, outcome assessors, and data analysts will be blinded to the group assignment until the trial is completed.\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e\\n\\u003ch3\\u003eProcedure for unblinding if needed\\u003c/h3\\u003e\\n\\u003cp\\u003eThe blinding code will not be broken during the trial period except in the case of a severe adverse event that requires an urgent breaking of the blinding code, e.g., any new cardiovascular or cerebral events, atrial fibrillation, myxedema coma, or severe psychiatric disorders. Finally, the trial steering committee will take a terminal decision.\\u003c/p\\u003e\\n\\u003ch3\\u003eData collection and management\\u003c/h3\\u003e\\n\\u003cdiv id=\\\"Sec36\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003ePlans for assessment and collection of outcomes\\u003c/h2\\u003e \\u003cdiv id=\\\"Sec37\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003eMedical History and Clinical Examination\\u003c/h2\\u003e \\u003c/div\\u003e \\u003c/div\\u003e\\n\\u003ch3\\u003eConfidentiality\\u003c/h3\\u003e\\n\\u003cp\\u003eTo protect participants' privacy, all participant's data will be collected in a specific reception room rather than in public areas. Every participant's information throughout the trial is recorded in the Case report form (CRF). On the CRF, the initials of patient names will be used, and all documents will be stored confidentially in a secure location. All data collected from enrolled participants will be stored in a secure database, and only anonymized data will be shared. Subjects have their own independent codes for uploading test results. A third party will manage the final statistical process.\\u003c/p\\u003e \\u003cp\\u003e \\u003cb\\u003ePlans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use\\u003c/b\\u003e \\u003c/p\\u003e \\u003cp\\u003eBlood for a research biobank will be collected at baseline and after 12,24 and 48 weeks of treatment. The biobank aims to measure and compare potential changes in biomarkers related to metabolic efficacy, musculoskeletal efficacy, ferritin, and metabolomics from baseline to the end of the study, at 48 weeks, in two trial groups and the control group. Any excess blood will be stored for a period of ten years. Informed consent is obtained from all participants to enable the analysis for other research purposes. Genetic polymorphisms (rs225014, rs225015, rs12885300, rs17606253) are also assessed and compared between the responders and non-responders.\\u003c/p\\u003e\\n\\u003ch3\\u003eLaboratory measurements\\u003c/h3\\u003e\\n\\u003cp\\u003eAt baseline blood sampling, a complete blood count (CBC) will be performed using a KX-21 hematology analyzer (Sysmex, Japan). At the follow-up visits, 20 cc fasting blood samples will be collected from all participants between 7:00 and 9:00 am into vacutainer tubes at each reassessment. After standard centrifugation, serum samples will be stored at -70\\u0026deg; C until analysis. Measurements of serum TSH, 25(OH) Vit D, and Vit B12 at baseline sample and serum total tri-iodothyronine(TT3), total thyroxine (TT4), free T4 (FT4), TSH, ferritin, SHBG, and insulin at baseline and follow-ups will be performed by electrochemiluminescence immunoassay (ECLIA) method, using Roche Diagnostics kits and the Roche/Hitachi Cobas e-411 analyzer (GmbH, Mannheim, Germany). Thyroid peroxidase antibody (TPO Ab) will be assayed by immunoenzymometric assay (IEMA) using a commercial kit (Monobind, USA) and the Sunrise ELISA reader (Tecan Co., Austria).\\u003c/p\\u003e \\u003cp\\u003eTo monitor the accuracy of immunoassays, lyophilized quality control materials Lyphochek Immunoassay plus Control (Bio-Rad Laboratories, USA) and PreciControl (Roche, GmbH, Germany) will be used. In our institute's endocrine laboratory, the intra- and inter-assay coefficients of variation (CVs) for all tests performed by the ECLIA and IEMA methods have been less than 4.7% and 5.7%, respectively.\\u003c/p\\u003e \\u003cp\\u003eSerum total cholesterol (TC) and triglycerides (TG) will be measured using enzymatic calorimetric methods. High-density lipoprotein cholesterol (HDL-C) will be measured after precipitation of apolipoprotein B-containing lipoproteins with phosphotungstic acid. Low-density lipoprotein cholesterol (LDL-C) will be calculated using the modified Friedwald formula (\\u003cspan citationid=\\\"CR34\\\" class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e). CK and LDH will be measured using the NAC kinetic UV test and the DGKC photometric method, respectively.\\u003c/p\\u003e \\u003cp\\u003eAll these simple biochemical tests will be performed using commercial kits (Pars Azmon Inc., Iran) and the Pictus 700 clinical chemistry analyzer (Diatron MI Plc, Hungary). Assay performance for simple biochemical tests will be monitored using quality control materials in two concentrations, TruLab N and TruLab P (Pars Azmon Inc., Iran). Inter- and intra-assay CVs for all the mentioned biochemical tests, i.e., FBS, lipid profile, and enzymes, have been less than 3.0% in the biochemical laboratory of our institute. HbA1C will be determined by enzymatic method using a commercial kit (Pishtaz Teb, Iran) and Hitachi 911 chemistry analyzer (Roche Diagnostics, GmbH, Germany) with intra- and inter-assay CVs of less than 1.7%. The Homeostatic Model Assessment (HOMA) will be used as a surrogate marker of insulin resistance (IR) and calculated as HOMA-IR\\u0026thinsp;=\\u0026thinsp;fasting insulin (IU/mL) \\u0026times; fasting glucose (mM/L) / 22.5.\\u003c/p\\u003e\\n\\u003ch3\\u003eMeasurement of body composition and resting energy expenditure\\u003c/h3\\u003e\\n\\u003cp\\u003eBody Composition will be assessed using a portable multi-frequency bioimpedance analysis (BIA) device (brand: InBody 570, InBody Co., Ltd.). The InBody 570 is renowned for its reliability and consistency across various groups; however, its precision may be influenced by factors such as hydration, body temperature, and population-specific characteristics. The BIA technique involves utilizing a portable multi-frequency BIA device with an eight-electrode arrangement. Participants must follow specific preparation guidelines, including fasting for 2 hours, abstaining from caffeine for 2 hours, refraining from physical activity for 4\\u0026ndash;6 hours, and dressing in light, comfortable clothing without shoes or socks. The BIA device conducted a safe electrical current through the body at low levels, measuring impedance at various frequencies. It uses predictive formulas to determine different BC parameters. It is essential to note that BIA should not be used in individuals with heart