Design and Rationale for a Randomized, Open-Label, Parallel Clinical Trial Evaluating Major Cardiovascular Events (Pharmacological Treatment Versus Diet Control) in Patients with High-Normal Blood Pressure: The PRINT-TAHA9 Trial

Design and Rationale for a Randomized, Open-Label, Parallel Clinical Trial Evaluating Major Cardiovascular Events (Pharmacological Treatment Versus Diet Control) in Patients with High-Normal Blood Pressure: The PRINT-TAHA9 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 Design and Rationale for a Randomized, Open-Label, Parallel Clinical Trial Evaluating Major Cardiovascular Events (Pharmacological Treatment Versus Diet Control) in Patients with High-Normal Blood Pressure: The PRINT-TAHA9 Trial Armin Attar, Seyed Alireza Mirhosseini, Roham Borazjani, Mehrab Sayadi, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4375541/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Aug, 2024 Read the published version in Trials → Version 1 posted 5 You are reading this latest preprint version Abstract Background: The distinction between normal and high blood pressure remains a debated topic, with varying guidelines on when to start medication. Contemporary guidelines advocate for the initiation of antihypertensive therapy in individuals who present with high-normal blood pressure, particularly those exhibiting elevated 10-year atherosclerotic cardiovascular disease (ASCVD) risk scores. Despite these recommendations, there is a notable lack of direct evidence supporting the efficacy of treating high-normal blood pressure to prevent major cardiovascular events (MACE). Methods: The PRINT-TAHA9 trial, which is a unicentric, randomized, open-label, placebo-controlled, parallel clinical study, seeks to explore the effects of intensive blood pressure control on MACE in participants with high-normal blood pressure. We will enroll 1620 adults aged 18 years and above with a systolic blood pressure range of 130-140 mmHg, diastolic blood pressure under 90 mmHg, and atherosclerotic cardiovascular disease (ASCVD) risk score exceeding 7.5%. The study will be executed in five distinct phases, with each phase enrolling between 300 and 400 participants. Participants will be randomly allocated to either the treatment group receiving antihypertensive medication (amlodipine/valsartan) and a low-salt/low-fat diet or to the control group receiving a similar diet. Follow-up visits are scheduled every six months over a three-year period to monitor blood pressure, evaluate medication adherence, document any adverse events, and adjust the intervention as necessary. Cox proportional hazards regression analysis will be employed to examine the disparities between the two arms. The study's design adheres to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines. Discussion : The literature on managing high-normal blood pressure reveals a significant gap in medical understanding, especially regarding when to start pharmacological intervention. Despite guidelines advocating early treatment, the debate continues due to insufficient evidence that such interventions significantly reduce major cardiovascular events. This trial seeks to address this critical evidence gap. Trial registration : The PRINT-TAHA9 trial was registered in October 2019 with the Iranian Registry of Clinical Trials (IRCT.ir) under the registration number IRCT20191002044961N1. https://irct.behdasht.gov.ir/trial/43092 prehypertension high-normal blood pressure cardiovascular outcome adverse events major adverse cardiovascular events intensive blood pressure control Figures Figure 1 Figure 2 Introduction Background and rationale Exploring the exact border between normotension and hypertension shows that their actual cutoff values and definitions have always been a subject of dispute. In 2017, the AHA identified hypertension as having a systolic blood pressure (SBP) ≥ 130 mmHg or a diastolic blood pressure (DBP) ≥ 80 mmHg. ( 1 ). A year later, the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH) raised the hypertension threshold by 10 mmHg compared to the prior year's standard ( 2 ). Notably, any blood pressure between the optimal and the hypertensive values were interpreted as “high-normal blood pressure” and “elevated blood pressure” by the ESC/ESH and AHA, respectively. In 2023, the ESC/ESH guidelines recommended antihypertensive drug initiation for patients with high-normal blood pressure and previous cerebrovascular disease (CVD), especially coronary artery disease (CAD) ( 3 ). Nevertheless, according to the ACC/AHA, patients with an SBP between 130 and 140 mmHg should receive pharmacological intervention if their 10-year atherosclerotic cardiovascular risk (ASCVD) is above 10% ( 1 ). Although this recommendation is supported by some secondary analyses of large clinical trials ( 4 , 5 ), there is a lack of direct evidence evaluating this recommendation, and consequently, this decision has been criticized by some experts ( 6 ). Despite these criticisms, some other investigators claim that there are sufficient data to support this recommendation ( 7 ). There is solid evidence available on the association between elevated blood pressure, other cardiovascular risk factors, and hypertension progression. However, the direct effect of high-normal blood pressure on long-term major cardiovascular events (such as any type of acute coronary syndromes (ACS) or heart failure) and whether to treat it remain unclear ( 8 – 10 ). Russel et al. reported that prehypertension is associated with approximately 3.4% of hospitalizations and 9.1% of cardiovascular-related deaths while increasing the risk of end-stage renal disease (ESRD) development ( 11 ). Moreover, prehypertension associated with other predisposing conditions, such as obesity, smoking, and diabetes, is believed to be a major risk factor for cardiovascular events ( 12 ). Notably, the exact relationship between prehypertension and major adverse cardiovascular events (MACE) has not been thoroughly evaluated; Qureshi et al. reported a clear association between prehypertension and ACS ( 13 ). Additionally, a recently published cohort study in China reported a greater risk for MACEs and stroke incidence, suggesting early identification of high-risk individuals ( 14 ). Considering the importance of prehypertension (high-normal blood pressure) on cardiovascular outcomes and the controversies in the field, we designed a study on the prevention of major cardiovascular events involving intensive blood pressure reduction in patients with high-normal blood pressure at the T raditional and A dvanced H eart A pproaches Clinical Center, trial 9 . (PRINT-TAHA9 trial). This trial aimed to evaluate the hypothesis that pharmacologically reducing SBP in patients with an SBP between 130 and 140 mmHg would reduce major cardiovascular events. This hypothesis is based on our previous study, a post hoc analysis of the Systolic Blood Pressure Intervention Trial (SPRINT), which revealed that prehypertensive patients might benefit from antihypertensive treatment, which cannot be confidently recommended because it was not exclusively designed and randomized for this specific population ( 5 ). Furthermore, based on our other analysis, we chose to enroll patients with an ASCVD risk above 7.5% instead of 10% ( 15 ). Objectives This trial focused on assessing the effects of intensive blood pressure control in subjects with high-normal blood pressure and an ASCVD risk score of 7.5% or higher. Methods Study design and setting This investigation is a unicentric, randomized, superiority, open-label, placebo-controlled, parallel clinical trial. MACE will be compared between two groups with high-normal blood pressure, defined as an office SBP of 130–140 mmHg and DBP of 80–90 mmHg, measured at the Imam Reza Cardiovascular Clinic in Shiraz, Iran. The study's design adheres to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines. Study participants and eligibility criteria The study will enroll adults aged 18 years and older without diabetes or any underlying cardiovascular conditions who had a baseline SBP of 130–140 mmHg and DBP under 90 mmHg, as well as a 10-year ASCVD risk of 7.5% or greater. The exclusion criteria included a history of diabetes mellitus (DM), cerebrovascular accident (CVA), heart failure, ischemic heart disease (IHD), or the use of statins, antiplatelet agents, or antihypertensive agents for other conditions. Intervention In addition to obtaining blood and urine specimens for initial biochemical and hematological analyses, skilled nurses will collect medical histories and baseline data. Blood samples will be analyzed at the local health service laboratory following standard procedures. Following the initial screening, candidates who are deemed potentially eligible will undergo further evaluation to identify possible secondary hypertension. Blood samples will be collected for complete blood count (CBC), thyroid function test (TFT), blood urea nitrogen (BUN), and creatinine (Cr) analyses, along with measurements of serum sodium (Na), potassium (K), calcium (Ca), and phosphorus (Ph) levels. Subsequently, patients will be allocated to the treatment and control groups through permuted block randomization. The intervention group will be administered an antihypertensive regimen (amlodipine/valsartan at an initial dose of 5/80 mg; Valzomix®, Abidi Pharmaceutical Company, Tehran, Iran) taken daily for 36 months, along with a low-salt, low-fat diet aimed at maintaining SBP below 130/80 mmHg. Conversely, the control group will follow a similar diet but will recieve antihypertensive medication only if their SBP exceeds 140/90 mmHg during the diet phase, following the same medication protocol. Adherence Individuals will be provided with a comprehensive set of information about the importance and necessity of routine drug consumption and attending scheduled visits while providing informed consent. At each visit, patients will receive a complete set of checkups, and their compliance will be assessed via returned tablet counts. Concomitant Care Participants will undergo follow-up at one, three, six, twelve, eighteen, twenty-four, thirty, and thirty-six months. At each visit, SBP and DBP will be measured following a standardized protocol. Uncontrolled blood pressure (defined as a blood pressure greater than 130/80 mmHg in the intervention group and 140/90 mmHg in the control group) in any of the further visits will be managed by gradual increases in the antihypertensive medication dosage (such as amlodipine/valsartan 5/160 mg, 10/160 mg, and finally adding indapamide 1.5 mg (step-up approach)). If the SBP drops below 100 mmHg at one visit or below 110 mmHg at two consecutive visits, the dosage decreases (through a step-down approach), as shown in Fig. 1 . Outcomes The primary endpoints of this study are the incidence of any major adverese cardiovascular outcomes as a composite of cardiac death, acute coronary syndrome (ACS), stroke (CVA), and hospitalization due to cardiovascular causes including heart failure, arrhythmia, anigina pectoris, or