Evaluation of Tirzepatide for Ovarian Dysfunction in Overweight or Obese Patients with Polycystic Ovary Syndrome: A Randomized Controlled Trial

The primary objective of this clinical trial is to demonstrate that **tirzepatide** at its maximum tolerated dose is superior to placebo in improving ovarian dysfunction, specifically defined by menstrual irregularity, in individuals with overweight or obesity-related **Polycystic Ovary Syndrome (PCOS)**. This is clinically relevant as PCOS is a common endocrine disorder that can lead to significant reproductive and metabolic complications, and effective management of ovarian dysfunction is crucial for improving patient outcomes.

Secondary objectives include:

• To demonstrate that tirzepatide is superior to placebo for improvement of ovarian dysfunction as defined by ovulation frequency in overweight or obesity-related PCOS.
• To assess the superiority of tirzepatide over placebo in improving ovarian dysfunction and hyperandrogenism.
• To evaluate the impact of tirzepatide on body weight measures.
• To assess improvements in glycemic status and lipid profile.
• To evaluate the effect on Metabolic dysfunction-associated steatotic liver disease (MASLD).
• To assess the impact on blood pressure.
• To evaluate systemic meta-inflammation.
• To assess patient-reported outcomes.
• Exploratory objectives over 72 weeks include evaluating dose-dependent efficacy regarding ovarian dysfunction, PCOM Morphology, clinical hyperandrogenism, and hyperglycemia in women with type 2 diabetes.
• Exploratory objectives over 124 weeks include assessing maintained improvement of ovarian function and hyperandrogenism, successful fertilization, body weight maintenance, and maintenance of glycemic status and lipid profile, as well as effects on MASLD, blood pressure, systemic meta-inflammation, and patient-reported outcomes at 52 weeks after drug discontinuation.

The clinical trial focuses on **Polycystic Ovary Syndrome (PCOS)** in conjunction with overweight or obesity. The study population comprises exclusively female participants aged 18 to 45 years, who are of childbearing potential and at least three years post-menarche and premenopausal. Participants are required to have a Body Mass Index (BMI) of 27 kg/m² or higher and a previous diagnosis of PCOS. The trial does not include male subjects or vulnerable populations. The sponsor has not provided information regarding the total number of participants. Selection criteria emphasize the presence of biochemical or clinical signs of hyperandrogenism, and participants must not have used hormonal contraceptives six months prior to screening. Lifestyle considerations include adherence to dietary and exercise advice, and participants must be willing to self-inject the investigational medicinal product (IMP) and complete trial diaries and questionnaires. The trial aims to assess the efficacy of tirzepatide in improving ovarian dysfunction, specifically menstrual irregularity, in the context of PCOS related to overweight or obesity.

The clinical trial is designed to evaluate the efficacy of **tirzepatide** in subjects with **Polycystic Ovary Syndrome (PCOS)** and overweight or obesity. This is a randomized, double-blind, placebo-controlled trial, with a primary objective to demonstrate the superiority of tirzepatide over placebo in improving ovarian dysfunction, as defined by menstrual irregularity. The trial is expected to last until October 2029, with recruitment starting in October 2025. Participants will be involved for a total of 72 weeks, during which they will receive tirzepatide or placebo via subcutaneous injection, alongside an oral blood glucose-lowering drug.

The study will include several key visits: an initial screening visit to confirm eligibility based on inclusion criteria such as biochemical signs of hyperandrogenism and a BMI of at least 27 kg/m², followed by regular follow-up visits to monitor progress and collect data on primary and secondary endpoints. These endpoints include the mean menstrual bleeding ratio, changes in body weight, and various hormonal and metabolic parameters. The end-of-study visit will occur at 72 weeks post-randomization, where final assessments will be conducted.

Participants may be withdrawn from the study early if they experience significant adverse effects, fail to comply with study procedures, or withdraw consent. The trial will employ a placebo that matches tirzepatide in various doses, ensuring blinding is maintained throughout the study. The trial's methodology and design are structured to provide robust data on the efficacy and safety of tirzepatide in the target population, contributing valuable insights into the management of PCOS-related ovarian dysfunction in individuals with overweight or obesity.

The clinical trial involves the administration of **Tirzepatide**, an experimental medication, which is provided as a solution for injection in a pre-filled pen. The active substance, tirzepatide, is a protein of other origin. The medication is administered via subcutaneous injection. The trial includes multiple dosing regimens with maximum daily doses ranging from 2.5 mg to 15 mg, and the maximum total dose varies from 180 mg to 780 mg, depending on the specific regimen. The treatment periods range from 52 to 72 weeks. The administration of tirzepatide is blinded, and it is used in conjunction with an oral blood glucose-lowering drug.

In addition to the experimental medication, a **Placebo** is utilized in the trial. The placebo is designed to match tirzepatide in doses of 2.5, 5, 7.5, 10, 12.5, and 15 mg. It is manufactured and incorporated into an auto-injector, packaged, and labeled to be identical to tirzepatide. The placebo is provided by the original manufacturer, Eli Lilly, and is used to maintain blinding in the study.

**Glucose** is used as a diagnostic agent in the trial. It is administered orally with a maximum daily dose of 75 g and a total maximum dose of 225 g over a treatment period of 3 days. The active substance, glucose, is of chemical origin and is also known by synonyms such as anhydrous dextrose and dextrose anhydrous.

**Medroxyprogesterone Acetate** is included as an auxiliary treatment in the trial. It is administered orally with a maximum daily dose of 10 mg and a total maximum dose of 100 mg over a treatment period of 10 days. The active substance is of chemical origin and is also referred to by synonyms such as medroxyprogesterone 17-acetate and methylacetoxyprogesterone.

**Dydrogesterone** is another auxiliary treatment used in the trial. It is administered orally with a maximum daily dose of 10 mg and a total maximum dose of 100 mg over a treatment period of 10 days. The active substance is of chemical origin and is used as a progestin in the study.

The efficacy of the clinical trial involving **tirzepatide** will be assessed through a series of primary and secondary endpoints. The primary endpoints include the mean menstrual bleeding ratio, which is calculated as the number of menstrual bleedings divided by the treatment period in months during the last 52 weeks of treatment. This will be assessed at 72 weeks after randomization. Additionally, the mean change in menstrual bleeding ratio from baseline will be evaluated, with baseline defined as the mean menstrual bleeding ratio during the 6 months before randomization.

Secondary endpoints will encompass a range of biochemical and clinical measures. These include the total number of biochemically confirmed ovulatory events within 24 weeks after completed dose titration, measured by weekly serum progesterone. The percentage of subjects achieving normalization of the menstrual cycle at 72 weeks post-randomization will also be assessed. Other secondary endpoints involve serum levels of Anti Müllerian Hormone (AMH), early follicular total testosterone, estradiol, progesterone, sex hormone-binding globulin (SHBG), DHEA-S, androstenedione, LH, and FSH. Calculated free androgen index (FAI) and free testosterone will be measured as well.

Further assessments will include changes in body weight, body composition, waist circumference, fasting glucose, HbA1c, systemic insulin sensitivity, fasting triglycerides, cholesterol levels, liver enzymes, and non-invasive biomarkers. Blood pressure changes, hs-CRP levels, and quality of life scores using validated questionnaires such as the 36-Item Short Form Survey (SF-36), Patient Global Impression of Severity (PGI-S), European Quality of Life 5 Dimensions 5 Level Version (EQ-5D-5L5L), and the Polycystic Ovary Syndrome Health-Related Quality of Life Questionnaire (PCOSQ) will also be evaluated.