A multicentre phase III study comparing efficacy & safety of novel extended-release vs. conventional formulation of Dydrogesterone in Indian patients with endometriosis

A multicentre phase III study comparing efficacy & safety of novel extended-release vs. conventional formulation of Dydrogesterone in Indian patients with endometriosis | 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 A multicentre phase III study comparing efficacy & safety of novel extended-release vs. conventional formulation of Dydrogesterone in Indian patients with endometriosis Dr. T Sasikala, Dr Shikha Kushwaha, Dr Mukta Agarwal, Dr. Vandana Jain, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4121316/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose : To compare the efficacy and safety of novel once-daily extended-release (ER) dydrogesterone 20 mg versus conventional twice-daily dydrogesterone 10 mg in Indian patients with endometriosis Method: A phase III prospective, randomized, double-blind, single-dummy, two-arm, active-controlled, parallel, multicenter study was performed in six gynecology centers across India. The patients of 18 to 45 years of age with a confirmed diagnosis of endometriosis on ultrasonography (USG) and having endometriosis-associated pelvic pain score (EAPP) of at least 30mm on a 100 mm visual analog scale (VAS) were randomly assigned to a 1:1 ratio to either once-daily dydrogesterone ER 20 mg or twice-daily dydrogesterone 10 mg arms for a treatment period of 90 days. The primary outcome was a change from baseline in EAPP score at the end of the treatment. Results : A total of 288 patients with a mean age of 31.8 ± 6.9 years were enrolled in the study. At day 90, both the treatment arms showed a significant reduction (p<0.05) in EAPP score from baseline (i.e. –34.2 ± 15.3mm and –33.1 ± 14.8mm in once daily dydrogesterone ER and twice daily dydrogesterone 10 mg, respectively), with no significant difference between the two arms (p=0.53). With both formulations, patients experienced a significant reduction in the size of endometrioma, serum vascular endothelial growth factors (VEGF) levels, use of rescue analgesics, and significant improvement in the health-related quality-of-life parameters. A favorable safety profile of dydrogesterone was confirmed, and no significant safety concerns were reported during the study. Conclusion : Once daily dydrogesterone ER 20 mg and twice daily dydrogesterone 10 mg demonstrated a significant and similar reduction in EAPP and all other secondary parameters along with marked improvements in parameters related to quality of life. Registration Number: CTRI/2023/03/050698 Dydrogesterone endometriosis extended-release pelvic pain progesterone Figures Figure 1 Figure 2 What does this study add to the clinical work? Endometriosis significantly impacts the quality of life of the patients. Symptomatic relief remains the major focus when it comes to the management of endometriosis. This study evaluates the safety and the efficacy of the new formulation of Dydrogesterone 20mg extended-release formulation in managing the symptoms of endometriosis and further adding to the clinical options available for the medical treatment. Introduction Endometriosis is a chronic illness that impairs the quality of life of the patients.[ 1 ] According to estimates, between 2 and 10% of women who are of reproductive age and between 25 and 50% of women suffering from infertility have endometriosis.[ 2 , 3 ] It is estimated that endometriosis affects ~ 247 million girls and women globally and ~ 42 million girls and women in India.[ 4 ] Endometriosis patients often appear with one or more related symptoms, such as dysmenorrhea, profound dyspareunia, cyclical intestinal problems, fatigue/weariness, and infertility, while some may not exhibit any symptoms at all. [ 1 ] The symptoms of endometriosis gradually make it more difficult for women to do specific everyday tasks, which worsens their general health and well-being.[ 5 ] Furthermore, this condition may result in sexual dysfunction in 2–4% of sexually active women. [ 6 ] Lastly, symptoms associated with endometriosis significantly hinder afflicted women's ability to work, frequently leading to many lost workdays. [ 5 ] Symptomatic endometriosis remains the prime indication for treatment. Ideally, treatment should provide pain relief and allow pregnancy to occur safely while undergoing treatment. The current treatments for endometriosis include surgery (ablation using either laser or electrosurgery if laparoscopy is performed), pharmacological therapy, or a combination of both. Symptomatic patients always receive pharmacological therapy, which can include analgesics for women with endometriosis-related pain, hormonal treatments such as hormonal contraceptives, progestogens (e.g., progesterone), anti-progestogens (e.g., gestrinone), or gonadotropin-releasing hormone agonists (e.g., leuprolide) as it reduces endometriosis-associated pain or alternative treatments such as aromatase inhibitors (e.g., letrozole). [ 7 ] Dydrogesterone (6-dihydro-retroprogesterone) is a retroprogesterone derived from progesterone that is similar in structure and pharmacology to endogenous progesterone. It acts as a selective progesterone receptor agonist and has better oral bioavailability compared with oral micronized progesterone.[ 8 ] Dydrogesterone has been on the market since the 1960s and is used as postmenopausal hormone replacement as well as for the treatment of menstrual disorders and endometriosis.[ 9 ] As per the approved package insert of dydrogesterone, it has to be used in a dose of 10 mg to be taken two times daily for the management of endometriosis.[ 10 ] Taking these tablets two times in a day may lead to inconvenience and non-compliance, thus impacting the efficacy of the drug in real-world clinical practice. Taking this into consideration, an extended-release (ER), once-daily formulation of dydrogesterone 20 mg has been developed by M/s Zydus Healthcare Limited. This pre-licensure Phase III study was designed to evaluate the efficacy and safety of the new formulation of dydrogesterone Extended-Release Tablets 20mg for the treatment of endometriosis in women as compared to the dydrogesterone 10 mg twice daily. Materials & Method Study Design This was a prospective, randomized, double-blind, single-dummy, two-arm, active-controlled, parallel, multicenter, phase III clinical trial. The study was conducted in accordance with national Good Clinical Practice guidelines, all applicable national standards, and the Declaration of Helsinki. The study was approved by the institutional ethics committees of all the participating centers and registered in the clinical trials registry India (CTRI/2023/03/050698). All participants provided written informed consent prior to enrollment. Study Subjects The participants were female patients, 18–45 years of age, diagnosed with endometriosis based on ultrasonography, with an endometriosis pain score of at least 30mm on a 100mm visual analog scale. These patients were willing to give written informed consent and comply with the study procedures. The key exclusion criteria of the study were women who were