percutaneous coronary intervention (PCI). An independent expert will assess all measurements to ensure their accuracy. In the case of poor recordings, the expert chose whether the measurement was of adequate quality to be used for endpoint assessment. Measurements of inadequate quality will not be used in the analysis as missing measurements. Emerging MACEs will be evaluated by an independent Safety Committee. All laboratory data and adjudications will be finalized and archived in the computer database prior to the unbinding process. Participant timeline As shown in Fig. 1 and Fig. 2 , participants will follow a comprehensive timeline from enrollment through various follow-up stages to evaluate the effect of intensive blood pressure management in individuals with high-normal blood pressure. Initially, potential participants will be screened for eligibility and, upon meeting the criteria, will be enrolled and randomized to receive either the intervention or control treatment. Baseline assessments included medical history, baseline variables, and blood and urine samples for biochemistry and hematologic tests. Follow-up visits at 1, 3, 6, 12, 18, 24, 30, and 36 months postenrollment involve monitoring SBP and DBP, checking medication adherence through returned tablet counts, and recording any adverse events. The intervention may be adjusted based on blood pressure control at these visits. This study aimed to assess the primary outcome of major cardiovascular events with a comprehensive approach to participant management and data collection. Sample size This study is a superior clinical trial that aimed to detect a difference between the anticipated 3% incidence of MACEs in the intervention group and the 6% incidence in the control group based on our previous study ( 4 ). Given a predetermined significance level (alpha) of 5% coupled with a desired study power of 80% (1-beta) and considering an acceptable clinical difference margin set at 50% of the projected difference, adjustments were made to account for an estimated dropout rate of 10%. By utilizing Formula 1 ( 16 ) for these calculations, it is determined that each arm of the study requires an estimated sample size of approximately 730 participants to achieve the outlined objectives. A total of 1620 participants accounted for potential dropouts and nonadherence at a conservative rate, ensuring comprehensive data collection and analysis. Enrolling the required sample size at one site may present challenges; therefore, we decided to conduct the study in five phases, beginning with the recruitment of 300 patients in phase 1 and pursuing national or international collaborations to complete the remaining phases. Recruitment The selection of the Imam-Reza Clinic for our study is strategically justified by its high patient volume, status as a key referral center for comprehensive patient management, and proactive engagement in blood pressure screening campaigns, which are integral to our research focus. The clinic's economic accessibility, through low consultation fees and broad insurance coverage, ensures inclusivity, enabling participation from diverse socioeconomic backgrounds. Furthermore, our initiative to educate potential participants at the clinic leverages its robust patient education framework, enhancing recruitment efforts and reinforcing the clinic's pivotal role in promoting cardiovascular health. Collectively, these attributes make the Imam-Reza Clinic an ideal setting for our study, providing a rich data pool and facilitating impactful research on blood pressure management. Randomization method (sequence generation and concealment mechanism) The randomization method for the study will employ permuted block randomization. This approach involves assigning various sequences to numbers 1 through 6 to create blocks, specifically: 1. AABB, 2. ABAB, 3. ABBA, 4. BBAA, 5. BABA, and 6.BAAB. In these sequences, 'A' represents patients allocated to the treatment group, while 'B' denotes those in the control group. We will select block numbers using a random numbers table, continuing until 36 blocks of four-letter sequences have been chosen. This method ensures balanced allocation of participants across the two study groups. Implementation Patients who provide informed consent and meet the eligibility requirements will be subjected to randomization. The well-trained nursing staff, who are in charge of recruitment and conducting clinical interviews at the Imam-Reza Clinic, will initiate the randomization request. Blinding As an open-label trial, participants and physicians responsible for follow-up visits will not be blinded. The outcome assessors and data analyzist are blinded in this study. Data collection methods During the baseline visit, all patient information and data will be recorded and securely archived at the Imam-Reza Clinic. At each follow-up visit, a blinded staff member (a well-trained nurse) will interview the patient and record the follow-up (outcome) data. Subsequently, the patient will be examined by a physician who is not blinded to the treatment allocation. All documents and records will be securely archived. Data management Our study adheres to SPIRIT Statement guidelines, employing a detailed data management approach to safeguard data integrity, confidentiality, and accuracy. We utilized standardized data collection methods and a secure, electronic database at Imam-Reza Clinic, managed by a specialized team that ensures data quality through regular audits and data cleaning. Access is strictly controlled, with advanced security measures such as encryption and backups to prevent unauthorized access. An independent committee conducts periodic data monitoring for safety and integrity. Following ethical and regulatory standards, data analysis will be carried out as per a predefined plan, ensuring transparent and reproducible reporting of findings, thereby maintaining research excellence and protecting participant privacy. Statistical analysis Data analysis will be conducted using the Statistical Package for Social Sciences (SPSS), version 20.0 (SPSS Inc., Chicago, IL, USA). Quantitative data are presented as the mean ± standard deviation (SD), and categorical data are presented as frequencies and percentages. For quantitative comparisons, either the independent t test or Mann‒Whitney U test will be utilized. Cox regression analysis was used to determine the specific impact of antihypertensive treatment on cardiovascular events, and a P value ≤ 0.05 will be considered to indicate statistical significance. Participants who did not complete the follow-up were censored at their last known contact. The analysis will primarily focus on the intention-to-treat population to test the primary hypothesis aimed at proving superiority. Additional analysis Subgroup analysis will be performed, focusing on factors of clinical significance such as age, sex, existing health conditions, and additional indicators of risk. For all hypothesis testing, a two-sided approach will be adopted, with the significance level set at 5%. Analysis Population and Missing Data In our study, the primary analysis focusing on the endpoints will proceed without adjustments for covariates, and we will not employ imputation techniques for missing baseline variable values. Patients who are lost to follow-up will be censored at the last known point of contact and considered not to have reached the primary endpoint in the calculation of Kaplan–Meier event rates. This approach ensures a straightforward and transparent analysis of the data, reflecting the true nature of the study's outcomes. Data monitoring, harms, and auditing Before the statistical analysis is initiated, a cardiology department expert, external to our research team, will critically assess and approve all the data measurements. Measurements that fail to adhere to the requisite quality standards will be excluded and considered missing for analytical purposes. Moreover, a neutral safety committee, unaware of participant treatment allocations, will evaluate the occurrence of significant MACE. Upon the completion of this adjudication stage, the database will be unlocked for analysis. Communication regarding any adverse incidents will be directed to an autonomous Data, Safety, and Monitoring Board (DSMB) by the study's executive committee. The DSMB, acting independently, has the authority to terminate the trial early if there are concerns over patient safety or the achievement of primary study objectives, applying strict statistical criteria for such decisions. Regular monitoring of safety data, including unexpected serious adverse events, mortality, procedural complications, and severe arrhythmias, among others, will be a DSMB responsibility, with quarterly safety reports generated for review. Additionally, all deaths will be promptly communicated to the DSMB, which also undertakes bimonthly audits, functioning independently from the study researchers. Ethical considerations This survey was conducted in compliance with the Declaration of Helsinki ( 17 ) and received ethics approval from the Institutional Review Board and Ethics Committee of Shiraz University of Medical Sciences (SUMS) on October 2, 2019, under the approval number IR.SUMS.MED.REC.1398.420. The study has been registered with the Iranian Registry of Clinical Trials at https://www.irct.ir under the trial identifier IRCT20191002044961N1. Furthermore, all participants were required to provide informed consent, a process facilitated by experienced nurses or clinical staff. Protocol amendments In our research, any changes to the protocol that might affect the conduct of the study, potential patient benefits, or patient safety will require a formal amendment to the protocol. This encompasses alterations in the study objectives, methodology, participant characteristics, sample sizes, study procedures, or significant administrative adjustments. Prior endorsement from the Ethics Committee/Institutional Review Board (IRB) of Shiraz University of Medical Sciences is mandatory for these amendments to uphold ethical guidelines and safeguard participant well-being. Consent and assent The process of obtaining consent or assent involves the staff introducing the trial to potential participants and providing them with detailed information sheets for thorough understanding. Following this, patients will engage in informed discussions with the consulting specialist. Written consent will then be acquired from those patients who decide to participate in the trial by a trained general practitioner. There will be no ancillary studies conducted using data collected from this trial, ensuring that all participant information is solely used for the intended research purposes as outlined in the study protocol. Confidentiality Participant information will be safeguarded in locked file cabinets situated in restricted-access areas. To preserve confidentiality, laboratory samples, reports, data collection sheets, processing, and administrative documents will be tagged with a coded ID rather than personal identifiers. Records