pacemakers, platinum or metal prostheses, or a Holter device implanted in their bodies. Individuals should remove any metal or jewelry before undergoing BIA measurements. This step is taken to minimize the potential interference and improve the reliability of the BIA results. After cleaning the palm and sole with an electrolyte tissue, individuals place their soles on the foot electrodes and hold the hand-held paddle electrodes with their hands. Additional information, such as gender, height, weight, and age, is also documented. FM (fat mass, kg), PBF (percentage of body fat), and FFM (fat-free mass, kg) will be measured. The FMI, FFMI, and SMMI will be calculated by dividing their values by the square of the height, measured in kg/m\\u0026sup2;. The ratio of fat mass to skeletal muscle mass will be determined by dividing the fat mass by the skeletal muscle mass. BMR values will be estimated using the BIA software, which employs prediction equations based on age, weight, height, and sex. These values represent calculated estimates and should not be interpreted as direct measurements of BMR(\\u003cspan citationid=\\\"CR35\\\" class=\\\"CitationRef\\\"\\u003e35\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003ch3\\u003eStatistical methods\\u003c/h3\\u003e\\n\\u003cp\\u003e \\u003cb\\u003eStatistical methods for primary and secondary outcomes\\u003c/b\\u003e \\u003c/p\\u003e \\u003cp\\u003eAll study practices and statistical methods are based on the International Conference on Harmonization (IHC) document \\u0026ldquo;Statistical Principles for Clinical Trials.\\u0026rdquo;\\u003c/p\\u003e \\u003cp\\u003eDescriptive statistics will be computed for each treatment group, with medians and percentiles reported for continuous variables that exhibit skewness. Descriptive statistics and 95% confidence intervals will be used to summarize the differences between groups for both primary and secondary outcomes. The intervention arms will be compared against the control for all preliminary analyses. We will use the chi-squared test for binary outcomes and ANCOVA for continuous outcomes. For subgroup analyses, we will use regression methods. Multivariable analyses will be based on logistic regression for binary outcomes and linear regression for continuous outcomes. For analyzing repeated measurements, repeated measures ANOVA and, if needed, the Generalized Estimation Equation will be used. Relative Risk (RR) with corresponding 95% confidence intervals will be estimated by logistic regression to compare dichotomous variables. SPSS (Chicago, IL) will be used for data analysis. For all tests, we will use two-sided p-values with an alpha level of significance of less than 0.05. For data analysis, the intention-to-treat approach and the superiority hypothesis will be considered.\\u003c/p\\u003e\\n\\u003ch3\\u003eInterim analyses\\u003c/h3\\u003e\\n\\u003cp\\u003eThe Trial Steering Committee comprises five investigators, including the PI, who supervise and monitor the project. The investigators review the data every two months, and in the event of unexpected findings, an interim analysis will be conducted to inform a pertinent decision. The Trial Steering Committee may decide to terminate the project under specific circumstances.\\u003c/p\\u003e\\n\\u003ch3\\u003eMethods for additional analyses (e.g., subgroup analyses)\\u003c/h3\\u003e\\n\\u003cp\\u003eThe subgroup analysis will be performed in different sex groups and respondents and non-respondents groups regarding the quality of life and patient preference,\\u003c/p\\u003e\\n\\u003ch3\\u003eMethods in analysis to handle protocol non-adherence and any statistical methods to handle missing data\\u003c/h3\\u003e\\n\\u003cp\\u003eParticipants with poor adherence or those who are no longer undergoing testing and receiving medication during the study will be included in the intention-to-treat analysis and excluded from the per-protocol analysis. In cases of missing data, single or multiple imputation methods will be employed, depending on the nature and extent of the missing data.\\u003c/p\\u003e\\n\\u003ch3\\u003ePlans to give access to the complete protocol, participant-level data, and statistical code\\u003c/h3\\u003e\\n\\u003cp\\u003eThe protocol and the statistical analysis plan (SAP) will be accessible at \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e\\u003ca href=\\\"http://www.clinicaltrials.gov\\\" target=\\\"_blank\\\"\\u003ewww.clinicaltrials.gov\\u003c/a\\u003e\\u003c/span\\u003e\\u003cspan address=\\\"http://www.clinicaltrials.gov\\\" targettype=\\\"URL\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e, identifier: \\u003cb\\u003eIRCT20100922004794N12\\u003c/b\\u003e. The corresponding author makes the participant-level data and statistical code available upon reasonable request.\\u003c/p\\u003e\\n\\u003ch3\\u003eOversight and monitoring\\u003c/h3\\u003e\\n\\u003cp\\u003e \\u003cb\\u003eComposition of the coordinating Center and trial steering committee\\u003c/b\\u003e \\u003c/p\\u003e \\u003cp\\u003e The coordinating center is the Endocrine Research Center, Research Institute for Endocrine Sciences, at Shahid Beheshti University of Medical Sciences, which will assist in recruiting participants and obtaining their consent. The trial steering committee comprises five investigators who will supervise the trial and review its progress.\\u003c/p\\u003e\\n\\u003ch3\\u003eComposition of the data monitoring committee, its role, and reporting structure\\u003c/h3\\u003e\\n\\u003cp\\u003eThe Data Monitoring Committee (DMC) is an independent group of individuals selected from the Endocrine Research Council who work closely with investigators and sponsors to monitor data collection, trial conduct, patient safety, and efficacy, as well as to ensure the trial's validity and integrity, and to make a benefit-risk assessment. DMC has no relationship with a sponsor organization.\\u003c/p\\u003e\\n\\u003ch3\\u003eAdverse event reporting and harms\\u003c/h3\\u003e\\n\\u003cp\\u003eAny unintended adverse effects, including clinical or biochemical symptoms of hyperthyroidism or hypothyroidism, as measured by thyroid hormones and other unexpected events, will be reported to the steering committee for final decision.\\u003c/p\\u003e \\u003cp\\u003eSymptoms: Dyspnea, palpitations, tiredness, preference for heat, preference for cold, excessive sweating, nervousness, increased appetite, decreased appetite, decreased weight, increased weight, hair loss\\u003c/p\\u003e \\u003cp\\u003eSigns: Palpable thyroid, bruit over the thyroid, exophthalmos, lid retraction, lid lag, hyperkinesia, hands hot, hands moist, casual pulse rate: \\u0026gt;80/min, \\u0026gt;\\u0026thinsp;90/min, atrial fibrillation\\u003c/p\\u003e\\n\\u003ch3\\u003eFrequency and plans for auditing trial conduct\\u003c/h3\\u003e\\n\\u003cp\\u003eThe trial will be supervised by the steering committee and data monitoring committee, which will be independent of the sponsor organization.