pregnant, lactating, having childbearing potential unwilling to use effective barrier contraception, menopausal, having premature ovarian insufficiency, had undergone laparoscopic surgery for endometriosis in the last 6 months, had taken hormonal therapy in the last 6 months or oral contraceptives in the last 3 months, any other significant concomitant gynecological disorder or uncontrolled systemic diseases. Study Conduct At the end of 3 days of screening period, the eligible endometriosis patients were randomized to either of the two study groups; test arm received dydrogesterone Extended-Release 20mg tablet in the morning and a matching placebo for dydrogesterone 10 mg tablet in the evening, while patients in reference arm received dydrogesterone 10mg tablets twice daily for the total treatment duration of 90 days. Patients were also dispensed paracetamol 500mg tablets for use as rescue medication only. The patients were instructed to take one tablet of paracetamol in case of unbearable endometriosis-associated pelvic pain. A maximum of 4 tablets of paracetamol were allowed in a day. In case the patients still had unbearable pain, the patient was withdrawn from the study. Study Endpoints The primary endpoint was the change in EAPP from baseline to end of study i.e. at Day 90 as assessed on a 100mm VAS scale in the two groups. The secondary endpoints included the consumption of rescue pain medication and change from baseline in the health-related quality of life using the HRQoL-4 questionnaire (Table 1 ) in the two groups during the study period. The secondary endpoints also included the changes from baseline in the size of endometrioma as assessed by USG and serum VEGF levels at the end of the study. The safety was assessed based on the reported adverse events (AEs) throughout the study. Table 1 The HRQoL-4 questionnaire included the following four questions: 1. Health as self-assessed (Excellent 1; Very good 2; Good 3; Fair 4; Poor 5) 2. Number of days feeling physically unhealthy 3. Number of days feeling mentally unhealthy 4. Lost days (defined as days when work or other daily activities are not possible) Statistical Analysis: The sample size was calculated based on the primary endpoint of the study i.e., change from baseline in EAPP at the end of the study. At least 204 patients (Test: 102, Reference: 102) were required to achieve 90% power with 2.5% one-sided level of significance, considering a non-inferiority margin of 10 mm on VAS [ 11 ] and assuming no difference between the test and the reference groups in the change in EAPP from baseline and common standard deviation of 22. Considering a treatment allocation ratio of 1:1 and an attrition rate of 10%, 228 subjects are required to be enrolled in the study (Test: 114, Reference: 114). For efficacy analysis, both Per Protocol (PP) and modified Intention to Treat (mITT) analyses were planned. The PP population was comprised of all the randomized patients who had completed all the post-randomization visits as per the protocol including the patients with minor protocol deviations. The mITT population was comprised of all the randomized patients who had completed at least one post-randomization visit including the patients with major protocol deviations. The PP analysis was considered as the primary analysis while the mITT analysis was considered as the supportive analysis. The test drug was considered non-inferior to the reference drug if the upper bound of 95% confidence interval (CI) for the difference between the study groups (Test - Reference) for the change in EAPP from baseline to the end of the study was below the non-inferiority margin of 10 mm. From the safety perspective, all the randomized subjects who had used at least a single dose of the study drug were considered for the safety analysis. Results A total of 228 patients with confirmed diagnoses of endometriosis were evaluated for efficacy and safety. The baseline demographics and characteristics of the patients are mentioned in Table 2 . The flow of patients in the two study groups is shown in Fig. 1 . Table 2 Demographics and baseline characteristics of the patients Parameter Test group (N = 112) Reference group (N = 116) P value Age (years) 31.8 ± 6.9 (30.5 to 33.1) 32.0 ± 6.3 (30.8 to 33.1) 0.85 Height (cm) 159.2 ± 5.6 (158.2 to 160.2) 159.5 ± 6.0 158.3 to 160.6) 0.74 Weight (kg) 58.4 ± 6.9 (57.1 to 59.7) 58.8 ± 6.9 (57.5 to 60.0) 0.68 Body Mass Index (kg/m 2 ) 23.1 ± 2.9 (22.6 to 23.6) 23.2 ± 2.9 (22.7 to 23.7) 0.82 Data presented as mean ± SD (95% CI) P value calculated using unpaired T Test Primary Outcome After 90 days of treatment, the mean change in EAPP from baseline was − 34.2 ± 15.3mm (p < 0.05 vs baseline) in the test group and − 33.1 ± 14.8mm (p < 0.05 vs baseline) in the reference group. The difference between the two groups for the mean change in EAPP at Day 90 from baseline was statistically not significant (P = 0.53) [Table 3 ]. The upper limit of 95% CI for the difference between the test group and the reference group for the mean change in EAPP at day 90 from baseline was 2.8 mm which was well below the non-inferiority margin (10 mm). Hence, the test drug was found to be non-inferior to the reference drug for change in EAPP from baseline at the end of the study. Table 3 Change in EAPP from baseline to end of study VAS Score Test group (N = 110) Reference group (N = 111) P value* Day 0 (Baseline) 61.8 ± 10.0 (59.9 to 63.7) 61.8 ± 8.8 (60.1 to 63.5) 0.98 Day 30 50.8 ± 9.5 (49.0 to 52.6) 51.5 ± 9.1 (49.8 to 53.2) 0.55 Day 60 41.0 ± 11.2 (38.9 to 43.1) 41.7 ± 11.5 (39.5 to 43.8) 0.67 Day 90 (End of study) 27.5 ± 14.1 (24.9 to 30.2) 28.7 ± 14.3 (26.0 to 31.4) 0.53 Data presented as mean ± SD (95% CI) *P value calculated using unpaired T Test Secondary endpoints: During the last 30 days of the study period, there was a significant decrease in the use of rescue medication compared to the first 30 days of the study period in both the treatment arms (Fig. 2A) The patients in both arms experienced a significant decrease size of endometrioma (Fig. 2B), and serum VEGF (Fig. 2C) levels from baseline to the end of the study. Significant improvements were also observed in measures of HR-QoL, including perceived health status, mental health, pain, and physical, role, and social functioning in both arms at the end of the treatment (Fig. 2D). There were no significant differences observed between the two treatment groups in any of the secondary endpoints. The efficacy results mentioned above belonged to PP population. The results in mITT population were similar to that reported in PP population (data not shown). Safety During the study, a total of 14 AEs were reported in 14 (12.5%) patients in the test group, and 14 AEs were reported in 12 (10.3%) patients in the reference group [Table 4 ]. Two adverse events in the test group were moderate in severity, however, both were not related to the study medication. All the AEs in both the study groups resolved completely with or without treatment. There were no serious adverse event (SAE) reported during the study. Table 4 Adverse events reported in the study Preferred Term Test group (N = 112) Reference group (N = 116) P value* Headache 6 (5.4%) 1 (0.9%) 0.06 Weight gain 2 (1.8%) 0 (0.0%) 0.24 Back pain 2 (1.8%) 0 (0.0%) 0.24 Fever 1 (0.9%) 3 (2.6%) 0.62 Breast tenderness 1 (0.9%) 1 (0.9%) 1.0 Acidity 1 (0.9%) 0 (0.0%) 0.49 Dizziness 1 (0.9%) 0 (0.0%) 0.49 Nausea 0 (0.0%) 3 (2.6%) 0.25 Vomiting 0 (0.0%) 3 (2.6%) 0.25 Bloating 0 (0.0%) 1 (0.9%) 1.0 Cold 0 (0.0%) 1 (0.9%) 1.0 Myalgia 0 (0.0%) 1 (0.9%) 1.0 Data presented as n(%); % calculated from No. of subjects analyzed for safety *Fisher’s exact test (test group vs. reference group) Discussion Endometriosis is a condition that significantly affects HR-QoL and is linked to severe pain and morbidity. The objective of best-practice therapy is to control symptoms by avoiding recurrent surgical operations and making the most use of medical care through a personalized lifetime plan.