Abstract
BACKGROUND: Current guidelines for polycystic ovary syndrome (PCOS) recommend combined oral hormonal contraceptives as first-line pharmacological treatment to reduce androgen excess and to treat clinical hyperandrogenic skin manifestations, such as hirsutism. However, these are used off-label. We aimed to demonstrate the efficacy of a prolonged-release oral formulation in a 24/4-day regimen for up to nine 28-day consecutive cycles compared with placebo for the clinical management of hirsutism in women with PCOS. METHODS: This was a multinational, multicentre, double-blind, placebo-controlled trial done across 46 sites in Czech Republic, Hungary, Lithuania, Poland, Serbia, Slovakia, Spain and Ukraine. Eligible participants were 2-year-post-menarche women (14-40 years old) with a body mass index (BMI) of 18 to <35 kg/m(2) who were diagnosed with clinical hyperandrogenism (adapted modified Ferriman-Gallwey [mFG] score ≥7) plus oligomenorrhea of ≤6 menses per year and/or polycystic ovary morphology. Enrolled participants were randomised (4:1) to prolonged-release once-daily oral dienogest 2 mg (DNG) + ethinylestradiol 0.02 mg (EE) in a 24/4-day regimen (DNG + EE group) or placebo for up to nine 28-day cycles. Co-primary endpoints were: (1) the change from baseline in the adapted mFG score at the end of Cycle 9 or at the early discontinuation visit (EDV), and (2) proportion of responders, defined as participants with an adapted mFG score reduction of 50% from baseline to the end of Cycle 9/EDV. An adapted mFG score was used to assess for specific regions of body hair. No facial hair was assessed. We used a mixed-model repeated measure (MMRM) analysis that was repeated for BMI subgroups ≤30 or >30 kg/m(2) but without BMI stratification. Adverse events and safety were monitored throughout. This study is registered with EudraCT, 2021-002178-17. FINDINGS: Between Nov 2, 2021, and Dec 5, 2023, of 500 patients screened, 305 participants were enrolled and randomised to study groups and 202 participants completed the trial to the end of Cycle 9. The safety set comprised 291 participants (DNG + EE, n = 234; placebo, n = 57) and 256 participants were included in the full analysis set (FAS; DNG + EE, n = 209; placebo, n = 47). 76 (DNG + EE) and 27 (placebo) participants discontinued the trial early, including 18 and four who discontinued due to adverse events; 168 and 34 participants, respectively, completed the trial. Least squares (LS) mean changes from baseline to end of Cycle 9/EDV in adapted mFG score were -3.8 and -1.5 for the DNG + EE and placebo groups, respectively (difference -2.24 ± 0.49 (98.75% CI: -∞, -1.14; p < 0.0001; MMRM, FAS). In the ≤30 and > 30 kg/m(2) BMI subgroups, the LS mean changes from baseline in adapted mFG score were -3.8 and -3.7 for DNG + EE-treated participants, and -1.9 and -0.6 for placebo, respectively; LS mean treatment group differences were -1.9 (98.75% CI -∞, -0.7; p = 0.0004) and -3.14 (98.75% CI -∞, -0.9; p = 0.0011), respectively (MMRM, FAS). No new safety signals for DNG + EE were observed. The proportion of treatment-emergent adverse events (TEAEs) was similar between study groups. The most frequent TEAEs were headache (n = 49, 17%), intermenstrual bleeding (n = 41, 14%), and nasopharyngitis (n = 33, 11%). Serious TEAEs were reported for six participants (2%): five participants (2%) in the DNG + EE group (abdominal pain [n = 2], pain in extremity [n = 1], hypoesthesia [n = 1] and pulmonary embolism [n = 1]) and one participant (2%) in the placebo group (vestibular neuronitis). INTERPRETATION: Our findings show that oral prolonged-release DNG 2 mg plus EE 0.2 mg in a 24/4-day regimen for up to 9 cycles is an effective treatment for hirsutism in women with PCOS, with an acceptable safety profile. Further research is required to assess DNG + EE in treating hirsutism among different cultural and ethnic populations as well its impact on mood disorders (depression and anxiety) in women with hirsutism-associated PCOS. FUNDING: Chemo Research S.L.