\\u003c/p\\u003e\\n\\u003ch3\\u003ePlans for communicating necessary protocol amendments to relevant parties (e.g., trial participants, ethical committees)\\u003c/h3\\u003e\\n\\u003cp\\u003eAny changes and modifications made to each part of the protocol, such as updates to eligibility criteria, outcomes, and analyses, will be reported in trial registries as well as to the Ethics Approval Committee of the Research Institute for Endocrine Sciences.\\u003c/p\\u003e\\n\\u003ch3\\u003eDissemination plans\\u003c/h3\\u003e\\n\\u003cp\\u003eBefore enrolling the first patient, information about the trial is published on ClinicalTrials.gov. The protocol and study findings will be published in peer-reviewed international journals. Positive, negative, and inconclusive results will all be made public. Following publication, the trial results will be disseminated to trial participants, healthcare professionals, and other relevant groups via email, scientific webinars, conferences, and other data-sharing arrangements as needed, and to the general public through written and online media.\\u003c/p\\u003e \\u003cp\\u003e \\u003cb\\u003eConsistency of the current trial with the recently published consensus document to guide well-designed trials on lt4/lt3 combination therapy\\u003c/b\\u003e \\u003c/p\\u003e \\u003cp\\u003eATA, BTA, and ETA jointly held a conference to review the new evidence on combination therapy (\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e). Out of 10 area topics identified by the Joint Association, 34 summary Consensus Statements were developed regarding the appropriate design of future clinical trials of combination therapy, incorporating features that may increase the likelihood of demonstrating efficacy. Of 28 statements with at least 75% agreement, 22 items are considered in the current trial, including 11 items out of 13 statements for which 100% consensus has been achieved. The most important items included in the design of the current trial are as follows: the use of a slow-release preparation, the use of patient-reported outcomes as a primary outcome (measured by a valid and responsive tool) and patient preference as a secondary outcome, applying a randomized placebo-controlled adequately powered with double-blinded design although not being parallel, inclusion of patients dissatisfied with their LT4 monotherapy with at least 1.2 \\u0026micro;g/kg of LT4 daily and studying the effect of deiodinase and thyroid hormone transporter polymorphisms on study outcomes (might not be powered sufficiently for this aim). The combination therapy used in the current study, consisting of 75 \\u0026micro;g LT4 plus 5 \\u0026micro;g SRT3, was based on the results of our two clinical trials. We found that SRT3 monotherapy in patients with hypothyroidism, administered at an equivalent dose to L-T4, maintained normal serum T3 levels and decreased serum TSH levels. In another clinical trial, combined treatment with a single dose of SR-T3 plus LT4 at a 1:5-7.5 ratio was associated with a more favorable serum T3/T4 ratio and minimal fluctuations in serum T3 concentration over 24 hours.\\u003c/p\\u003e \\u003cp\\u003eTable\\u0026nbsp;2 presents a detailed comparison of the consistency between the recommended suggestions in the consensus documents and the current trial.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eImportant considerations based on the Consensus Document developed by the American Thyroid Association (ATA), British Thyroid Association (BTA), and European Thyroid Association (ETA) for guiding well-designed clinical trials of LT4/SRT3 combination therapy\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"3\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eConsensus statement under each topic area\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eDegree of agreement\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eRCT inclusion\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eTopi. Local control of thyroid hormone action, type 2 deiodinase polymorphisms, and the effects of LT4 monotherapy versus combination therapy\\u003c/p\\u003e \\u003cp\\u003eCS. Future trials of combination therapy in humans should consider including genotyping for the Thr92AlaD2 polymorphism and should be adequately powered to study the effect of this polymorphism on study outcomes.\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e100\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026radic;\\u003c/p\\u003e \\u003cp\\u003eStudy power?\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eTopic. Non-classical actions of thyroid hormone\\u003c/p\\u003e \\u003cp\\u003eCS. Consideration should be given to assessing the effects of thyroid hormones that may manifest via non-canonical as well as canonical pathways (e.g., triglyceride levels and cardiac function) in future trials of combination therapy.\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e83\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026radic;\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eTopic. Thyroid Hormone Transporters and CNS Levels of Thyroid Hormone\\u003c/b\\u003e\\u003c/p\\u003e \\u003cp\\u003e\\u003cb\\u003eCS.\\u003c/b\\u003e A consideration for future trials of combination therapy in humans is that they could be adequately powered to study the effect of polymorphisms in thyroid hormone transporters (e.g. MCT8, MCT10, OATP1C1) on study outcomes.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e100\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026radic;\\u003c/p\\u003e \\u003cp\\u003eStudy power?\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eTopic. Selection of participants for combination therapy trials\\u003c/b\\u003e\\u003c/p\\u003e \\u003cp\\u003eCS. Following the exclusion of other causes of these symptoms, patients who do not experience relief of their symptoms with LT4 therapy should be specifically recruited for combination therapy trials.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e75\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026radic; in subgroup analysis\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCS. One or more of several previously validated thyroid-related quality of life questionnaires should be used to assess baseline dissatisfaction, which can be used as an inclusion criterion.