[ 12 , 13 ] The difficulty in evaluating the efficacy of medical treatments for endometriosis and identifying specific patients' treatment options stems from the dearth of randomized controlled trials and the influence of the placebo effect, as noted in earlier research.[ 14 , 15 ] Progestogens are advised as the first line of treatment for persistent pelvic discomfort associated with endometriosis, along with analgesics and oral contraceptives.[ 12 , 13 , 14 ] The use of progestogens in this situation is supported by high-quality evidence; however, when deciding which therapy is best for a given patient, clinicians are supposed to take into account the various side-effect profiles, such as irregular bleeding, as well as irreversible effects, like thrombosis and androgenic effects.[ 13 , 17 , 18 ] Limited and low-to-moderate quality data supports other treatment alternatives, such as the use of combination oral contraceptives, which are also thought to be the first-line treatment for endometriosis pain-associated symptoms. [ 12 , 19 ] Additionally, there is insufficient data to support the use of some pharmaceutical treatments that are suggested as second-line therapies, such as aromatase inhibitors and gonadotropin-releasing hormone agonists, as they are linked to serious side effects like decreased bone mineral density or hypoestrogenic symptoms that necessitate add-back estrogen therapy.[ 12 , 13 , 20 , 21 ] According to Schweppe et al., dydrogesterone was typically dosed between 10 and 30 mg daily for varying numbers of days per cycle over a period of three to nine months is a successful endometriosis therapy that lessens persistent pelvic discomfort. The majority of women reported a significant decrease in the quantity and/or intensity of symptoms across studies, and laparoscopic inspection corroborated these results in many trials. [ 22 – 24 ] This prospective, randomized, double-blind study evaluated the once-daily extended-release dydrogesterone 20 mg in comparison to dydrogesterone 10 mg twice daily in women with endometriosis. We observed significant and similar improvements in EAPP in both arms. All patients receiving dydrogesterone experienced significant improvements in the quality of life as well as a reduction in the size of endometrioma, serum VEGF levels, and, analgesic use. Both formulations of dydrogesterone were well tolerated during the study, with a safety profile that was generally in line with previous studies of dydrogesterone in endometriosis.[ 22 , 25 , 26 ] All the AEs in both the study groups resolved completely with or without treatment. The shorter duration of the treatment in the study was a limitation. In conclusion, the results of this prospective randomized controlled clinical study established the efficacy and safety of once-daily dydrogesterone ER 20mg in patients with endometriosis. The study showed similar efficacy and safety of dydrogesterone ER 20mg once daily compared to dydrogesterone 10 mg twice daily in the treatment of endometriosis. Declarations Funding: The phase III clinical trial was sponsored by Zydus Healthcare Limited. Conflicts of interest: Dr Pavan Kumar Daultani, Dr Ravindra Mittal, Dr Monika Chinda, Dr Ashok Jaiswal are employees of Zydus Healthcare Limited Author Contributions: The study concept, design, and material preparation were done by Dr Pavan Daultani, Dr Ravindra Mittal, and Dr Ashok Jaiswal. Data collection and analysis were performed by Dr. T Sasikala, Dr Shikha Kushwaha, Dr Mukta Agarwal, Dr. Vandana Jain, Dr. Deepti Bawa, and Dr. Suchitra Narayan. The first draft of the manuscript was written by Dr Monika Chinda and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Ethics Approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Ethics Committee of the six gynecological centers across the country. Consent to participate: Written informed consent was obtained from the patients. References Dunselman GAJ, Vermeulen N, Becker C, Calhaz-Jorge C, D’Hooghe T, Bie BD et al (2014) ESHRE guideline: management of women with endometriosis. Hum Reprod 29(3):400–412. Meuleman C, Vandenabeele B, Fieuws S, Spiessens C, Timmerman D, D’Hooghe T (2009) High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners. Fertil Steril 92(1):68–74 Missmer SA, Hankinson SE, Spiegelman D, Barbieri RL, Marshall LM, Hunter DJ (2004) Incidence of laparoscopically confirmed endometriosis by demographic, anthropometric, and lifestyle factors. Am J Epidemiol 160:784–796 Gajbhiye RK, Montgomery G, Pai MV, Phukan P, Shekhar S, Padte K, et al. Protocol for a case-control study investigating the clinical phenotypes and genetic regulation of endometriosis in Indian women: the ECGRI study. BMJ Open. 2021;11:e050844 La Rosa VL, De Franciscis P, Barra F, Schiattarella A, Török P, Shah M, Karaman E, Marques Cerentini T, Di Guardo F, Gullo G, Ponta M, Ferrero S (2020) Quality of life in women with endometriosis: a narrative overview. Minerva Med 111(1):68–78 La Rosa VL, De Franciscis P, Barra F, Schiattarella A, Tropea A, Tesarik J, Shah M, Kahramanoglu I, Marques Cerentini T, Ponta M, Ferrero S (2020) Sexuality in women with endometriosis: a critical narrative review. Minerva Med 111(1):79–89 National Institute for Health and Care Excellence (2017) Endometriosis: diagnosis and management. UK. Griesinger G, Tournaye H, Macklon N, Petraglia F, Arck P, Blockeel C et al (2019) Dydrogesterone: pharmacological profile and mechanism of action as luteal phase support in assisted reproduction. Reprod Biomed Online 38(2):249– 259 Rižner TL, Brožič P, Doucette C, Turek-Etienne T, Muller-Vieira U, Sonneveld E et al (2011) Selectivity and potency of the retroprogesterone dydrogesterone in vitro. Steroids 76(6):607–615 Johnston WIH (1976) Dydrogesterone and endometriosis. Br J Obstetr Gynaecol 83(1):77–80 Gerlinger C, Schumacher U, Faustmann T, Colligs A, Schmitz H, Seitz C. Defining a minimal clinically important difference for endometriosis-associated pelvic pain measured on a visual analog scale: analyses of two placebo-controlled, randomized trials. Health Qual Life Outcomes. 