containing personal identifiers, such as locator forms and consent documents, will be stored separately from those identified by code. Additionally, all local databases will be fortified with password-protected access systems, ensuring that data security and participant privacy are maintained throughout the study. Discussion The latest ACC/AHA High Blood Pressure Guidelines no longer use the term "prehypertension." Instead, they classify blood pressure as either elevated (120–129/<80 mmHg) or hypertensive, diverging from previous guidelines that defined 140/90 mmHg as stage 1 hypertension—now reclassified as stage 2 in the new guidelines. It further recommends addressing high blood pressure medically at an earlier threshold of 130/80 mmHg rather than the previous 140/90 mmHg standard ( 18 ). A 2004 Epidemiologic Follow-up Study sought to assess the impact of prehypertension on hospital admissions and mortality rates. A total of 3.4% of hospitalizations, 6.5% of nursing home admissions, and 9.1% of deaths could be directly attributed to prehypertension. The study concluded that eliminating prehypertension could significantly decrease the rates of hospitalization, nursing home entry, and early death ( 11 ). A cross-sectional study in 2007 showed that after ten years, 31.1% of subjects with prehypertension became hypertensive ( 9 ). The progression of prehypertension to hypertension can increase the risk of cognitive function impairment, increased left ventricular mass, and end-stage renal disease and is also associated with arteriosclerosis. Therefore, it "might" be beneficial to treat prehypertension with antihypertensive medications in addition to lifestyle modifications ( 12 ). Despite the apparent importance of this issue, it has not been exclusively addressed in a clinical trial before. Previous studies were conducted in the general population and did not stratify patients according to their comorbidities ( 19 , 20 ). Therefore, the authors could not clearly determine whether the MACEs were directly the result of hypertension or other associated diseases, leading to selection bias. In this recent study, we excluded all diabetic patients and those with other comorbidities previously described in the "Study Participants" section and enrolled only nondiabetic prehypertensive adults to obtain more pure and specific results on this matter. A post hoc secondary analysis of the SPRINT trial designed to determine the practical cutoff limit of cardiovascular risk for starting intensive blood pressure reduction showed a J-shaped relationship between intensive blood pressure control and 10-year Framingham cardiovascular risk levels at a cutoff limit of approximately < 7% ( 15 ). In this trial, we decided to set this cutoff limit as an inclusion criterion rather than a 10-year risk of more than 10%, which was used in the SPRINT trial. According to the latest hypertension guidelines of the ESC/ESH, the initiation of antihypertensive therapy with a two-drug combination might be recommended for high-risk individuals. In older patients (65–80), the initiation of antihypertensive treatment with a two-drug combination, preferably a single-pill combination (SPC), is suggested ( 2 ). Multiple studies have proven that the efficacy of SPCs is greater than that of noncombined medications, and SPCs have improved tolerability and safety profiles ( 21 – 24 ). Several SPCs have been made worldwide, and the two most common SPCs available in Iran are amlodipine/valsartan and amlodipine/valsartan/hydrochlorothiazide as Triple SPC. Other SPCs are neither widely accessible nor inexpensive. Considering these points, we chose amlodipine/valsartan 5–80 mg as the medication of choice in our study. Moreover, we did not use triple SPC to avoid hypotension and subsequent adverse events. We are aware that the two-year follow-up might be insufficient to detect the exact extent to which treatment could affect long-term major cardiovascular events. We aim to carry out a primary analysis after this time, and the decision on whether to end the trial will be made based on our primary analysis. Abbreviations Systolic Blood Pressure SBP: Diastolic Blood Pressure DBP: American Heart Association AHA: Major Adverse Cardiovascular Events MACE: Systolic Blood Pressure Intervention Trial SPRINT: European Society Of Cardiology and The European Society Of Hypertension ESC/ESH: Acute Coronary Syndromes ACS: Percutaneous Coronary Intervention PCI: End-Stage Renal Disease ESRD: Diabetes Mellitus DM: Atherosclerosis Cardiovascular Disease Risk ASCVD: Ischemic Heart Diseases IHD: Cerebrovascular Accident CVA: Complete Blood Count CBC: Thyroid Function Test TFT: Blood Urea Nitrogen BUN: Creatinine Cr: Single-Pill Combination SPC: Declarations Issue Date: 23 April 2024 Protocol Amendment Number: 0 2 Author(s): AA; SAM; RB; MS; MA; MZ; IR; NP. Funding: No specific funding is declared for this study until the issue date of this draft. Roles and responsibilities Contributorship: AA, RB, MA, MS, and SAM contributed to the development of the protocol, preparation of the proposal, and critical revisions. AA took the lead in conceptualizing the study design with the help of MZ, IR, and NP. All the authors agreed to bear responsibility and accountability for the entirety of the project. Sponsor Contact Information: None. Sponsor And Funder: None. Committees Principal Investigator and Research Physician: AA. Steering Committee (SC): AA, RB, MI, MS, and SAM. Trial Management Committee (TMC): AA and SAM. Data, Safety, and Monitoring Board (DSMB): MS and SAM. Data Manager: MS and SAM. Lead Investigators: AA. Declaration of interest The authors declare no conflicts of interest in this study. Access to data Only the TMC members have access to patient data and files. Ancillary and posttrial care The Shiraz University of Medical Sciences will offer insurance coverage for any nonnegligent harm that participants might experience as a result of the study protocol. This insurance will encompass additional healthcare costs, compensation, or damage that is demonstrably linked to the study's procedures. Dissemination policy Trial results The findings of the study will be promptly disseminated to the physicians involved in the study, those referring patients, the participants themselves, and the broader medical community to ensure timely access to the new insights gained. Authorship Authorship will be discussed and determined in TMC. Reproducible research The full protocol of the study will be made publicly available as soon as possible. Appendices: Appendix 1 shows the variables and components of the medical evaluation of the enrolled patients. Informed consent materials are presented in appendix 2. Biological specimens Blood samples were collected to conduct a comprehensive blood count (CBC), assess thyroid function (TFT), and measure the levels of blood urea nitrogen (BUN) and creatinine (Cr). Additionally, the serum levels of sodium (Na), potassium (K), calcium (Ca), and phosphorus (Ph) were evaluated. Table of execution time-lines Figure 1. Trial status This document outlines protocol version number 02, finalized on April 23, 2024. The recruitment for phase 1 started in December 3 2019, following the trial registration on IRCT.ir, and concluded in February 2020. The follow-up for phase 1 has been completed. Recruitment for the subsequent phases is currently ongoing. As we seek national and international collaboration, we estimate that the recruitment will be completed by January 2026. References Carey RM, Whelton PK. 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Effect of intensive blood pressure lowering on cardiovascular outcomes based on cardiovascular risk: A secondary analysis of the SPRINT trial. Eur J Prev Cardiol. 2019;26(3):238-45. Borazjani R, Kojuri J, Abdi-Ardekani A, Izadpanah P, Dehghani P, Sayadi M, et al. Pharmacological treatment of high-normal blood pressure (prehypertension) in high-risk patients for primary prevention of cardiovascular events. J Clin Hypertens (Greenwich). 2020;22(9):1627-34. Bakris G, Sorrentino M. Redefining Hypertension - Assessing the New Blood-Pressure Guidelines. N Engl J Med. 2018;378(6):497-9. Carey RM, Whelton PK. Evidence for the Universal Blood Pressure Goal of <130/80 mm Hg Is Strong: Controversies in Hypertension - Pro Side of the Argument. Hypertension. 2020;76(5):1384-90. Han M, Li Q, Liu L, Zhang D, Ren Y, Zhao Y, et al. Prehypertension and risk of cardiovascular diseases: a meta-analysis of 47 cohort studies. Journal of hypertension. 2019;37(12):2325-32. Bawazier LA, Sja'bani M, Irijanto F, Zulaela Z, Widiatmoko A, Kholiq A, et al. Association of serum uric acid, morning home blood pressure and cardiovascular risk factors in a population with previous prehypertension: a cross-sectional study. BMJ open. 2020;10(9):e038046. Egan BM, Stevens-Fabry S. Prehypertension—prevalence, health risks, and management strategies. Nature Reviews Cardiology. 2015;12(5):289. Russell LB, Valiyeva E, Carson JL. Effects of prehypertension on admissions and deaths: a simulation. Archives of Internal Medicine. 2004;164(19):2119-24. Materson BJ, Garcia-Estrada M, Degraff SB, Preston RA. Prehypertension is real and can be associated with target organ damage. J Am Soc Hypertens. 2017;11(11):704-8. Qureshi AI, Suri MFK, Kirmani JF, Divani AA, Mohammad Y. Is Prehypertension a Risk Factor for Cardiovascular Diseases? Stroke. 2005;36(9):1859-63. Duan W, Wu J, Liu S, Jiao Y, Zheng L, Sun Y, et al. Impact of Prehypertension on the Risk of Major Adverse Cardiovascular Events in a Chinese Rural Cohort. American Journal of Hypertension. 2020;33(5):465-70. Attar A, Nouri F, Borazjani R, Sayadi M. J-shaped relationship between cardiovascular risk and efficacy of intensive blood pressure reduction: A post hoc analysis of the SPRINT trial. PLoS One. 2020;15(10):e0240102. Zhong B. How to calculate sample size in randomized controlled trial? J Thorac Dis. 2009;1(1):51-4. Association WM. World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. JAMA. 2013;310(20):2191-4. Soni D, Singh K, Ambalam C, Vamadevan A, Kinra S, Singh K, et al. A16184 Clinical profile of acute myocardial infarction patients with and without hypertension. Journal of Hypertension. 2018;36:e229-e30. Zhang Y, Lee ET, Devereux RB, Yeh J, Best LG, Fabsitz RR, et al. Prehypertension, diabetes, and cardiovascular disease risk in a population-based sample: the Strong Heart Study. Hypertension. 2006;47(3):410-4. Ren Y, Zuo Y, Wang A, Chen S, Tian X, Li H, et al. Diabetes modifies the association of prehypertension with cardiovascular disease and all‐cause mortality. The Journal of Clinical Hypertension. 2021. Iellamo F, Werdan K, Narkiewicz K, Rosano G, Volterrani M. Practical applications for single pill combinations in the cardiovascular continuum. Cardiac failure review. 2017;3(1):40. Shao L, Chan P, Tomlinson B, Zhang Y, Liu Z-M. Single-pill combinations for hypertension: first line treatment for all? Current Medical Research and Opinion. 