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e100\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026radic;\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCS. Patients should be treated with at least 1.2 mcg/kg/day of LT4 to be eligible for treatment.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e100\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026radic;\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eTopic. T3/T4 Dose Equivalence\\u003c/b\\u003e \\u003cb\\u003e\\u0026ndash;\\u003c/b\\u003e \\u003cb\\u003eClinical and Trial Data\\u003c/b\\u003e\\u003c/p\\u003e \\u003cp\\u003eCS. Future combination therapy trials should incorporate measurement of trough levels of both serum FT4 and total T3 (for example, as a nested pharmacokinetic study in a representative small sub-group).\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e92\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026radic;\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCS. Future combination therapy trials should incorporate measurement of peak levels of serum total T3 (approximately 1.8\\u0026ndash;2.5 hours after LT3 administration) as a nested pharmacokinetic study in a representative small sub-group.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e83\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026radic;\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eTopic. Target T3 and TSH levels and Slow Release T3\\u003c/b\\u003e\\u003c/p\\u003e \\u003cp\\u003eCS. The goal of future LT4/LT3 combination studies should be to achieve a physiological ratio of FT3 to FT4.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e67\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026radic;\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCS. If non-slow-release LT3 therapy is used, it should be given at least twice daily.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e100\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eNA\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCS. The use of slow-release T3 preparations is desirable in future trials of combination LT4/ LT3 to achieve physiological levels of thyroid function. However, no approved slow-release T3 therapies are currently available.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e100\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026radic;\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eTopic. Psychological and Quality of Life Measures\\u003c/b\\u003e\\u003c/p\\u003e \\u003cp\\u003eCS. If a PRO is used as a primary outcome in clinical trials, the measure should have well-documented content and validity for thyroid-related QoL as well as responsiveness to change.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e100\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026radic;\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCS. Future studies need to be appropriately powered for PROs as primary outcomes based on the primary endpoint on an effect size of at least 0.5, and preferably 0.3.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e100\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026radic;\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCS.ThyPRO-39 is considered the primary quality of life (QoL) endpoint for the study.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e100\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026radic;\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCS. Patient preference should be included as a secondary outcome in the trial.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e100\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026radic;\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCS. A qualitative study should be considered to explain patient preferences for thyroid hormone formulations.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e75\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026radic;\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eTopic. Biological Outcomes, Biomarkers, and Safety Measures\\u003c/b\\u003e\\u003c/p\\u003e \\u003cp\\u003eCS. Metabolic efficacy outcomes in future trials should include body weight and lipid panel. Resting energy expenditure should be considered for study in a nested subgroup.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e92\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026radic;\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCS. Cardiac efficacy outcomes in future trials should include resting heart rate.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e100\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026radic;\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCS. Cognition efficacy outcomes should include fluid cognition testing. The NIH Toolbox cognitive battery is a viable option.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e92\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026times;\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCS. Musculoskeletal efficacy outcomes in future trials should include a bone biomarker (e.g., C-telopeptide) and consider measuring bone density using a DXA scan if the trial is 12 months or longer in duration.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e92\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026radic;\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCS. Safety monitoring should incorporate measurement of thyrotoxic symptoms, hypothyroid symptoms, and adverse events.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e92\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026radic;\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCS. Safety monitoring should incorporate cardiac monitoring with ECG at baseline and 3-month intervals. Cardiac rhythm monitoring of longer duration could be considered in a nested sub-group.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e83\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026radic;\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eTopic. Trial Design Considerations\\u003c/b\\u003e\\u003c/p\\u003e \\u003cp\\u003eCS. A future combination therapy trial should be randomized, placebo-controlled, and double-blinded.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e100\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026radic;\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCS. A future combination therapy trial should be at least a year in duration, with interim outcome assessments at 3 and 6 months.