2010 Nov 24;8:138. doi: 10.1186/1477-7525-8-138. PMID: 21106059; PMCID: PMC3002916 Dunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, D'Hooghe T, De Bie B, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod 2014;29:400–12. Practice Committee of the American Society for Reproductive Medicine. Treatment of pelvic pain associated with endometriosis: a committee opinion. Fertil Steril 2014;101:927–35 Hodgson RM, Lee HL, Wang R, Mol BW, Johnson N. Interventions for endometriosis-related infertility: a systematic review and network metaanalysis. Fertil Steril 2020;113:374–82.e2. Harada T, Momoeda M, Taketani Y, Hoshiai H, Terawaka N. Low-dose oral contraceptive pill for dysmenorrhea associated with endometriosis: a placebocontrolled, double-blind, randomized trial. Fertil Steril 2008;90:1583–8 Johnson NP, Hummelshoj L, World Endometriosis Society Montpellier Consortium. Consensus on current management of endometriosis. Hum Reprod 2013;28:1552–68 Bedaiwy MA, Allaire C, Alfaraj S. Long-term medical management of endometriosis with dienogest and with a gonadotropin-releasing hormone agonist and add-back hormone therapy. Fertil Steril 2017;107:537–48. Casper RF. Progestin-only pills may be a better first-line treatment for endometriosis than combined estrogen-progestin contraceptive pills. Fertil Steril 2017;107:533–6 Brown J, Crawford TJ, Datta S, Prentice A. Oral contraceptives for pain associated with endometriosis. Cochrane Database Syst Rev 2018;5: CD001019 von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP, STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet 2007;370:1453–7. Sagsveen M, Farmer JE, Prentice A, Breeze A. Gonadotrophin-releasing hormone analogues for endometriosis: bone mineral density. Cochrane Database Syst Rev 2003;2003:CD001297 Schweppe K-W. The place of dydrogesterone in the treatment of endometriosis and adenomyosis. Maturitas 2009;65(Suppl 1):S23–7 Johnston WI. Dydrogesterone and endometriosis. Br J Obstet Gynaecol 1976;83:77–80. Walker SM. The treatment of endometriosis with dydrogesterone. Br J Clin Pract 1983;24(Suppl):40–6 Griesinger G, Tournaye H, Macklon N, Petraglia F, Arck P, Blockeel C, et al. Dydrogesterone: pharmacological profile and mechanism of action as luteal phase support in assisted reproduction. Reprod Biomed Online 2019;38: 249–59. Trivedi P, Selvaraj K, Mahapatra PD, Srivastava S, Malik S. Effective postlaparoscopic treatment of endometriosis with dydrogesterone. Gynecol Endocrinol 2007;23(Suppl 1):73–6 Cite Share Download PDF Status: Posted Version 1 posted 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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Ltd","correspondingAuthor":true,"prefix":"","firstName":"Monika","middleName":"","lastName":"Chinda","suffix":""},{"id":290426727,"identity":"e6822841-baa5-4214-ad72-49478ec516ee","order_by":9,"name":"Dr. Anit Singh","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"Dr.","firstName":"Anit","middleName":"","lastName":"Singh","suffix":""}],"badges":[],"createdAt":"2024-03-18 08:22:30","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4121316/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4121316/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":55003101,"identity":"92b4c105-79f4-4206-b030-758f6976a01d","added_by":"auto","created_at":"2024-04-19 18:41:29","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":128146,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4121316/v1/c46dc3066cf4b3e3ee5ab739.png"},{"id":55003102,"identity":"fc9350df-8c6c-4357-af3f-915ddaa6a08e","added_by":"auto","created_at":"2024-04-19 18:41:29","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1800900,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4121316/v1/c625fd74a33447c62cfe4533.png"},{"id":55551640,"identity":"6f1b031c-0f2e-4ff2-8735-15c8eb2e345d","added_by":"auto","created_at":"2024-04-29 22:09:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1133144,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4121316/v1/12cda517-a3bf-4e9d-9494-089de34c21e1.pdf"}],"financialInterests":"","formattedTitle":"A multicentre phase III study comparing efficacy \u0026amp; safety of novel extended-release vs. conventional formulation of Dydrogesterone in Indian patients with endometriosis","fulltext":[{"header":"What does this study add to the clinical work?","content":"\u003cp\u003eEndometriosis significantly impacts the quality of life of the patients. Symptomatic relief remains the major focus when it comes to the management of endometriosis. This study evaluates the safety and the efficacy of the new formulation of Dydrogesterone 20mg extended-release formulation in managing the symptoms of endometriosis and further adding to the clinical options available for the medical treatment.\u003c/p\u003e\n"},{"header":"Introduction","content":"\u003cp\u003eEndometriosis is a chronic illness that impairs the quality of life of the patients.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] According to estimates, between 2 and 10% of women who are of reproductive age and between 25 and 50% of women suffering from infertility have endometriosis.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] It is estimated that endometriosis affects\u0026thinsp;~\u0026thinsp;247\u0026nbsp;million girls and women globally and ~\u0026thinsp;42\u0026nbsp;million girls and women in India.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] Endometriosis patients often appear with one or more related symptoms, such as dysmenorrhea, profound dyspareunia, cyclical intestinal problems, fatigue/weariness, and infertility, while some may not exhibit any symptoms at all. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] The symptoms of endometriosis gradually make it more difficult for women to do specific everyday tasks, which worsens their general health and well-being.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] Furthermore, this condition may result in sexual dysfunction in 2\u0026ndash;4% of sexually active women. [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] Lastly, symptoms associated with endometriosis significantly hinder afflicted women's ability to work, frequently leading to many lost workdays. [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eSymptomatic endometriosis remains the prime indication for treatment. Ideally, treatment should provide pain relief and allow pregnancy to occur safely while undergoing treatment. The current treatments for endometriosis include surgery (ablation using either laser or electrosurgery if laparoscopy is performed), pharmacological therapy, or a combination of both. Symptomatic patients always receive pharmacological therapy, which can include analgesics for women with endometriosis-related pain, hormonal treatments such as hormonal contraceptives, progestogens (e.g., progesterone), anti-progestogens (e.g., gestrinone), or gonadotropin-releasing hormone agonists (e.g., leuprolide) as it reduces endometriosis-associated pain or alternative treatments such as aromatase inhibitors (e.g., letrozole). [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eDydrogesterone (6-dihydro-retroprogesterone) is a retroprogesterone derived from progesterone that is similar in structure and pharmacology to endogenous progesterone. It acts as a selective progesterone receptor agonist and has better oral bioavailability compared with oral micronized progesterone.[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] Dydrogesterone has been on the market since the 1960s and is used as postmenopausal hormone replacement as well as for the treatment of menstrual disorders and endometriosis.