This clinical study examines whether tirzepatide can improve ovarian dysfunction in premenopausal women with polycystic ovary syndrome (PCOS) who are overweight or have obesity. Tirzepatide is already approved for the treatment of diabetes and obesity, but its effects on ovarian dysfunction in PCOS are not yet known. Participants will be randomly assigned to tirzepatide or placebo in a double-blinded manner.
The goal of the study is to demonstrate that tirzepatide, at the maximum tolerated dose, is superior to placebo for improvement of ovarian dysfunction as defined by menstrual irregularity in overweight or obesity-related PCOS.
All participants will have a screening visit, followed by 72 weeks of treatment. Treatment includes a 20-week dose-escalation period and a 52-week maintenance period. Lower doses may be used if side effects occur, and the highest tolerated dose will be continued through the maintenance phase. A 4-week safety follow-up will take place after treatment, and long-term follow-up will continue for one year. The study will take place at five clinical trial sites in Germany.
Subjects
motivated, capable, and willing to self-inject IMP, as required for this protocol.
motivated, capable, and willing to follow trial procedures for the duration of the clinical trial, includ-ing, but not limited to lifestyle, dietary and exercise advice.
motivated, capable, and willing to complete trial diaries and required questionnaires.
Subjects without legal capacity who are unable to understand the nature, scope, significance and consequences of this clinical trial
Subjects with a physical or psychiatric condition which at the investigator's discretion may put the subject at risk, may confound the trial results, or may interfere with the subject's participation in this clinical trial
Note: Patients with depression or other psychiatric disorder whose disease state is considered stable and expected to remain stable throughout the course of the clinical trial, in the opinion of the investigator, may be considered for inclusion.
Note: Subjects with a lifetime suicidal event cannot be considered for inclusion
Parallel
Tirzepatide as an adjunct to lifestyle intervention
DrugDoses: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg Mode of application: weekly subcutaneous injection, prefilled pen injector Duration of treatment: 72 weeks (20 weeks dose escalation, 52 weeks treatment with maximum tolerated dose)
Placebo as an adjunct to lifestyle intervention
DrugDose: Placebo Pens to mimic doses 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg Mode of Application: weekly subcutaneous injection, prefilled pen injector Duration of Treatment: 72 weeks
Improvement of ovarian dysfunction as defined by menstrual irregularity in overweight or obesity-related PCOS
1. Mean menstrual bleeding ratio (number of menstrual bleedings divided by treatment period in months) during the last 52 weeks of treatment, assessed at 72 weeks after randomization 2. Mean change in menstrual bleeding ratio from baseline, calculated at 72 weeks after randomization (with baseline defined as mean menstrual bleeding ratio during the 6 months before randomization)
Key Secondary - Improvement of ovarian dysfunction as defined by ovulation frequency in overweight or obesity-related PCOS
Total number of biochemically confirmed ovulatory events (within 24 weeks after completed dose titration) measured by weekly serum progesterone
Percentage of Participants With Normalization of Menstrual Cycle
Normalization of the menstrual cycle is defined as a cycle length greater than 21 days and less than 35 days, or more than 8 cycles per year. This endpoint compares the proportion of subjects achieving this criteria in the tirzepatide group versus the placebo group.
Change From Baseline in Serum Anti-Müllerian Hormone (AMH)
Assessment of AMH as a surrogate marker for ovarian follicle pool and ovarian morphology.
Change From Baseline in Biochemical Androgen Profile
Evaluation of the androgenic status including Total Testosterone, Sex Hormone-Binding Globulin (SHBG), DHEA-S, and Androstenedione. Results will be reported as the change from baseline or the ratio of Week 72 to baseline.
Change From Baseline in Calculated Free Androgen Index (FAI) and Calculated Free Testosterone
FAI is calculated as (Total Testosterone/SHBG) x 100. Free Testosterone is calculated using the Vermeulen formula or a similar validated method based on Total Testosterone and SHBG levels.
Dose-Dependent Menstrual Bleeding Ratio at Week 72
Evaluation of the dose-response relationship of tirzepatide (5 mg, 10 mg, and 15 mg) compared to placebo. Mean menstrual bleeding ratio at 72 weeks after randomization.
Dose-Dependent Change in Mean Menstrual Bleeding Ratio at Week 72
Evaluation of the dose-response relationship of tirzepatide (5 mg, 10 mg, and 15 mg) compared to placebo. Mean change in menstrual bleeding ratio at 72 weeks after randomization
Dose-Dependent Normalization of Menstrual Cycle
Evaluation of the dose-response relationship (5 mg, 10 mg, and 15 mg) compared to placebo. Percentage of subjects achieving a cycle length \> 21 and \< 35 days or \> 8 cycles/year.
Total Number of Biochemically Confirmed Ovulatory Events (Dose-Response)
Evaluation of the dose-response relationship (5 mg, 10 mg, and 15 mg) compared to placebo. Number of ovulatory events (serum progesterone ≥ 3 ng/mL) during the 24 weeks following completed dose titration.
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University of Bonn
Lead sponsor
University Hospital, Bonn
Sponsor institution
Heart and Diabetes Center North Rhine-Westphalia
Collaborator
University Hospital, Essen
Collaborator
Ruhr University of Bochum
Collaborator
LMU Klinikum
Collaborator