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e80\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026radic;\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCS. A future combination therapy trial should incorporate a parallel design.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e100\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026times;\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCS. Future trials should be pragmatic and include patients with managed, stable comorbidities to ensure the results are generalizable to the broader hypothyroid patient population.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e90\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026times;\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e\\u003cb\\u003eTopic. Incorporation of patient experiences\\u003c/b\\u003e\\u003c/p\\u003e \\u003cp\\u003eCS. The level of interaction between patient and physician should be considered as a factor affecting satisfaction with therapy in future trials and should, therefore, be carefully standardized.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e92\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026times;\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCS. Fatigue/tiredness measures can be assessed in future trials using the composite scale of ThyPRO39 or the full Tiredness scale from the 85-item ThyPRO\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e92\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026times;\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCS. Neurocognitive testing instruments selected for future trials should be tested to determine if they are responsive to changes in \\u0026ldquo;brain fog.\\u0026rdquo;\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e92\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026times;\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCS refers to the consensus statement.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eAmong the remaining statements presented as potential additional considerations with less than 75% agreement, the goal to achieve a physiological FT3/FT4 ratio is considered in the current study. Table .. summarizes the inclusion status of the Consensus Statements with higher than 75% agreement under each topic area. We did not include the following potential additional considerations: 1. assessment for the effects of thyroid hormones that may operate by non-thyroid hormone receptor-mediated pathways (e.g., cancer progression); 2. Including Patients who have low baseline serum total T3 levels while taking LT4 monotherapy; 3. Pilot trials to explore additional outcomes of secondary importance as well as relationships between variables; 4. Incorporating an arm treated with DTE, in addition to the LT4 and LT4/LT3 arms; and 5. Randomizing patients to either LT4 or combination therapy and to either a lifestyle intervention (e.g., education, diet, exercise, or a combination) or no lifestyle intervention for finding the effects of pharmacologic and nonpharmacologic interventions on patient experiences of their therapy.\\u003c/p\\u003e\\n\\u003ch3\\u003eLimitations\\u003c/h3\\u003e\\n\\u003cp\\u003eFormulating a slow-release preparation to maintain serum T3 levels for an extended period can be technically challenging due to the short half-life of T3 (approximately 16 hours). Nevertheless, the new slow-release preparation demonstrated a 24-hour drug release in in-vitro studies. Moreover, we were unable to formulate a single tablet containing SR-T3 and LT4 to improve patient adherence due to the complexity of mixing a delayed-release medication with one that is normally absorbed.\\u003c/p\\u003e\\n\\u003ch3\\u003eInnovation\\u003c/h3\\u003e\\n\\u003cp\\u003eThis upcoming trial will be the initial substantial effort in the management of hypothyroidism to evaluate the impact of combining LT4 with SR-T3 versus LT4 monotherapy alone in terms of quality of life, thyroid hormone levels, and metabolic efficacy outcomes to address the limitations of T4 monotherapy. Furthermore, creating new global products has the potential to boost research and innovation while also enhancing employment opportunities in Iran.\\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eAbnormal findings in clinical and biochemical indices of patients on T4 monotherapy and residual symptoms of hypothyroidism in a substantial minority of hypothyroid patients treated with LT4 monotherapy emerged the need for a new approach using levothyroxine plus slow-release liothyronine preparations to mimic the normal physiological serum values of T4, T3, TSH, and T3/T4 ratio. Randomized controlled trials have failed to demonstrate superiority for the new approach, mostly due to the non-physiological T3 doses used in these studies and the existing barriers to co-administration of LT4 plus T3, resulting from their different pharmacokinetics, especially in the slow-release form of T3. Additionally, individual heterogeneity in set points for optimal thyroid homeostasis, residual thyroid function, and deiodinase polymorphisms in tissues that regulate the activation and deactivation of circulating thyroid hormones may lead to varied responses to combination therapy. Future clinical trials using combined preparation of LT4 plus SRT3 with more appropriate doses, which provide a more extended period of relatively stable serum T3 concentrations and support a more individualized approach, are warranted. The results of these studies might help to resolve the shortcomings of levothyroxine monotherapy, especially in patients with persistent symptoms or metabolic abnormalities.\\u003c/p\\u003e \\u003cp\\u003e \\u003cb\\u003eTrial status\\u003c/b\\u003e \\u003c/p\\u003e\\n\\u003ch3\\u003eTrial Id: 44220\\u003c/h3\\u003e\\n\\u003cp\\u003e \\u003cb\\u003eIRCT Id: IRCT20100922004794N12\\u003c/b\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cb\\u003eTrial registration ID: IRCT20100922004794N12\\u003c/b\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cb\\u003eRegistration date: 2020-02-27\\u003c/b\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cb\\u003eFirst revision : 2023-07-09\\u003c/b\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cb\\u003eSecond revision: 2024-07-01\\u003c/b\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cb\\u003eExpected recruitment start date: 2024-10-06\\u003c/b\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cb\\u003eExpected recruitment end date: 2025-10-23\\u003c/b\\u003e \\u003c/p\\u003e\"},{\"header\":\"Abbreviations\",\"content\":\"\\u003cdiv