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eAs per the approved package insert of dydrogesterone, it has to be used in a dose of 10 mg to be taken two times daily for the management of endometriosis.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] Taking these tablets two times in a day may lead to inconvenience and non-compliance, thus impacting the efficacy of the drug in real-world clinical practice. Taking this into consideration, an extended-release (ER), once-daily formulation of dydrogesterone 20 mg has been developed by M/s Zydus Healthcare Limited.\u003c/p\u003e \u003cp\u003eThis pre-licensure Phase III study was designed to evaluate the efficacy and safety of the new formulation of dydrogesterone Extended-Release Tablets 20mg for the treatment of endometriosis in women as compared to the dydrogesterone 10 mg twice daily.\u003c/p\u003e"},{"header":"Materials \u0026 Method","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eThis was a prospective, randomized, double-blind, single-dummy, two-arm, active-controlled, parallel, multicenter, phase III clinical trial. The study was conducted in accordance with national Good Clinical Practice guidelines, all applicable national standards, and the Declaration of Helsinki. The study was approved by the institutional ethics committees of all the participating centers and registered in the clinical trials registry India (CTRI/2023/03/050698). All participants provided written informed consent prior to enrollment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy Subjects\u003c/h2\u003e \u003cp\u003eThe participants were female patients, 18\u0026ndash;45 years of age, diagnosed with endometriosis based on ultrasonography, with an endometriosis pain score of at least 30mm on a 100mm visual analog scale. These patients were willing to give written informed consent and comply with the study procedures.\u003c/p\u003e \u003cp\u003eThe key exclusion criteria of the study were women who were pregnant, lactating, having childbearing potential unwilling to use effective barrier contraception, menopausal, having premature ovarian insufficiency, had undergone laparoscopic surgery for endometriosis in the last 6 months, had taken hormonal therapy in the last 6 months or oral contraceptives in the last 3 months, any other significant concomitant gynecological disorder or uncontrolled systemic diseases.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eStudy Conduct\u003c/strong\u003e \u003cp\u003eAt the end of 3 days of screening period, the eligible endometriosis patients were randomized to either of the two study groups; test arm received dydrogesterone Extended-Release 20mg tablet in the morning and a matching placebo for dydrogesterone 10 mg tablet in the evening, while patients in reference arm received dydrogesterone 10mg tablets twice daily for the total treatment duration of 90 days. Patients were also dispensed paracetamol 500mg tablets for use as rescue medication only. The patients were instructed to take one tablet of paracetamol in case of unbearable endometriosis-associated pelvic pain. A maximum of 4 tablets of paracetamol were allowed in a day. In case the patients still had unbearable pain, the patient was withdrawn from the study.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eStudy Endpoints\u003c/strong\u003e \u003cp\u003eThe primary endpoint was the change in EAPP from baseline to end of study i.e. at Day 90 as assessed on a 100mm VAS scale in the two groups. The secondary endpoints included the consumption of rescue pain medication and change from baseline in the health-related quality of life using the HRQoL-4 questionnaire (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) in the two groups during the study period. The secondary endpoints also included the changes from baseline in the size of endometrioma as assessed by USG and serum VEGF levels at the end of the study. The safety was assessed based on the reported adverse events (AEs) throughout the study.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe HRQoL-4 questionnaire included the following four questions:\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"1\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1. Health as self-assessed (Excellent 1; Very good 2; Good 3; Fair 4; Poor 5)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2. Number of days feeling physically unhealthy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3. Number of days feeling mentally unhealthy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4. Lost days (defined as days when work or other daily activities are not possible)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis:\u003c/h2\u003e \u003cp\u003eThe sample size was calculated based on the primary endpoint of the study i.e., change from baseline in EAPP at the end of the study. At least 204 patients (Test: 102, Reference: 102) were required to achieve 90% power with 2.5% one-sided level of significance, considering a non-inferiority margin of 10 mm on VAS [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] and assuming no difference between the test and the reference groups in the change in EAPP from baseline and common standard deviation of 22. Considering a treatment allocation ratio of 1:1 and an attrition rate of 10%, 228 subjects are required to be enrolled in the study (Test: 114, Reference: 114).\u003c/p\u003e \u003cp\u003eFor efficacy analysis, both Per Protocol (PP) and modified Intention to Treat (mITT) analyses were planned. The PP population was comprised of all the randomized patients who had completed all the post-randomization visits as per the protocol including the patients with minor protocol deviations. The mITT population was comprised of all the randomized patients who had completed at least one post-randomization visit including the patients with major protocol deviations. The PP analysis was considered as the primary analysis while the mITT analysis was considered as the supportive analysis. The test drug was considered non-inferior to the reference drug if the upper bound of 95% confidence interval (CI) for the difference between the study groups (Test - Reference) for the change in EAPP from baseline to the end of the study was below the non-inferiority margin of 10 mm. From the safety perspective, all the randomized subjects who had used at least a single dose of the study drug were considered for the safety analysis.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 228 patients with confirmed diagnoses of endometriosis were evaluated for efficacy and safety. The baseline demographics and characteristics of the patients are mentioned in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The flow of patients in the two study groups is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographics and baseline characteristics of the patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTest group\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;112)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReference group\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;116)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31.8\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9\u003c/p\u003e \u003cp\u003e(30.5 to 33.