2019;35(1):113-5. Dézsi CA, Glezer M, Karpov Y, Brzozowska-Villatte R, Farsang C. Effectiveness of Perindopril/Indapamide Single-Pill Combination in Uncontrolled Patients with Hypertension: A Pooled Analysis of the FORTISSIMO, FORSAGE, ACES and PICASSO Observational Studies. Advances in Therapy. 2021;38(1):479-94. Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension: 2. Effects at different baseline and achieved blood pressure levels--overview and meta-analyses of randomized trials. J Hypertens. 2014;32(12):2296-304. Formula 1 Formula 1 is available in the Supplementary Files section. Supplementary Files Formula1.jpg Formula1. The formula used for sample size determination of PRINT-TAHA9 trial. N= size per group; p= the response rate of the standard treatment group; p0= the response rate of the treatment group; zx= the standard normal deviate for a one-sided x; d= the real difference between two treatment effect; δ0= a clinically acceptable margin HumanSubjectsResearchChecklist.docx PRINTTAHA9SPIRITchecklist.doc appendix1.docx appendix2.pdf Cite Share Download PDF Status: Published Journal Publication published 26 Aug, 2024 Read the published version in Trials → Version 1 posted Editorial decision: Major revision 09 Jul, 2024 Reviewers agreed at journal 28 May, 2024 Reviewers invited by journal 27 May, 2024 Editor assigned by journal 23 May, 2024 First submitted to journal 10 May, 2024 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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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4375541","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":307418342,"identity":"407faa0f-056b-4400-918a-3b6230032b2d","order_by":0,"name":"Armin Attar","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3UlEQVRIiWNgGAWjYFADZgbGBwwMB4hQycYM18JsQKIWIFOCKC388/sPfq5gsMvXbec9Vs1Tc0eOn4H54aMbeLRIHGNmljzDkGy57TBf2m2eY8+MJRvYjI1z8FlzjJlBsgHoDbPDPGa3edgOJ244wMMmjU+LPNCWnw0M9WAtxTz/iNBicIyZDWjLYbAWZt42IrQYHks2s2xgOA7SYiw5t++wsWQzAb/IHT74+GYDQ7WB2fkzhh/efDssx8/e/PAxXu+DAOM/CM3EAyKZ8SnF0PqDFNWjYBSMglEwYgAAqTZE/CDPaPUAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-4133-4870","institution":"Shiraz University of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Armin","middleName":"","lastName":"Attar","suffix":""},{"id":307418343,"identity":"c5b41c60-e042-4b38-9e8b-04160d06c551","order_by":1,"name":"Seyed Alireza Mirhosseini","email":"","orcid":"","institution":"Shiraz University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Seyed","middleName":"Alireza","lastName":"Mirhosseini","suffix":""},{"id":307418344,"identity":"054f63af-c6f4-432c-9535-7cb1c524778f","order_by":2,"name":"Roham Borazjani","email":"","orcid":"","institution":"Shiraz University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Roham","middleName":"","lastName":"Borazjani","suffix":""},{"id":307418345,"identity":"d84de3d0-1aac-4735-84c7-98bbb46eff57","order_by":3,"name":"Mehrab Sayadi","email":"","orcid":"","institution":"Shiraz University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Mehrab","middleName":"","lastName":"Sayadi","suffix":""},{"id":307418346,"identity":"fbbe7a97-5d8b-4747-9b9b-66c1ad7d2295","order_by":4,"name":"Mahsa Ahadi","email":"","orcid":"","institution":"Shiraz University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Mahsa","middleName":"","lastName":"Ahadi","suffix":""},{"id":307418347,"identity":"bd8866d6-69f2-4c42-bd2b-903441d4892c","order_by":5,"name":"MohammadJavad Zibaeenezhad","email":"","orcid":"","institution":"Shiraz University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"MohammadJavad","middleName":"","lastName":"Zibaeenezhad","suffix":""},{"id":307418348,"identity":"feb2fa3e-e84d-47f1-aada-107e54374564","order_by":6,"name":"Iman Razeghian-Jahromi","email":"","orcid":"","institution":"Shiraz University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Iman","middleName":"","lastName":"Razeghian-Jahromi","suffix":""},{"id":307418349,"identity":"03bd57c0-96f7-4a19-894b-4a8e84c371d9","order_by":7,"name":"Nader Parsa","email":"","orcid":"","institution":"Shiraz University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Nader","middleName":"","lastName":"Parsa","suffix":""}],"badges":[],"createdAt":"2024-05-06 09:01:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4375541/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4375541/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-024-08420-2","type":"published","date":"2024-08-26T15:57:13+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":58170168,"identity":"7e48d351-85aa-44ab-a2c3-80235ff6d274","added_by":"auto","created_at":"2024-06-12 03:37:25","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":102985,"visible":true,"origin":"","legend":"\u003cp\u003eSPIRIT schedule of study timeline; PRINT-TAHA9 Trial\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e**\u003c/sup\u003e The treatment group receives Amlodipine/Valsartan (5/80 mg daily, Valzomix®, Abidi Pharmaceutical Company) and follows a low-salt, low-fat diet for 36 months to maintain SBP below 130/80 mmHg. The control group adheres to a similar diet but receives antihypertensive medication only if SBP exceeds 140/90 mmHg, following the same protocol.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e*\u003c/sup\u003e Eligibility Criteria: Adults aged 18+ with no diabetes or undisclosed cardiovascular conditions, baseline SBP of 130-140 mmHg, DBP \u0026lt; 90 mmHg, and a 10-year ASCVD risk ≥ 7.5%. Exclusions: History of DM, CVA, HF, IHD, or use of statins, antiplatelets, and antihypertensives for other conditions.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4375541/v1/4551cabe327e0671fa6de27a.jpg"},{"id":58170172,"identity":"088ff2a5-1ecf-4632-b88d-c6b328331cd5","added_by":"auto","created_at":"2024-06-12 03:37:25","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":81845,"visible":true,"origin":"","legend":"\u003cp\u003eSPIRIT flowchart of the study. OBP, Office Blood Pressure; SBP, Systolic Blood Pressure; Val/Aml, Valsartan-Amlodipine as a single-pill combination.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4375541/v1/44d05315171cb54ef1db0e16.jpg"},{"id":63820837,"identity":"f74b200b-ca42-417e-ae8b-8fcb4410871c","added_by":"auto","created_at":"2024-09-02 16:09:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":877716,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4375541/v1/ceb46094-6676-4779-993a-fc076059318b.pdf"},{"id":58170167,"identity":"fc994146-0d7f-4b44-baf6-9c0ed280694d","added_by":"auto","created_at":"2024-06-12 03:37:25","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":11304,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFormula1.\u003c/strong\u003e The formula used for sample size determination of PRINT-TAHA9 trial.\u003c/p\u003e\n\u003cp\u003eN= size per group; p= the response rate of the standard treatment group; p0= the response rate of the treatment group; zx= the standard normal deviate for a one-sided x; d= the real difference between two treatment effect; δ0= a clinically acceptable margin\u003c/p\u003e","description":"","filename":"Formula1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4375541/v1/1a6363e07bea74b4e7071094.jpg"},{"id":58170169,"identity":"2c372484-6dce-4433-870a-a0a6acb95109","added_by":"auto","created_at":"2024-06-12 03:37:25","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":27288,"visible":true,"origin":"","legend":"","description":"","filename":"HumanSubjectsResearchChecklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-4375541/v1/152271ccdbf9531a508a69e0.docx"},{"id":58170171,"identity":"02c7b9ed-67d7-4481-9ad3-1f59565281d5","added_by":"auto","created_at":"2024-06-12 03:37:25","extension":"doc","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":124416,"visible":true,"origin":"","legend":"","description":"","filename":"PRINTTAHA9SPIRITchecklist.doc","url":"https://assets-eu.researchsquare.com/files/rs-4375541/v1/b73b5792e4d44b4f496deedf.doc"},{"id":58171339,"identity":"644722b4-2cd4-40c8-a827-6c3baf5e1522","added_by":"auto","created_at":"2024-06-12 03:45:25","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":18057,"visible":true,"origin":"","legend":"","description":"","filename":"appendix1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4375541/v1/12daa20dab7ca4e70e1ba01c.docx"},{"id":58170173,"identity":"ff2cebef-0313-4a32-9b63-e76927217a5b","added_by":"auto","created_at":"2024-06-12 03:37:25","extension":"pdf","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":396981,"visible":true,"origin":"","legend":"","description":"","filename":"appendix2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4375541/v1/54aab6f9a96a229fd269addd.pdf"}],"financialInterests":"","formattedTitle":"Design and Rationale for a Randomized, Open-Label, Parallel Clinical Trial Evaluating Major Cardiovascular Events (Pharmacological Treatment Versus Diet Control) in Patients with High-Normal Blood Pressure: The PRINT-TAHA9 Trial","fulltext":[{"header":"Introduction","content":"\n\u003ch3\u003eBackground and rationale\u003c/h3\u003e\n\u003cp\u003eExploring the exact border between normotension and hypertension shows that their actual cutoff values and definitions have always been a subject of dispute. In 2017, the AHA identified hypertension as having a systolic blood pressure (SBP)\u0026thinsp;\u0026ge;\u0026thinsp;130 mmHg or a diastolic blood pressure (DBP)\u0026thinsp;\u0026ge;\u0026thinsp;80 mmHg. (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). A year later, the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH) raised the hypertension threshold by 10 mmHg compared to the prior year's standard (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Notably, any blood pressure between the optimal and the hypertensive values were interpreted as \u0026ldquo;high-normal blood pressure\u0026rdquo; and \u0026ldquo;elevated blood pressure\u0026rdquo; by the ESC/ESH and AHA, respectively. In 2023, the ESC/ESH guidelines recommended antihypertensive drug initiation for patients with high-normal blood pressure and previous cerebrovascular disease (CVD), especially coronary artery disease (CAD) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Nevertheless, according to the ACC/AHA, patients with an SBP between 130 and 140 mmHg should receive pharmacological intervention if their 10-year atherosclerotic cardiovascular risk (ASCVD) is above 10% (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Although this recommendation is supported by some secondary analyses of large clinical trials (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), there is a lack of direct evidence evaluating this recommendation, and consequently, this decision has been criticized by some experts (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Despite these criticisms, some other investigators claim that there are sufficient data to support this recommendation (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThere is solid evidence available on the association between elevated blood pressure, other cardiovascular risk factors, and hypertension progression. However, the direct effect of high-normal