class=\\\"DefinitionList\\\"\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eLT4\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eLevothyroxine\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eLT3\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eLiothyronine\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eFT3\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eFree tri-iodothyronine\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eFT4\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eFree thyroxine\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eTT4\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eTotal thyroxine\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eTT3\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eTotal tri-iodothyronine\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eLT3\\u0026thinsp;+\\u0026thinsp;LT4\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eLevothyroxine plus Liothyronine\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eQOL\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003equality of life\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eThyPRO-39\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eThyroid-specific Patient-Reported Outcome short-form\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eTTS\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eTehran thyroid study\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eTLGS\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eTehran lipid and glucose study\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003ePTU\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003ePolytuiuracil\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eREE\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eResting Energy Expenditure\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eSHBG\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003esex hormone-binding globulin\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eTC\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003etotal cholesterol\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eTG\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003etriglycerides\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eHDL-C\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eHigh-density lipoprotein cholesterol\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eLDL-C\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eLow-density lipoprotein cholesterol\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eCK\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eCreatine kinase\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eLDH\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eLactate dehydrogenase\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eHOMA\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eHomeostasis model assessment\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eANCOVA\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eAnalysis of covariance\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eRR\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eRelative Risk\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eDMC\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eData Monitoring Committee\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eSAP\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003estatistical analysis plan\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eATA\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eAmerican Thyroid Association\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eBTA\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eBritish Thyroid Association\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e \\u003cdiv class=\\\"Term\\\"\\u003eETA\\u003c/div\\u003e \\u003cdiv class=\\\"Description\\\"\\u003e \\u003cp\\u003eand European Thyroid Association\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003c/div\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgments\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eWe sincerely acknowledge the participants in the Tehran Thyroid study for their cooperation and commitment.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthors\\u0026rsquo; contributions\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eFA; principal investigator; Concept and idea generation, AA: Administrative Support; Ensured regulatory compliance and IRB approval; HA; Clinical expertise; MT: Laboratory manager; SM: Data Management and analysis; KhD: Technical support; Mehrabi Y: Biostatistical expertise and sample size calculations; ZA: Genetic consultant; HA: Paraclinical expertise; \\u0026nbsp; AAM: Acquisition of Data; LM: Co-principal investigator, supervision, design, protocol writing; All authors contributed to the writing and editing of the proposal, including drafting, revising, and proofreading.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis trial is financially supported by the Research Institute for Endocrine Sciences and Dorsa Pharmaceutical Company. Dorsa Pharmaceutical Company played no role in the design, collection, analysis, or interpretation of the study\\u0026apos;s data, nor in the writing of the manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAvailability of data and materials\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe data supporting the findings of this study are available from the corresponding author upon reasonable request.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eEthics approval and consent to participate\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe study design was registered by the Iranian Registry of Clinical Trials, IRCT20100922004794N12. This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki, and all procedures involving the study participants were approved by the National Research Council of the Islamic Republic of Iran (IR.SBMU.ENDOCRINE.REC.1403.061), the Human Research Review Committee of the Endocrine Research Center, Shahid Beheshti University, Tehran, Iran. Trial participants sign informed consent forms at baseline, and their personal information remains strictly confidential.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConsent for publication\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u0026ldquo;Not applicable.\\u0026rdquo;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCompeting interests\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u0026quot;The authors declare that they have no competing interests.\\u0026quot;\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eDavies TF. The pathogenesis of Graves\\u0026rsquo; disease. In Werner and Ingbar\\u0026rsquo;s the Thyroid te, pp 884-925. Eds Braverman LE \\u0026amp; Utiger RD. Philadelphia: Lippincott-Raven Publishers. 