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32.0\u0026thinsp;\u0026plusmn;\u0026thinsp;6.3\u003c/p\u003e \u003cp\u003e(30.8 to 33.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHeight (cm)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e159.2\u0026thinsp;\u0026plusmn;\u0026thinsp;5.6\u003c/p\u003e \u003cp\u003e(158.2 to 160.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e159.5\u0026thinsp;\u0026plusmn;\u0026thinsp;6.0\u003c/p\u003e \u003cp\u003e158.3 to 160.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWeight (kg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58.4\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9\u003c/p\u003e \u003cp\u003e(57.1 to 59.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58.8\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9\u003c/p\u003e \u003cp\u003e(57.5 to 60.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBody Mass Index (kg/m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9\u003c/p\u003e \u003cp\u003e(22.6 to 23.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9\u003c/p\u003e \u003cp\u003e(22.7 to 23.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eData presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (95% CI)\u003c/p\u003e \u003cp\u003eP value calculated using unpaired T Test\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePrimary Outcome\u003c/p\u003e \u003cp\u003eAfter 90 days of treatment, the mean change in EAPP from baseline was \u0026minus;\u0026thinsp;34.2\u0026thinsp;\u0026plusmn;\u0026thinsp;15.3mm (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 vs baseline) in the test group and \u0026minus;\u0026thinsp;33.1\u0026thinsp;\u0026plusmn;\u0026thinsp;14.8mm (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 vs baseline) in the reference group. The difference between the two groups for the mean change in EAPP at Day 90 from baseline was statistically not significant (P\u0026thinsp;=\u0026thinsp;0.53) [Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e]. The upper limit of 95% CI for the difference between the test group and the reference group for the mean change in EAPP at day 90 from baseline was 2.8 mm which was well below the non-inferiority margin (10 mm). Hence, the test drug was found to be non-inferior to the reference drug for change in EAPP from baseline at the end of the study.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eChange in EAPP from baseline to end of study\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVAS Score\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTest group\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;110)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReference group\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;111)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value*\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDay 0 (Baseline)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61.8\u0026thinsp;\u0026plusmn;\u0026thinsp;10.0\u003c/p\u003e \u003cp\u003e(59.9 to 63.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.8\u003c/p\u003e \u003cp\u003e(60.1 to 63.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.98\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDay 30\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50.8\u0026thinsp;\u0026plusmn;\u0026thinsp;9.5\u003c/p\u003e \u003cp\u003e(49.0 to 52.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.1\u003c/p\u003e \u003cp\u003e(49.8 to 53.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDay 60\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41.0\u0026thinsp;\u0026plusmn;\u0026thinsp;11.2\u003c/p\u003e \u003cp\u003e(38.9 to 43.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41.7\u0026thinsp;\u0026plusmn;\u0026thinsp;11.5\u003c/p\u003e \u003cp\u003e(39.5 to 43.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDay 90 (End of study)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27.5\u0026thinsp;\u0026plusmn;\u0026thinsp;14.1\u003c/p\u003e \u003cp\u003e(24.9 to 30.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.7\u0026thinsp;\u0026plusmn;\u0026thinsp;14.3\u003c/p\u003e \u003cp\u003e(26.0 to 31.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eData presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (95% CI)\u003c/p\u003e \u003cp\u003e*P value calculated using unpaired T Test\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eSecondary endpoints:\u003c/p\u003e \u003cp\u003eDuring the last 30 days of the study period, there was a significant decrease in the use of rescue medication compared to the first 30 days of the study period in both the treatment arms (Fig.\u0026nbsp;2A) The patients in both arms experienced a significant decrease size of endometrioma (Fig.\u0026nbsp;2B), and serum VEGF (Fig.\u0026nbsp;2C) levels from baseline to the end of the study. Significant improvements were also observed in measures of HR-QoL, including perceived health status, mental health, pain, and physical, role, and social functioning in both arms at the end of the treatment (Fig.\u0026nbsp;2D). There were no significant differences observed between the two treatment groups in any of the secondary endpoints.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe efficacy results mentioned above belonged to PP population. The results in mITT population were similar to that reported in PP population (data not shown).\u003c/p\u003e \u003cp\u003eSafety\u003c/p\u003e \u003cp\u003eDuring the study, a total of 14 AEs were reported in 14 (12.5%) patients in the test group, and 14 AEs were reported in 12 (10.3%) patients in the reference group [Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e]. Two adverse events in the test group were moderate in severity, however, both were not related to the study medication. All the AEs in both the study groups resolved completely with or without treatment. There were no serious adverse event (SAE) reported during the study.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAdverse events reported in the study\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreferred Term\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTest group\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;112)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReference group\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;116)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value*\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeadache\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (5.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight gain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (1.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBack pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (1.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFever\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (2.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast tenderness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcidity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDizziness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNausea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (2.