blood pressure on long-term major cardiovascular events (such as any type of acute coronary syndromes (ACS) or heart failure) and whether to treat it remain unclear (\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). \u003cem\u003eRussel\u003c/em\u003e et al. reported that prehypertension is associated with approximately 3.4% of hospitalizations and 9.1% of cardiovascular-related deaths while increasing the risk of end-stage renal disease (ESRD) development (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Moreover, prehypertension associated with other predisposing conditions, such as obesity, smoking, and diabetes, is believed to be a major risk factor for cardiovascular events (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eNotably, the exact relationship between prehypertension and major adverse cardiovascular events (MACE) has not been thoroughly evaluated; Qureshi et al. reported a clear association between prehypertension and ACS (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Additionally, a recently published cohort study in China reported a greater risk for MACEs and stroke incidence, suggesting early identification of high-risk individuals (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eConsidering the importance of prehypertension (high-normal blood pressure) on cardiovascular outcomes and the controversies in the field, we designed a study on the prevention of major cardiovascular events involving intensive blood pressure reduction in patients with high-normal blood pressure at the \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eT\u003c/span\u003eraditional and \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eA\u003c/span\u003edvanced \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eH\u003c/span\u003eeart \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eA\u003c/span\u003epproaches Clinical Center, trial \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003e9\u003c/span\u003e. (PRINT-TAHA9 trial). This trial aimed to evaluate the hypothesis that pharmacologically reducing SBP in patients with an SBP between 130 and 140 mmHg would reduce major cardiovascular events. This hypothesis is based on our previous study, a post hoc analysis of the Systolic Blood Pressure Intervention Trial (SPRINT), which revealed that prehypertensive patients might benefit from antihypertensive treatment, which cannot be confidently recommended because it was not exclusively designed and randomized for this specific population (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Furthermore, based on our other analysis, we chose to enroll patients with an ASCVD risk above 7.5% instead of 10% (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e"},{"header":"Objectives","content":"\u003cp\u003eThis trial focused on assessing the effects of intensive blood pressure control in subjects with high-normal blood pressure and an ASCVD risk score of 7.5% or higher.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and setting\u003c/h2\u003e \u003cp\u003eThis investigation is a unicentric, randomized, superiority, open-label, placebo-controlled, parallel clinical trial. MACE will be compared between two groups with high-normal blood pressure, defined as an office SBP of 130\u0026ndash;140 mmHg and DBP of 80\u0026ndash;90 mmHg, measured at the Imam Reza Cardiovascular Clinic in Shiraz, Iran. The study's design adheres to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStudy participants and eligibility criteria\u003c/h2\u003e \u003cp\u003eThe study will enroll adults aged 18 years and older without diabetes or any underlying cardiovascular conditions who had a baseline SBP of 130\u0026ndash;140 mmHg and DBP under 90 mmHg, as well as a 10-year ASCVD risk of 7.5% or greater. The exclusion criteria included a history of diabetes mellitus (DM), cerebrovascular accident (CVA), heart failure, ischemic heart disease (IHD), or the use of statins, antiplatelet agents, or antihypertensive agents for other conditions.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eIntervention\u003c/h2\u003e \u003cp\u003eIn addition to obtaining blood and urine specimens for initial biochemical and hematological analyses, skilled nurses will collect medical histories and baseline data. Blood samples will be analyzed at the local health service laboratory following standard procedures. Following the initial screening, candidates who are deemed potentially eligible will undergo further evaluation to identify possible secondary hypertension. Blood samples will be collected for complete blood count (CBC), thyroid function test (TFT), blood urea nitrogen (BUN), and creatinine (Cr) analyses, along with measurements of serum sodium (Na), potassium (K), calcium (Ca), and phosphorus (Ph) levels. Subsequently, patients will be allocated to the treatment and control groups through permuted block randomization. The intervention group will be administered an antihypertensive regimen (amlodipine/valsartan at an initial dose of 5/80 mg; Valzomix\u0026reg;, Abidi Pharmaceutical Company, Tehran, Iran) taken daily for 36 months, along with a low-salt, low-fat diet aimed at maintaining SBP below 130/80 mmHg. Conversely, the control group will follow a similar diet but will recieve antihypertensive medication only if their SBP exceeds 140/90 mmHg during the diet phase, following the same medication protocol.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eAdherence\u003c/h2\u003e \u003cp\u003eIndividuals will be provided with a comprehensive set of information about the importance and necessity of routine drug consumption and attending scheduled visits while providing informed consent. At each visit, patients will receive a complete set of checkups, and their compliance will be assessed via returned tablet counts.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eConcomitant Care\u003c/h2\u003e \u003cp\u003eParticipants will undergo follow-up at one, three, six, twelve, eighteen, twenty-four, thirty, and thirty-six months. At each visit, SBP and DBP will be measured following a standardized protocol. Uncontrolled blood pressure (defined as a blood pressure greater than 130/80 mmHg in the intervention group and 140/90 mmHg in the control group) in any of the further visits will be managed by gradual increases in the antihypertensive medication dosage (such as amlodipine/valsartan 5/160 mg, 10/160 mg, and finally adding indapamide 1.5 mg (step-up approach)). If the SBP drops below 100 mmHg at one visit or below 110 mmHg at two consecutive visits, the dosage decreases (through a step-down approach), as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes\u003c/h2\u003e \u003cp\u003eThe primary endpoints of this study are the incidence of any major adverese cardiovascular outcomes as a composite of cardiac death, acute coronary syndrome (ACS), stroke (CVA), and hospitalization due to cardiovascular causes including heart failure, arrhythmia, anigina pectoris, or percutaneous coronary intervention (PCI).\u003c/p\u003e \u003cp\u003eAn independent expert will assess all measurements to ensure their accuracy. In the case of poor recordings, the expert chose whether the measurement was of adequate quality to be used for endpoint assessment. Measurements of inadequate quality will not be used in the analysis as missing measurements. Emerging MACEs will be evaluated by an independent Safety Committee. All laboratory data and adjudications will be finalized and archived in the computer database prior to the unbinding process.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eParticipant timeline\u003c/h2\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e2\u003c/span\u003e, participants will follow a comprehensive timeline from enrollment through various follow-up stages to evaluate the effect of intensive blood pressure management in individuals with high-normal blood pressure. Initially, potential participants will be screened for eligibility and, upon meeting the criteria, will be enrolled and randomized to receive either the intervention or control treatment. Baseline assessments included medical history, baseline variables, and blood and urine samples for biochemistry and hematologic tests. Follow-up visits at 1, 3, 6, 12, 18, 24, 30, and 36 months postenrollment involve monitoring SBP and DBP, checking medication adherence through returned tablet counts, and recording any adverse events. The intervention may be adjusted based on blood pressure control at these visits. This study aimed to assess the primary outcome of major cardiovascular events with a comprehensive approach to participant management and data collection.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSample size\u003c/h2\u003e \u003cp\u003eThis study is a superior clinical trial that aimed to detect a difference between the anticipated 3% incidence of MACEs in the intervention group and the 6% incidence in the control group based on our previous study (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Given a predetermined significance level (alpha) of 5% coupled with a desired study power of 80% (1-beta) and considering an acceptable clinical difference margin set at 50% of the projected difference, adjustments were made to account for an estimated dropout rate of 10%. By utilizing Formula 1 (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) for these calculations, it is determined that each arm of the study requires an estimated sample size of approximately 730 participants to achieve the outlined objectives. A total of 1620 participants accounted for potential dropouts and nonadherence at a conservative rate, ensuring comprehensive data collection and analysis. Enrolling the required sample size at one site may present challenges; therefore, we decided to conduct the study in five phases, beginning with the recruitment of 300 patients in phase 1 and pursuing national or international collaborations to complete the remaining phases.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eRecruitment\u003c/h2\u003e \u003cp\u003eThe selection of the Imam-Reza Clinic for our study is strategically justified by its high patient volume, status as a key referral center for comprehensive patient management, and proactive engagement in blood pressure screening campaigns, which are integral to our research focus. The clinic's economic accessibility, through low consultation fees and broad insurance coverage, ensures inclusivity, enabling participation from diverse socioeconomic backgrounds. Furthermore, our initiative to educate potential participants at the clinic leverages its robust patient education framework, enhancing recruitment efforts and reinforcing the clinic's pivotal role in promoting cardiovascular health. Collectively, these attributes make the Imam-Reza Clinic an ideal setting for our study, providing a rich data pool and facilitating impactful research on blood pressure management.