2021.\\u003c/li\\u003e\\n\\u003cli\\u003eDiStefano J, 3rd, Jonklaas J. Predicting Optimal Combination LT4 + LT3 Therapy for Hypothyroidism Based on Residual Thyroid Function. Frontiers in endocrinology. 2019;10:746.\\u003c/li\\u003e\\n\\u003cli\\u003eJonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, et al. Guidelines for the treatment of hypothyroidism: prepared by the American thyroid association task force on thyroid hormone replacement. Thyroid : official journal of the American Thyroid Association. 2014;24(12):1670-751.\\u003c/li\\u003e\\n\\u003cli\\u003eStagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid : official journal of the American Thyroid Association. 2011;21(10):1081-125.\\u003c/li\\u003e\\n\\u003cli\\u003eChaker L, Bianco AC, Jonklaas J, Peeters RP. Hypothyroidism. Lancet (London, England). 2017;390(10101):1550-62.\\u003c/li\\u003e\\n\\u003cli\\u003eAsvold BO, Vatten LJ, Bj\\u0026oslash;ro T. Changes in the prevalence of hypothyroidism: the HUNT Study in Norway. European journal of endocrinology. 2013;169(5):613-20.\\u003c/li\\u003e\\n\\u003cli\\u003eCanaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Archives of internal medicine. 2000;160(4):526-34.\\u003c/li\\u003e\\n\\u003cli\\u003eAmouzegar A, Ghaemmaghami Z, Beigy M, Gharibzadeh S, Mehran L, Tohidi M, et al. Natural Course of Euthyroidism and Clues for Early Diagnosis of Thyroid Dysfunction: Tehran Thyroid Study. Thyroid : official journal of the American Thyroid Association. 2017;27(5):616-25.\\u003c/li\\u003e\\n\\u003cli\\u003eEscobar-Morreale HF, Obregon MJ, Escobar del Rey F, Morreale de Escobar G. Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. J Clin Invest. 1995;96(6):2828-38.\\u003c/li\\u003e\\n\\u003cli\\u003eGullo D, Latina A, Frasca F, Le Moli R, Pellegriti G, Vigneri R. Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PloS one. 2011;6(8):e22552.\\u003c/li\\u003e\\n\\u003cli\\u003eJonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, et al. Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid research. 2014;24(12):1670-751.\\u003c/li\\u003e\\n\\u003cli\\u003ePeterson SJ, McAninch EA, Bianco AC. Is a Normal TSH Synonymous With \\u0026quot;Euthyroidism\\u0026quot; in Levothyroxine Monotherapy? The Journal of clinical endocrinology and metabolism. 2016;101(12):4964-73.\\u003c/li\\u003e\\n\\u003cli\\u003eWiersinga WM, Duntas L, Fadeyev V, Nygaard B, Vanderpump MP. 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism. European thyroid journal. 2012;1(2):55-71.\\u003c/li\\u003e\\n\\u003cli\\u003eMcAninch EA, Jo S, Preite NZ, Farkas E, Mohacsik P, Fekete C, et al. Prevalent polymorphism in thyroid hormone-activating enzyme leaves a genetic fingerprint that underlies associated clinical syndromes. The Journal of clinical endocrinology and metabolism. 2015;100(3):920-33.\\u003c/li\\u003e\\n\\u003cli\\u003ePeeters RP, van Toor H, Klootwijk W, de Rijke YB, Kuiper GG, Uitterlinden AG, et al. Polymorphisms in thyroid hormone pathway genes are associated with plasma TSH and iodothyronine levels in healthy subjects. The Journal of clinical endocrinology and metabolism. 2003;88(6):2880-8.\\u003c/li\\u003e\\n\\u003cli\\u003ePeeters RP, van den Beld AW, Attalki H, Toor H, de Rijke YB, Kuiper GG, et al. A new polymorphism in the type II deiodinase gene is associated with circulating thyroid hormone parameters. Am J Physiol Endocrinol Metab. 2005;289(1):E75-81.\\u003c/li\\u003e\\n\\u003cli\\u003eSaravanan P, Chau WF, Roberts N, Vedhara K, Greenwood R, Dayan CM. Psychological well‐being in patients on \\u0026lsquo;adequate\\u0026rsquo;doses of l‐thyroxine: results of a large, controlled community‐based questionnaire study. Clinical endocrinology. 2002;57(5):577-85.\\u003c/li\\u003e\\n\\u003cli\\u003eLadenson PW. Psychological well-being in patients. Clin Endocrinol (Oxf). 2002;57(5):575-6.\\u003c/li\\u003e\\n\\u003cli\\u003eWekking EM, Appelhof BC, Fliers E, Schene AH, Huyser J, Tijssen JG, et al. Cognitive functioning and well-being in euthyroid patients on thyroxine replacement therapy for primary hypothyroidism. European journal of endocrinology. 2005;153(6):747-53.\\u003c/li\\u003e\\n\\u003cli\\u003eWalsh JP. Dissatisfaction with thyroxine therapy - could the patients be right? Curr Opin Pharmacol. 2002;2(6):717-22.\\u003c/li\\u003e\\n\\u003cli\\u003eGrozinsky-Glasberg S, Fraser A, Nahshoni E, Weizman A, Leibovici L. Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of randomized controlled trials. The Journal of clinical endocrinology and metabolism. 2006;91(7):2592-9.\\u003c/li\\u003e\\n\\u003cli\\u003eWalsh JP, Shiels L, Lim EM, Bhagat CI, Ward LC, Stuckey BG, et al. Combined thyroxine/liothyronine treatment does not improve well-being, quality of life, or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism. The Journal of clinical endocrinology and metabolism. 2003;88(10):4543-50.\\u003c/li\\u003e\\n\\u003cli\\u003eNygaard B, Jensen EW, Kvetny J, Jarlov A, Faber J. Effect of combination therapy with thyroxine (T4) and 3,5,3\\u0026apos;-triiodothyronine versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomised cross-over study. European journal of endocrinology. 2009;161(6):895-902.\\u003c/li\\u003e\\n\\u003cli\\u003eBunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ, Jr. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. The New England journal of medicine. 1999;340(6):424-9.\\u003c/li\\u003e\\n\\u003cli\\u003eEscobar-Morreale HF, Botella-Carretero JI, Gomez-Bueno M, Galan JM, Barrios V, Sancho J. Thyroid hormone replacement therapy in primary hypothyroidism: a randomized trial comparing L-thyroxine plus liothyronine with L-thyroxine alone. Ann Intern Med. 2005;142(6):412-24.\\u003c/li\\u003e\\n\\u003cli\\u003eBunevicius R, Jakuboniene N, Jurkevicius R, Cernicat J, Lasas L, Prange AJ, Jr. Thyroxine vs thyroxine plus triiodothyronine in treatment of hypothyroidism after thyroidectomy for Graves\\u0026apos; disease. Endocrine. 2002;18(2):129-33.\\u003c/li\\u003e\\n\\u003cli\\u003eEscobar-Morreale HF, Botella-Carretero JI, Escobar del Rey F, Morreale de Escobar G. REVIEW: Treatment of hypothyroidism with combinations of levothyroxine plus liothyronine. The Journal of clinical endocrinology and metabolism. 2005;90(8):4946-54.\\u003c/li\\u003e\\n\\u003cli\\u003e.\\u003c/li\\u003e\\n\\u003cli\\u003eWiersinga WM. Do we need still more trials on T4 and T3 combination therapy in hypothyroidism? European journal of endocrinology. 2009;161(6):955-9.