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVomiting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (2.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBloating\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCold\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMyalgia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eData presented as n(%); % calculated from No. of subjects analyzed for safety\u003c/p\u003e \u003cp\u003e*Fisher\u0026rsquo;s exact test (test group vs. reference group)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eEndometriosis is a condition that significantly affects HR-QoL and is linked to severe pain and morbidity. The objective of best-practice therapy is to control symptoms by avoiding recurrent surgical operations and making the most use of medical care through a personalized lifetime plan.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] The difficulty in evaluating the efficacy of medical treatments for endometriosis and identifying specific patients' treatment options stems from the dearth of randomized controlled trials and the influence of the placebo effect, as noted in earlier research.[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eProgestogens are advised as the first line of treatment for persistent pelvic discomfort associated with endometriosis, along with analgesics and oral contraceptives.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] The use of progestogens in this situation is supported by high-quality evidence; however, when deciding which therapy is best for a given patient, clinicians are supposed to take into account the various side-effect profiles, such as irregular bleeding, as well as irreversible effects, like thrombosis and androgenic effects.[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eLimited and low-to-moderate quality data supports other treatment alternatives, such as the use of combination oral contraceptives, which are also thought to be the first-line treatment for endometriosis pain-associated symptoms. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] Additionally, there is insufficient data to support the use of some pharmaceutical treatments that are suggested as second-line therapies, such as aromatase inhibitors and gonadotropin-releasing hormone agonists, as they are linked to serious side effects like decreased bone mineral density or hypoestrogenic symptoms that necessitate add-back estrogen therapy.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eAccording to Schweppe et al., dydrogesterone was typically dosed between 10 and 30 mg daily for varying numbers of days per cycle over a period of three to nine months is a successful endometriosis therapy that lessens persistent pelvic discomfort. The majority of women reported a significant decrease in the quantity and/or intensity of symptoms across studies, and laparoscopic inspection corroborated these results in many trials. [\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThis prospective, randomized, double-blind study evaluated the once-daily extended-release dydrogesterone 20 mg in comparison to dydrogesterone 10 mg twice daily in women with endometriosis. We observed significant and similar improvements in EAPP in both arms. All patients receiving dydrogesterone experienced significant improvements in the quality of life as well as a reduction in the size of endometrioma, serum VEGF levels, and, analgesic use.\u003c/p\u003e \u003cp\u003eBoth formulations of dydrogesterone were well tolerated during the study, with a safety profile that was generally in line with previous studies of dydrogesterone in endometriosis.[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] All the AEs in both the study groups resolved completely with or without treatment.\u003c/p\u003e \u003cp\u003eThe shorter duration of the treatment in the study was a limitation.\u003c/p\u003e \u003cp\u003eIn conclusion, the results of this prospective randomized controlled clinical study established the efficacy and safety of once-daily dydrogesterone ER 20mg in patients with endometriosis. The study showed similar efficacy and safety of dydrogesterone ER 20mg once daily compared to dydrogesterone 10 mg twice daily in the treatment of endometriosis.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003eFunding: The phase III clinical trial was sponsored by Zydus Healthcare Limited.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConflicts of interest: Dr Pavan Kumar Daultani, Dr Ravindra Mittal, Dr Monika Chinda, Dr Ashok Jaiswal are employees of Zydus Healthcare Limited\u003c/p\u003e\n\u003cp\u003eAuthor Contributions: The study concept, design, and material preparation were done by Dr Pavan Daultani, Dr Ravindra Mittal, and Dr Ashok Jaiswal. \u0026nbsp; Data collection and analysis were performed by Dr. T Sasikala, Dr Shikha Kushwaha, Dr Mukta Agarwal, Dr. Vandana Jain, Dr. Deepti Bawa, and Dr. Suchitra Narayan. The first draft of the manuscript was written by Dr Monika Chinda and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eEthics Approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Ethics Committee of the six gynecological centers across the country.\u003c/p\u003e\n\u003cp\u003eConsent to participate: Written informed consent was obtained from the patients.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDunselman GAJ, Vermeulen N, Becker C, Calhaz-Jorge C, D\u0026rsquo;Hooghe T, Bie BD et al (2014) ESHRE guideline: management of women with endometriosis. Hum Reprod 29(3):400\u0026ndash;412.\u003c/li\u003e\n\u003cli\u003eMeuleman C, Vandenabeele B, Fieuws S, Spiessens C, Timmerman D, D\u0026rsquo;Hooghe T (2009) High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners. Fertil Steril 92(1):68\u0026ndash;74\u003c/li\u003e\n\u003cli\u003eMissmer SA, Hankinson SE, Spiegelman D, Barbieri RL, Marshall LM, Hunter DJ (2004) Incidence of laparoscopically confirmed endometriosis by demographic, anthropometric, and lifestyle factors. Am J Epidemiol 160:784\u0026ndash;796\u003c/li\u003e\n\u003cli\u003eGajbhiye RK, Montgomery G, Pai MV, Phukan P, Shekhar S, Padte K, et al. Protocol for a case-control study investigating the clinical phenotypes and genetic regulation of endometriosis in Indian women: the ECGRI study. BMJ Open. 2021;11:e050844\u003c/li\u003e\n\u003cli\u003eLa Rosa VL, De Franciscis P, Barra F, Schiattarella A, T\u0026ouml;r\u0026ouml;k P, Shah M, Karaman E, Marques Cerentini T, Di Guardo F, Gullo G, Ponta M, Ferrero S (2020) Quality of life in women with endometriosis: a narrative overview. Minerva Med 111(1):68\u0026ndash;78\u003c/li\u003e\n\u003cli\u003eLa Rosa VL, De Franciscis P, Barra F, Schiattarella A, Tropea A, Tesarik J, Shah M, Kahramanoglu I, Marques Cerentini T, Ponta M, Ferrero S (2020) Sexuality in women with endometriosis: a critical narrative review. Minerva Med 111(1):79\u0026ndash;89\u003c/li\u003e\n\u003cli\u003eNational Institute for Health and Care Excellence (2017) Endometriosis: diagnosis and management. UK.