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eRandomization method (sequence generation and concealment mechanism)\u003c/h2\u003e \u003cp\u003eThe randomization method for the study will employ permuted block randomization. This approach involves assigning various sequences to numbers 1 through 6 to create blocks, specifically: 1. AABB, 2. ABAB, 3. ABBA, 4. BBAA, 5. BABA, and 6.BAAB. In these sequences, 'A' represents patients allocated to the treatment group, while 'B' denotes those in the control group. We will select block numbers using a random numbers table, continuing until 36 blocks of four-letter sequences have been chosen. This method ensures balanced allocation of participants across the two study groups.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eImplementation\u003c/h2\u003e \u003cp\u003ePatients who provide informed consent and meet the eligibility requirements will be subjected to randomization. The well-trained nursing staff, who are in charge of recruitment and conducting clinical interviews at the Imam-Reza Clinic, will initiate the randomization request.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eBlinding\u003c/h2\u003e \u003cp\u003eAs an open-label trial, participants and physicians responsible for follow-up visits will not be blinded. The outcome assessors and data analyzist are blinded in this study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eData collection methods\u003c/h2\u003e \u003cp\u003eDuring the baseline visit, all patient information and data will be recorded and securely archived at the Imam-Reza Clinic. At each follow-up visit, a blinded staff member (a well-trained nurse) will interview the patient and record the follow-up (outcome) data. Subsequently, the patient will be examined by a physician who is not blinded to the treatment allocation. All documents and records will be securely archived.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eData management\u003c/h2\u003e \u003cp\u003e Our study adheres to SPIRIT Statement guidelines, employing a detailed data management approach to safeguard data integrity, confidentiality, and accuracy. We utilized standardized data collection methods and a secure, electronic database at Imam-Reza Clinic, managed by a specialized team that ensures data quality through regular audits and data cleaning. Access is strictly controlled, with advanced security measures such as encryption and backups to prevent unauthorized access. An independent committee conducts periodic data monitoring for safety and integrity. Following ethical and regulatory standards, data analysis will be carried out as per a predefined plan, ensuring transparent and reproducible reporting of findings, thereby maintaining research excellence and protecting participant privacy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eData analysis will be conducted using the Statistical Package for Social Sciences (SPSS), version 20.0 (SPSS Inc., Chicago, IL, USA). Quantitative data are presented as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD), and categorical data are presented as frequencies and percentages. For quantitative comparisons, either the independent t test or Mann‒Whitney U test will be utilized. Cox regression analysis was used to determine the specific impact of antihypertensive treatment on cardiovascular events, and a P value\u0026thinsp;\u0026le;\u0026thinsp;0.05 will be considered to indicate statistical significance. Participants who did not complete the follow-up were censored at their last known contact. The analysis will primarily focus on the intention-to-treat population to test the primary hypothesis aimed at proving superiority.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eAdditional analysis\u003c/h2\u003e \u003cp\u003eSubgroup analysis will be performed, focusing on factors of clinical significance such as age, sex, existing health conditions, and additional indicators of risk. For all hypothesis testing, a two-sided approach will be adopted, with the significance level set at 5%.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eAnalysis Population and Missing Data\u003c/h2\u003e \u003cp\u003eIn our study, the primary analysis focusing on the endpoints will proceed without adjustments for covariates, and we will not employ imputation techniques for missing baseline variable values. Patients who are lost to follow-up will be censored at the last known point of contact and considered not to have reached the primary endpoint in the calculation of Kaplan\u0026ndash;Meier event rates. This approach ensures a straightforward and transparent analysis of the data, reflecting the true nature of the study's outcomes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eData monitoring, harms, and auditing\u003c/h2\u003e \u003cp\u003eBefore the statistical analysis is initiated, a cardiology department expert, external to our research team, will critically assess and approve all the data measurements. Measurements that fail to adhere to the requisite quality standards will be excluded and considered missing for analytical purposes. Moreover, a neutral safety committee, unaware of participant treatment allocations, will evaluate the occurrence of significant MACE. Upon the completion of this adjudication stage, the database will be unlocked for analysis. Communication regarding any adverse incidents will be directed to an autonomous Data, Safety, and Monitoring Board (DSMB) by the study's executive committee. The DSMB, acting independently, has the authority to terminate the trial early if there are concerns over patient safety or the achievement of primary study objectives, applying strict statistical criteria for such decisions. Regular monitoring of safety data, including unexpected serious adverse events, mortality, procedural complications, and severe arrhythmias, among others, will be a DSMB responsibility, with quarterly safety reports generated for review. Additionally, all deaths will be promptly communicated to the DSMB, which also undertakes bimonthly audits, functioning independently from the study researchers.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eEthical considerations\u003c/h2\u003e \u003cp\u003eThis survey was conducted in compliance with the Declaration of Helsinki (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) and received ethics approval from the Institutional Review Board and Ethics Committee of Shiraz University of Medical Sciences (SUMS) on October 2, 2019, under the approval number IR.SUMS.MED.REC.1398.420. The study has been registered with the Iranian Registry of Clinical Trials at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.irct.ir\u003c/span\u003e\u003cspan address=\"https://www.irct.ir\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e under the trial identifier IRCT20191002044961N1. Furthermore, all participants were required to provide informed consent, a process facilitated by experienced nurses or clinical staff.\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eProtocol amendments\u003c/h2\u003e \u003cp\u003eIn our research, any changes to the protocol that might affect the conduct of the study, potential patient benefits, or patient safety will require a formal amendment to the protocol. This encompasses alterations in the study objectives, methodology, participant characteristics, sample sizes, study procedures, or significant administrative adjustments. Prior endorsement from the Ethics Committee/Institutional Review Board (IRB) of Shiraz University of Medical Sciences is mandatory for these amendments to uphold ethical guidelines and safeguard participant well-being.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003eConsent and assent\u003c/h2\u003e \u003cp\u003eThe process of obtaining consent or assent involves the staff introducing the trial to potential participants and providing them with detailed information sheets for thorough understanding. Following this, patients will engage in informed discussions with the consulting specialist. Written consent will then be acquired from those patients who decide to participate in the trial by a trained general practitioner. There will be no ancillary studies conducted using data collected from this trial, ensuring that all participant information is solely used for the intended research purposes as outlined in the study protocol.\u003c/p\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003eConfidentiality\u003c/h2\u003e \u003cp\u003eParticipant information will be safeguarded in locked file cabinets situated in restricted-access areas. To preserve confidentiality, laboratory samples, reports, data collection sheets, processing, and administrative documents will be tagged with a coded ID rather than personal identifiers. Records containing personal identifiers, such as locator forms and consent documents, will be stored separately from those identified by code. Additionally, all local databases will be fortified with password-protected access systems, ensuring that data security and participant privacy are maintained throughout the study.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003e The latest ACC/AHA High Blood Pressure Guidelines no longer use the term \"prehypertension.\" Instead, they classify blood pressure as either elevated (120\u0026ndash;129/\u0026lt;80 mmHg) or hypertensive, diverging from previous guidelines that defined 140/90 mmHg as stage 1 hypertension\u0026mdash;now reclassified as stage 2 in the new guidelines. It further recommends addressing high blood pressure medically at an earlier threshold of 130/80 mmHg rather than the previous 140/90 mmHg standard (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA 2004 Epidemiologic Follow-up Study sought to assess the impact of prehypertension on hospital admissions and mortality rates. A total of 3.4% of hospitalizations, 6.5% of nursing home admissions, and 9.1% of deaths could be directly attributed to prehypertension. The study concluded that eliminating prehypertension could significantly decrease the rates of hospitalization, nursing home entry, and early death (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). A cross-sectional study in 2007 showed that after ten years, 31.1% of subjects with prehypertension became hypertensive (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). The progression of prehypertension to hypertension can increase the risk of cognitive function impairment, increased left ventricular mass, and end-stage renal disease and is also associated with arteriosclerosis. Therefore, it \"might\" be beneficial to treat prehypertension with antihypertensive medications in addition to lifestyle modifications (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Despite the apparent importance of this issue, it has not been exclusively addressed in a clinical trial before.\u003c/p\u003e \u003cp\u003ePrevious studies were conducted in the general population and did not stratify patients according to their comorbidities (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Therefore, the authors could not clearly determine whether the MACEs were directly the result of hypertension or other associated diseases, leading to selection bias. In this recent study, we excluded all diabetic patients and those with other comorbidities previously described in the \"Study Participants\" section and enrolled only nondiabetic prehypertensive adults to obtain more pure and specific results on this matter.