A multicentre phase III study comparing efficacy and safety of novel extended-release versus conventional formulation of dydrogesterone in Indian patients with endometriosis

The aim of the study was 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.

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 30 mm 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.

A total of 228 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±15.3 mm and -33.1±14.8 mm 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.

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. Metrics

Dunselman GAJ, Vermeulen N, Becker C, Calhaz-Jorge C, D’Hooghe T, Bie BD, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014;29(3):400-12. Meuleman C, Vandenabeele B, Fieuws S, Spiessens C, Timmerman D, D’Hooghe T. High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners. Fertil Steril. 2009;92(1):68-74. Missmer SA, Hankinson SE, Spiegelman D, Barbieri RL, Marshall LM, Hunter DJ. Incidence of laparoscopically confirmed endometriosis by demographic, anthropometric, and lifestyle factors. Am J Epidemiol. 2004;160:784-96. 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, et al. Quality of life in women with endometriosis: a narrative overview. Minerva Med. 2020;111(1):68-78. La Rosa VL, De Franciscis P, Barra F, Schiattarella A, Tropea A, Tesarik J, et al. Sexuality in women with endometriosis: a critical narrative review. Minerva Med. 2020;111(1):79-89. National Guideline Alliance (UK). Endometriosis: diagnosis and management. London: National Institute for Health and Care Excellence (NICE). 2017. 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(2):249-59. Rižner TL, Brožič P, Doucette C, Turek-Etienne T, Muller-Vieira U, Sonneveld E, et al. Selectivity and potency of the retroprogesterone dydrogesterone in vitro. Steroids. 2011;76(6):607-15. Johnston WIH. Dydrogesterone and endometriosis. Br J Obstetr Gynaecol. 1976;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;8:138. 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. Harada T, Momoeda M, Taketani Y, Hoshiai H, Terawaka N. Low-dose oral contraceptive pill for dysmenorrhea associated with endometriosis: a placebo controlled, 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(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;24:40-6. Trivedi P, Selvaraj K, Mahapatra PD, Srivastava S, Malik S. Effective postlaparoscopic treatment of endometriosis with dydrogesterone. Gynecol Endocrinol 2007;23(1):73-6.