\u003c/li\u003e\n\u003cli\u003eGriesinger G, Tournaye H, Macklon N, Petraglia F, Arck P, Blockeel C et al (2019) Dydrogesterone: pharmacological profile and mechanism of action as luteal phase support in assisted reproduction. Reprod Biomed Online 38(2):249\u0026ndash; 259\u003c/li\u003e\n\u003cli\u003eRižner TL, Brožič P, Doucette C, Turek-Etienne T, Muller-Vieira U, Sonneveld E et al (2011) Selectivity and potency of the retroprogesterone dydrogesterone in vitro. Steroids 76(6):607\u0026ndash;615\u003c/li\u003e\n\u003cli\u003eJohnston WIH (1976) Dydrogesterone and endometriosis. Br J Obstetr Gynaecol 83(1):77\u0026ndash;80\u003c/li\u003e\n\u003cli\u003eGerlinger C, Schumacher U, Faustmann T, Colligs A, Schmitz H, Seitz C. Defining a minimal clinically important difference for endometriosis-associated pelvic pain measured on a visual analog scale: analyses of two placebo-controlled, randomized trials. Health Qual Life Outcomes. 2010 Nov 24;8:138. doi: 10.1186/1477-7525-8-138. PMID: 21106059; PMCID: PMC3002916\u003c/li\u003e\n\u003cli\u003eDunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, D\u0026apos;Hooghe T, De Bie B, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod 2014;29:400\u0026ndash;12. \u003c/li\u003e\n\u003cli\u003ePractice Committee of the American Society for Reproductive Medicine. Treatment of pelvic pain associated with endometriosis: a committee opinion. Fertil Steril 2014;101:927\u0026ndash;35\u003c/li\u003e\n\u003cli\u003eHodgson RM, Lee HL, Wang R, Mol BW, Johnson N. Interventions for endometriosis-related infertility: a systematic review and network metaanalysis. Fertil Steril 2020;113:374\u0026ndash;82.e2. \u003c/li\u003e\n\u003cli\u003eHarada T, Momoeda M, Taketani Y, Hoshiai H, Terawaka N. Low-dose oral contraceptive pill for dysmenorrhea associated with endometriosis: a placebocontrolled, double-blind, randomized trial. Fertil Steril 2008;90:1583\u0026ndash;8\u003c/li\u003e\n\u003cli\u003eJohnson NP, Hummelshoj L, World Endometriosis Society Montpellier Consortium. Consensus on current management of endometriosis. Hum Reprod 2013;28:1552\u0026ndash;68\u003c/li\u003e\n\u003cli\u003eBedaiwy MA, Allaire C, Alfaraj S. Long-term medical management of endometriosis with dienogest and with a gonadotropin-releasing hormone agonist and add-back hormone therapy. Fertil Steril 2017;107:537\u0026ndash;48. \u003c/li\u003e\n\u003cli\u003eCasper RF. Progestin-only pills may be a better first-line treatment for endometriosis than combined estrogen-progestin contraceptive pills. Fertil Steril 2017;107:533\u0026ndash;6\u003c/li\u003e\n\u003cli\u003eBrown J, Crawford TJ, Datta S, Prentice A. Oral contraceptives for pain associated with endometriosis. Cochrane Database Syst Rev 2018;5: CD001019\u003c/li\u003e\n\u003cli\u003evon Elm E, Altman DG, Egger M, Pocock SJ, G\u0026oslash;tzsche PC, Vandenbroucke JP, STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet 2007;370:1453\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eSagsveen M, Farmer JE, Prentice A, Breeze A. Gonadotrophin-releasing hormone analogues for endometriosis: bone mineral density. Cochrane Database Syst Rev 2003;2003:CD001297\u003c/li\u003e\n\u003cli\u003eSchweppe K-W. The place of dydrogesterone in the treatment of endometriosis and adenomyosis. Maturitas 2009;65(Suppl 1):S23\u0026ndash;7\u003c/li\u003e\n\u003cli\u003eJohnston WI. Dydrogesterone and endometriosis. Br J Obstet Gynaecol 1976;83:77\u0026ndash;80. \u003c/li\u003e\n\u003cli\u003eWalker SM. The treatment of endometriosis with dydrogesterone. Br J Clin Pract 1983;24(Suppl):40\u0026ndash;6\u003c/li\u003e\n\u003cli\u003eGriesinger G, Tournaye H, Macklon N, Petraglia F, Arck P, Blockeel C, et al. Dydrogesterone: pharmacological profile and mechanism of action as luteal phase support in assisted reproduction. Reprod Biomed Online 2019;38: 249\u0026ndash;59.\u003c/li\u003e\n\u003cli\u003eTrivedi P, Selvaraj K, Mahapatra PD, Srivastava S, Malik S. Effective postlaparoscopic treatment of endometriosis with dydrogesterone. Gynecol Endocrinol 2007;23(Suppl 1):73\u0026ndash;6\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Dydrogesterone, endometriosis, extended-release, pelvic pain, progesterone","lastPublishedDoi":"10.21203/rs.3.rs-4121316/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4121316/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e: To compare the efficacy and safety of novel once-daily extended-release (ER) dydrogesterone 20 mg versus conventional twice-daily dydrogesterone 10 mg in Indian patients with endometriosis\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethod:\u003c/strong\u003e A phase III prospective, randomized, double-blind, single-dummy, two-arm, active-controlled, parallel, multicenter study was performed in six gynecology centers across India. The patients of 18 to 45 years of age with a confirmed diagnosis of endometriosis on ultrasonography (USG) and having endometriosis-associated pelvic pain score (EAPP) of at least 30mm on a 100 mm visual analog scale (VAS) were randomly assigned to a 1:1 ratio to either once-daily dydrogesterone ER 20 mg or twice-daily dydrogesterone 10 mg arms for a treatment period of 90 days. The primary outcome was a change from baseline in EAPP score at the end of the treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: A total of 288 patients with a mean age of 31.8 ± 6.9 years were enrolled in the study. At day 90, both the treatment arms showed a significant reduction (p\u0026lt;0.05) in EAPP score from baseline (i.e. –34.2 ± 15.3mm and –33.1 ± 14.8mm in once daily dydrogesterone ER and twice daily dydrogesterone 10 mg, respectively), with no significant difference between the two arms (p=0.53). With both formulations, patients experienced a significant reduction in the size of endometrioma, serum vascular endothelial growth factors (VEGF) levels, use of rescue analgesics, and significant improvement in the health-related quality-of-life parameters. A favorable safety profile of dydrogesterone was confirmed, and no significant safety concerns were reported during the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: Once daily dydrogesterone ER 20 mg and twice daily dydrogesterone 10 mg demonstrated a significant and similar reduction in EAPP and all other secondary parameters along with marked improvements in parameters related to quality of life.\u003c/p\u003e\n\u003cp\u003eRegistration Number: CTRI/2023/03/050698\u003c/p\u003e","manuscriptTitle":"A multicentre phase III study comparing efficacy \u0026amp; safety of novel extended-release vs. conventional formulation of Dydrogesterone in Indian patients with endometriosis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-19 18:41:25","doi":"10.21203/rs.3.rs-4121316/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7e27619d-88bb-48dc-bb48-fd634b59aaf9","owner":[],"postedDate":"April 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-04-29T22:01:12+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-19 18:41:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4121316","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4121316","identity":"rs-4121316","version":["v1"]},"buildId":"2u56kwukJI3zHK-uzyFNs","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}