\u003c/p\u003e \u003cp\u003eA post hoc secondary analysis of the SPRINT trial designed to determine the practical cutoff limit of cardiovascular risk for starting intensive blood pressure reduction showed a J-shaped relationship between intensive blood pressure control and 10-year Framingham cardiovascular risk levels at a cutoff limit of approximately\u0026thinsp;\u0026lt;\u0026thinsp;7% (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). In this trial, we decided to set this cutoff limit as an inclusion criterion rather than a 10-year risk of more than 10%, which was used in the SPRINT trial.\u003c/p\u003e \u003cp\u003e According to the latest hypertension guidelines of the ESC/ESH, the initiation of antihypertensive therapy with a two-drug combination might be recommended for high-risk individuals. In older patients (65\u0026ndash;80), the initiation of antihypertensive treatment with a two-drug combination, preferably a single-pill combination (SPC), is suggested (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Multiple studies have proven that the efficacy of SPCs is greater than that of noncombined medications, and SPCs have improved tolerability and safety profiles (\u003cspan additionalcitationids=\"CR22 CR23\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Several SPCs have been made worldwide, and the two most common SPCs available in Iran are amlodipine/valsartan and amlodipine/valsartan/hydrochlorothiazide as Triple SPC. Other SPCs are neither widely accessible nor inexpensive. Considering these points, we chose amlodipine/valsartan 5\u0026ndash;80 mg as the medication of choice in our study. Moreover, we did not use triple SPC to avoid hypotension and subsequent adverse events.\u003c/p\u003e \u003cp\u003eWe are aware that the two-year follow-up might be insufficient to detect the exact extent to which treatment could affect long-term major cardiovascular events. We aim to carry out a primary analysis after this time, and the decision on whether to end the trial will be made based on our primary analysis.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable dir=\"rtl\" border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"572\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"83.56643356643356%\"\u003e\n \u003cp dir=\"LTR\"\u003eSystolic Blood Pressure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.433566433566433%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eSBP:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"83.56643356643356%\"\u003e\n \u003cp dir=\"LTR\"\u003eDiastolic Blood Pressure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.433566433566433%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eDBP:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"83.56643356643356%\"\u003e\n \u003cp dir=\"LTR\"\u003eAmerican Heart Association\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.433566433566433%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eAHA:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"83.56643356643356%\"\u003e\n \u003cp dir=\"LTR\"\u003eMajor Adverse Cardiovascular Events\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.433566433566433%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eMACE:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"83.56643356643356%\"\u003e\n \u003cp dir=\"LTR\"\u003eSystolic Blood Pressure Intervention Trial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.433566433566433%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eSPRINT:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"83.56643356643356%\"\u003e\n \u003cp dir=\"LTR\"\u003eEuropean Society Of Cardiology and The European Society Of Hypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.433566433566433%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eESC/ESH:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"83.56643356643356%\"\u003e\n \u003cp dir=\"LTR\"\u003eAcute Coronary Syndromes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.433566433566433%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eACS:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"83.56643356643356%\"\u003e\n \u003cp dir=\"LTR\"\u003ePercutaneous Coronary Intervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.433566433566433%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003ePCI:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"83.56643356643356%\"\u003e\n \u003cp dir=\"LTR\"\u003eEnd-Stage Renal Disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.433566433566433%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eESRD:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"83.56643356643356%\"\u003e\n \u003cp dir=\"LTR\"\u003eDiabetes Mellitus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.433566433566433%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eDM:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"83.56643356643356%\"\u003e\n \u003cp dir=\"LTR\"\u003eAtherosclerosis Cardiovascular Disease Risk\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.433566433566433%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eASCVD:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"83.56643356643356%\"\u003e\n \u003cp dir=\"LTR\"\u003eIschemic Heart Diseases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.433566433566433%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eIHD:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"83.56643356643356%\"\u003e\n \u003cp dir=\"LTR\"\u003eCerebrovascular Accident\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.433566433566433%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eCVA:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"83.56643356643356%\"\u003e\n \u003cp dir=\"LTR\"\u003eComplete Blood Count\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.433566433566433%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eCBC:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"83.56643356643356%\"\u003e\n \u003cp dir=\"LTR\"\u003eThyroid Function Test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.433566433566433%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eTFT:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"83.56643356643356%\"\u003e\n \u003cp dir=\"LTR\"\u003eBlood Urea Nitrogen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.433566433566433%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eBUN:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"83.56643356643356%\"\u003e\n \u003cp dir=\"LTR\"\u003eCreatinine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.433566433566433%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eCr:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"83.56643356643356%\"\u003e\n \u003cp dir=\"LTR\"\u003eSingle-Pill Combination\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.433566433566433%\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eSPC:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eIssue Date:\u003c/strong\u003e 23 April 2024\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProtocol Amendment Number:\u0026nbsp;\u003c/strong\u003e0\u003cspan dir=\"RTL\"\u003e2\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor(s):\u0026nbsp;\u003c/strong\u003eAA; SAM; RB; MS; MA; MZ; IR; NP.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e No\u0026nbsp;specific funding is declared for this study until the issue date of this draft.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRoles and responsibilities\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eContributorship:\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eAA, RB, MA, MS, and SAM contributed to the development of the protocol, preparation of the proposal, and critical revisions. AA took the lead in conceptualizing the study design with the help of MZ, IR, and NP. All the authors agreed to bear responsibility and accountability for the entirety of the project.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSponsor Contact Information:\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSponsor And Funder:\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCommittees\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePrincipal Investigator and Research Physician:\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eAA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSteering\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003eCommittee\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;(SC):\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eAA, RB, MI, MS, and SAM.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTrial Management Committee (TMC):\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eAA and SAM.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eData, Safety, and Monitoring Board (DSMB):\u003c/em\u003e\u003c/strong\u003e MS and SAM.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eData Manager:\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eMS\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eand SAM.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eLead Investigators:\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eAA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAccess to data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOnly the TMC members have access to patient data and files.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAncillary and posttrial care\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eShiraz University of Medical Sciences will offer insurance coverage for any nonnegligent harm that participants might experience as a result of the study protocol. This insurance will encompass additional healthcare costs, compensation, or damage that is demonstrably linked to the study\u0026apos;s procedures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDissemination policy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTrial results\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe findings of the study will be promptly disseminated to the physicians involved in the study, those referring patients, the participants themselves, and the broader medical community to ensure timely access to the new insights gained.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthorship\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthorship will be discussed and determined in TMC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eReproducible research\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe full protocol of the study will be made publicly available as soon as possible.