\\u003c/li\\u003e\\n\\u003cli\\u003eHennemann G, Docter R, Visser TJ, Postema PT, Krenning EP. Thyroxine plus low-dose, slow-release triiodothyronine replacement in hypothyroidism: proof of principle. Thyroid : official journal of the American Thyroid Association. 2004;14(4):271-5.\\u003c/li\\u003e\\n\\u003cli\\u003eJonklaas J, Bianco AC, Cappola AR, Celi FS, Fliers E, Heuer H, et al. Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document. European thyroid journal. 2021;10(1):10-38.\\u003c/li\\u003e\\n\\u003cli\\u003eMehran L, Amouzegar A, Foroutan SM, Masoumi S, Tohidi M, Abdi H, et al. Pharmacodynamic and pharmacokinetic properties of the combined preparation of levothyroxine plus sustained- release liothyronine; a randomized controlled clinical trial. BMC endocrine disorders. 2023;23(1):182.\\u003c/li\\u003e\\n\\u003cli\\u003eAzizi F, Ghanbarian A, Momenan AA, Hadaegh F, Mirmiran P, Hedayati M, et al. Prevention of non-communicable disease in a population in nutrition transition: Tehran Lipid and Glucose Study phase II. Trials. 2009;10:5.\\u003c/li\\u003e\\n\\u003cli\\u003eChen Y, Zhang X, Pan B, Jin X, Yao H, Chen B, et al. A modified formula for calculating low-density lipoprotein cholesterol values. Lipids in health and disease. 2010;9:52.\\u003c/li\\u003e\\n\\u003cli\\u003eMalavolti M, Mussi C, Poli M, Fantuzzi AL, Salvioli G, Battistini N, et al. Cross-calibration of eight-polar bioelectrical impedance analysis versus dual-energy X-ray absorptiometry for the assessment of total and appendicular body composition in healthy subjects aged 21-82 years. Annals of human biology. 2003;30(4):380-91.\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":true,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"trials\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"trls\",\"sideBox\":\"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)\",\"snPcode\":\"13063\",\"submissionUrl\":\"https://www.editorialmanager.com/trls\",\"title\":\"Trials\",\"twitterHandle\":\"MedicalEvidence\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC/SO AJ\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Hypothyroidism, Levothyroxine, Slow-release Liothyronine, Combination therapy, Clinical trial, Patient-reported outcomes, Patient satisfaction\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-4851538/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-4851538/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cb\\u003eBackground\\u003c/b\\u003e\\u003c/p\\u003e \\u003cp\\u003eThere are emerging controversies regarding the priority of T4\\u0026thinsp;+\\u0026thinsp;T3 combination therapy over standard care with LT4 monotherapy in the management of hypothyroid subjects. Combination therapy with a slow-release form of liothyronine (SRT3) and levothyroxine may restore T3 concentrations and provide better outcomes, especially in individuals with persistent complaints despite having normal serum TSH levels.\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eMethods\\u003c/b\\u003e\\u003c/p\\u003e \\u003cp\\u003e100 patients with hypothyroidism\\u0026thinsp;\\u0026ge;\\u0026thinsp;20 years old., who achieve euthyroidism under LT4 monotherapy for at least three months will be randomized to two groups of LT4\\u0026thinsp;+\\u0026thinsp;SRT3 combined therapy (75 \\u0026micro;g LT4\\u0026thinsp;+\\u0026thinsp;25 \\u0026micro;g SRT3) and LT4 monotherapy for 48 weeks. Participants will be evaluated at baseline and three subsequent follow-ups, 12, 24, and 48 weeks after treatment allocation. Before and after the intervention, body weight, heart rate, blood pressure, ECG, quality of life ( by Thypro-39 and SF-12), resting energy expenditure, and body composition will be evaluated. Also, serum TSH, total T3, total T4, free T4, free T3, total cholesterol, LDL, HDL, triglycerides, FBS, insulin, HbA1C, HOMA-IR, SHBG, Enolase, LDH and CK, Ferritin and metabolomics will be assessed at baseline and compared with their corresponding values at 24 and 48 weeks. Epigenetic-related markers will be measured and compared between the responders and non-responders.\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eConclusion\\u003c/b\\u003e\\u003c/p\\u003e \\u003cp\\u003eIt is expected that LT4\\u0026thinsp;+\\u0026thinsp;SRT3 combined therapy more closely mimics the serum levels of T3, T4, and the T3/T4 ratio of euthyroid subjects than LT4 monotherapy, and improves health outcomes and quality of life, especially in hypothyroid patients with persistent symptoms under LT4 monotherapy. Genetic polymorphism sequencing may identify hypothyroid patients who are not responding well to levothyroxine alone.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Treatment of hypothyroidism with levothyroxine plus slow-release liothyronine; A Study Protocol for a Randomized Controlled Double-Blinded Clinical Trial\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-04-30 08:20:35\",\"doi\":\"10.21203/rs.3.rs-4851538/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Minor revision\",\"date\":\"2025-05-06T03:30:26+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"\",\"date\":\"2025-04-28T13:20:41+00:00\",\"index\":0,\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2025-04-28T12:37:58+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvited\",\"content\":\"Trials\",\"date\":\"2025-04-28T12:05:33+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2025-04-06T09:32:42+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"Trials\",\"date\":\"2025-04-06T03:12:04+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"trials\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"trls\",\"sideBox\":\"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)\",\"snPcode\":\"13063\",\"submissionUrl\":\"https://www.editorialmanager.com/trls\",\"title\":\"Trials\",\"twitterHandle\":\"MedicalEvidence\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC/SO AJ\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"d720bbab-f933-4164-b86d-6adfe28d0d45\",\"owner\":[],\"postedDate\":\"April 30th, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2025-07-07T16:10:51+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-4851538\",\"link\":\"https://doi.org/10.1186/s13063-025-08940-5\",\"journal\":{\"identity\":\"trials\",\"isVorOnly\":false,\"title\":\"Trials\"},\"publishedOn\":\"2025-07-01 15:57:47\",\"publishedOnDateReadable\":\"July 1st, 2025\"},\"versionCreatedAt\":\"2025-04-30 08:20:35\",\"video\":\"\",\"vorDoi\":\"10.1186/s13063-025-08940-5\",\"vorDoiUrl\":\"https://doi.org/10.1186/s13063-025-08940-5\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-4851538\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-4851538\",\"identity\":\"rs-4851538\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}