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAppendices:\u003c/strong\u003e Appendix 1 shows\u0026nbsp;the variables and components of\u0026nbsp;the\u0026nbsp;medical evaluation of\u0026nbsp;the\u0026nbsp;enrolled patients. Informed consent materials are presented in\u0026nbsp;appendix 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBiological specimens\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBlood samples were collected to conduct a comprehensive blood count (CBC), assess thyroid function (TFT), and measure the levels of blood urea nitrogen (BUN) and creatinine (Cr). Additionally, the serum levels of sodium (Na), potassium (K), calcium (Ca), and phosphorus (Ph) were evaluated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable of execution time-lines\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis document outlines protocol version number 02, finalized on April 23, 2024. The recruitment for phase 1 started in December 3 2019, following the trial registration on IRCT.ir, and concluded in February 2020. The follow-up for phase 1 has been completed. Recruitment for the subsequent phases is currently ongoing. As we seek national and international collaboration, we estimate that the recruitment will be completed by January 2026.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCarey RM, Whelton PK. Prevention, detection, evaluation, and management of high blood pressure in adults: synopsis of the 2017 American College of Cardiology/American Heart Association Hypertension Guideline. Annals of internal medicine. 2018;168(5):351-8.\u003c/li\u003e\n\u003cli\u003eWilliams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH). European heart journal. 2018;39(33):3021-104.\u003c/li\u003e\n\u003cli\u003eMancia G, Kreutz R, Brunstrom M, Burnier M, Grassi G, Januszewicz A, et al. 2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension: Endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA). J Hypertens. 2023;41(12):1874-2071.\u003c/li\u003e\n\u003cli\u003eAttar A, Sayadi M, Jannati M. Effect of intensive blood pressure lowering on cardiovascular outcomes based on cardiovascular risk: A secondary analysis of the SPRINT trial. Eur J Prev Cardiol. 2019;26(3):238-45.\u003c/li\u003e\n\u003cli\u003eBorazjani R, Kojuri J, Abdi-Ardekani A, Izadpanah P, Dehghani P, Sayadi M, et al. Pharmacological treatment of high-normal blood pressure (prehypertension) in high-risk patients for primary prevention of cardiovascular events. J Clin Hypertens (Greenwich). 2020;22(9):1627-34.\u003c/li\u003e\n\u003cli\u003eBakris G, Sorrentino M. Redefining Hypertension - Assessing the New Blood-Pressure Guidelines. N Engl J Med. 2018;378(6):497-9.\u003c/li\u003e\n\u003cli\u003eCarey RM, Whelton PK. Evidence for the Universal Blood Pressure Goal of \u0026lt;130/80 mm Hg Is Strong: Controversies in Hypertension - Pro Side of the Argument. Hypertension. 2020;76(5):1384-90.\u003c/li\u003e\n\u003cli\u003eHan M, Li Q, Liu L, Zhang D, Ren Y, Zhao Y, et al. Prehypertension and risk of cardiovascular diseases: a meta-analysis of 47 cohort studies. Journal of hypertension. 2019;37(12):2325-32.\u003c/li\u003e\n\u003cli\u003eBawazier LA, Sja\u0026apos;bani M, Irijanto F, Zulaela Z, Widiatmoko A, Kholiq A, et al. Association of serum uric acid, morning home blood pressure and cardiovascular risk factors in a population with previous prehypertension: a cross-sectional study. BMJ open. 2020;10(9):e038046.\u003c/li\u003e\n\u003cli\u003eEgan BM, Stevens-Fabry S. Prehypertension\u0026mdash;prevalence, health risks, and management strategies. Nature Reviews Cardiology. 2015;12(5):289.\u003c/li\u003e\n\u003cli\u003eRussell LB, Valiyeva E, Carson JL. Effects of prehypertension on admissions and deaths: a simulation. Archives of Internal Medicine. 2004;164(19):2119-24.\u003c/li\u003e\n\u003cli\u003eMaterson BJ, Garcia-Estrada M, Degraff SB, Preston RA. Prehypertension is real and can be associated with target organ damage. J Am Soc Hypertens. 2017;11(11):704-8.\u003c/li\u003e\n\u003cli\u003eQureshi AI, Suri MFK, Kirmani JF, Divani AA, Mohammad Y. Is Prehypertension a Risk Factor for Cardiovascular Diseases? Stroke. 2005;36(9):1859-63.\u003c/li\u003e\n\u003cli\u003eDuan W, Wu J, Liu S, Jiao Y, Zheng L, Sun Y, et al. Impact of Prehypertension on the Risk of Major Adverse Cardiovascular Events in a Chinese Rural Cohort. American Journal of Hypertension. 2020;33(5):465-70.\u003c/li\u003e\n\u003cli\u003eAttar A, Nouri F, Borazjani R, Sayadi M. J-shaped relationship between cardiovascular risk and efficacy of intensive blood pressure reduction: A post hoc analysis of the SPRINT trial. PLoS One. 2020;15(10):e0240102.\u003c/li\u003e\n\u003cli\u003eZhong B. How to calculate sample size in randomized controlled trial? J Thorac Dis. 2009;1(1):51-4.\u003c/li\u003e\n\u003cli\u003eAssociation WM. World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. JAMA. 2013;310(20):2191-4.\u003c/li\u003e\n\u003cli\u003eSoni D, Singh K, Ambalam C, Vamadevan A, Kinra S, Singh K, et al. A16184 Clinical profile of acute myocardial infarction patients with and without hypertension. Journal of Hypertension. 2018;36:e229-e30.\u003c/li\u003e\n\u003cli\u003eZhang Y, Lee ET, Devereux RB, Yeh J, Best LG, Fabsitz RR, et al. Prehypertension, diabetes, and cardiovascular disease risk in a population-based sample: the Strong Heart Study. Hypertension. 2006;47(3):410-4.\u003c/li\u003e\n\u003cli\u003eRen Y, Zuo Y, Wang A, Chen S, Tian X, Li H, et al. Diabetes modifies the association of prehypertension with cardiovascular disease and all‐cause mortality. The Journal of Clinical Hypertension. 2021.\u003c/li\u003e\n\u003cli\u003eIellamo F, Werdan K, Narkiewicz K, Rosano G, Volterrani M. Practical applications for single pill combinations in the cardiovascular continuum. Cardiac failure review. 2017;3(1):40.\u003c/li\u003e\n\u003cli\u003eShao L, Chan P, Tomlinson B, Zhang Y, Liu Z-M. Single-pill combinations for hypertension: first line treatment for all? Current Medical Research and Opinion. 2019;35(1):113-5.\u003c/li\u003e\n\u003cli\u003eD\u0026eacute;zsi CA, Glezer M, Karpov Y, Brzozowska-Villatte R, Farsang C. Effectiveness of Perindopril/Indapamide Single-Pill Combination in Uncontrolled Patients with Hypertension: A Pooled Analysis of the FORTISSIMO, FORSAGE, ACES and PICASSO Observational Studies. Advances in Therapy. 2021;38(1):479-94.\u003c/li\u003e\n\u003cli\u003eThomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension: 2. Effects at different baseline and achieved blood pressure levels--overview and meta-analyses of randomized trials. J Hypertens. 2014;32(12):2296-304.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Formula 1","content":"\u003cp\u003eFormula 1 is available in the Supplementary Files section.\u003c/p\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":"[email protected]","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":"prehypertension, high-normal blood pressure, cardiovascular outcome, adverse events, major adverse cardiovascular events, intensive blood pressure control","lastPublishedDoi":"10.21203/rs.3.rs-4375541/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4375541/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe distinction between normal and high blood pressure remains a debated topic, with varying guidelines on when to start medication. Contemporary guidelines advocate for the initiation of antihypertensive therapy in individuals who present with high-normal blood pressure, particularly those exhibiting elevated 10-year atherosclerotic cardiovascular disease (ASCVD) risk scores. Despite these recommendations, there is a notable lack of direct evidence supporting the efficacy of treating high-normal blood pressure to prevent major cardiovascular events (MACE).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe PRINT-TAHA9 trial, which is a unicentric, randomized, open-label, placebo-controlled, parallel clinical study, seeks to explore the effects of intensive blood pressure control on MACE in participants with high-normal blood pressure. We will enroll 1620 adults aged 18 years and above with a systolic blood pressure range of 130-140 mmHg, diastolic blood pressure under 90 mmHg, and atherosclerotic cardiovascular disease (ASCVD) risk score exceeding 7.5%. The study will be executed in five distinct phases, with each phase enrolling between 300 and 400 participants. Participants will be randomly allocated to either the treatment group receiving antihypertensive medication (amlodipine/valsartan) and a low-salt/low-fat diet or to the control group receiving a similar diet. Follow-up visits are scheduled every six months over a three-year period to monitor blood pressure, evaluate medication adherence, document any adverse events, and adjust the intervention as necessary. Cox proportional hazards regression analysis will be employed to examine the disparities between the two arms. The study's design adheres to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eDiscussion\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e:\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe literature on managing high-normal blood pressure reveals a significant gap in medical understanding, especially regarding when to start pharmacological intervention. Despite guidelines advocating early treatment, the debate continues due to insufficient evidence that such interventions significantly reduce major cardiovascular events. This trial seeks to address this critical evidence gap.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u003c/strong\u003e: The PRINT-TAHA9 trial was registered in October 2019 with the Iranian Registry of Clinical Trials (IRCT.ir) under the registration number IRCT20191002044961N1. https://irct.behdasht.gov.ir/trial/43092\u003c/p\u003e","manuscriptTitle":"Design and Rationale for a Randomized, Open-Label, Parallel Clinical Trial Evaluating Major Cardiovascular Events (Pharmacological Treatment Versus Diet Control) in Patients with High-Normal Blood Pressure: The PRINT-TAHA9 Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-12 03:37:20","doi":"10.21203/rs.3.rs-4375541/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2024-07-09T16:12:45+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-05-28T15:51:18+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-05-27T21:21:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-23T06:38:30+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2024-05-10T13:27:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","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":"02167b38-c0a3-4643-8eac-77bb3b5df0be","owner":[],"postedDate":"June 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-09-02T16:00:18+00:00","versionOfRecord":{"articleIdentity":"rs-4375541","link":"https://doi.org/10.1186/s13063-024-08420-2","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2024-08-26 15:57:13","publishedOnDateReadable":"August 26th, 2024"},"versionCreatedAt":"2024-06-12 03:37:20","video":"","vorDoi":"10.1186/s13063-024-08420-2","vorDoiUrl":"https://doi.org/10.1186/s13063-024-08420-2","workflowStages":[]},"version":"v1","identity":"rs-4375541","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4375541","identity":"rs-4375541","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}