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.
PERIODS is a prospective, phase IV, multi-centre, randomized, double-blind and placebo-controlled clinical trial that will investigate the effects of tirzepatide compared with placebo on ovarian dysfunction in premeno-pausal, overweight (BMI ≥ 27 kg/m2) women with PCOS. The primary endpoint is the improvement of ovarian dysfunction as defined by menstrual irregularity and ovulation frequency in overweight or obesity-related PCOS. All subjects will undergo a screening visit and a 72-week treatment period including a 20-week dose escalation up to the maximum tolerated dose. Lower doses of tirzepatide are permitted if intolerable side effects occur. However, even if a lower dose of tirzepatide turns out to be the maximum tolerated dose, this lower dose will be administered for the entire 20-week dose escalation period, followed by the 52-week maintenance dose. The safety follow-up period will be 4 weeks (for subjects completing or discontinuing IMP during the first 72 weeks). Long-term follow-up will be one year after discontinuation of IMP. The trial design is multi-centred with a planned number of 5 participating trial sites in Germany.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
198
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 (20 weeks dose escalation, 52 weeks treatment with maximum tolerated dose)
Dose: 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
University Hospital BG Bergmannsheil Bochum General internal medicine, endocrinology and diabetology, gastroenterology and hepatology
Bochum, Germany
ENROLLING_BY_INVITATIONUniversity Hospital Bonn Division of Endocrinology, Diabetes and Metabolism
Bonn, Germany
RECRUITINGImprovement 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)
Time frame: At 72 weeks after 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
Time frame: Within 24 weeks after completed dose titration
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.
Time frame: Week 72
Change From Baseline in Serum Anti-Müllerian Hormone (AMH)
Assessment of AMH as a surrogate marker for ovarian follicle pool and ovarian morphology.
Time frame: Baseline and Week 72
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.
Time frame: Baseline and Week 72
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.
Time frame: Baseline and Week 72
Change From Baseline in Pituitary-Gonadal Hormones (LH, FSH, Estradiol, Progesterone)
Assessment of the hormonal regulation of the ovarian cycle by measuring Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH), Estradiol, and Progesterone.
Time frame: Baseline and Week 72
Percentage Change in Body Weight from Baseline to Week 72
Relative change in total body weight compared to the starting weight.
Time frame: Baseline and Week 72
Percentage of Participants Achieving ≥ 5%, ≥ 10%, ≥ 15%, and ≥ 20% Body Weight Loss
Proportion of subjects in each treatment arm who reach the specified weight loss thresholds at Week 72.
Time frame: Baseline and Week 72
Change from Baseline in Body Composition (BIA) at Week 72
Mean change in fat mass and fat-free mass as measured by Bioelectrical Impedance Analysis (BIA).
Time frame: Baseline and Week 72
Change from Baseline in Waist Circumference and Waist-to-Hip Ratio
Measurement of abdominal fat distribution change from randomization to Week 72.
Time frame: Baseline and Week 72
Change from Baseline in Fasting Glucose and HbA1c at Week 72
Assessment of long-term and fasting glycemic control.
Time frame: Baseline and Week 72
Change from Baseline in Systemic Insulin Sensitivity Indices
Evaluation of insulin sensitivity using the Quantitative Insulin Sensitivity Check Index (QUICKI), Homeostasis Model Assessment (HOMA-IR), and Matsuda's Insulin-Sensitivity Index derived from OGTT data.
Time frame: Baseline and Week 72
Change from Baseline in Fasting Lipid Profile at Week 72
Mean change in Triglycerides and the Triglyceride-to-HDL Ratio.
Time frame: Baseline and Week 72
Change from Baseline in Fasting Lipid Profile at Week 72
Mean change in Total Cholesterol, LDL Cholesterol and HDL cholesterol
Time frame: Baseline and Week 72
Change from Baseline in Liver Enzymes and Non-invasive Biomarkers (FLI, FIB-4)
Assessment of liver health via Fatty Liver Index (FLI) and FIB-4 Score.
Time frame: Baseline and Week 72
Change from Baseline in Liver Stiffness and Fat Content at Week 72
Measurement of hepatic steatosis and fibrosis via imaging (e.g., Transient Elastography/FibroScan).
Time frame: Baseline and Week 72
Change from Baseline in Systolic and Diastolic Blood Pressure
Mean change in SBP and DBP from randomization to Week 72.
Time frame: Baseline and Week 72
Change from Baseline in High-Sensitivity C-Reactive Protein (hs-CRP)
Marker for systemic meta-inflammation.
Time frame: Baseline and Week 72
Change From Baseline in the 36-Item Short Form Survey (SF-36) at Week 72
The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields an 8-scale profile of functional health and well-being scores. Each scale is transformed to a 0-100 range, where 0 indicates the lowest level of health and 100 indicates the highest level of health (higher scores mean a better outcome).
Time frame: Baseline and Week 72
Change From Baseline in the Polycystic Ovary Syndrome Health-Related Quality of Life Questionnaire (PCOSQ)
The PCOSQ measures health-related quality of life in women with PCOS across five domains (Emotions, Body Hair, Weight, Infertility, and Menstrual Problems). Each item is scored on a 7-point scale. Domain scores range from 1 to 7, where higher scores indicate better health-related quality of life/less distress.
Time frame: Baseline and Week 72
Change From Baseline in the European Quality of Life 5 Dimensions 5 Level Version (EQ-5D-5L)
The EQ-5D-5L consists of a descriptive system (5 dimensions) and a Visual Analogue Scale (VAS). The VAS records the respondent's self-rated health on a vertical scale where the endpoints are labeled 'The best health you can imagine' (100) and 'The worst health you can imagine' (0). Higher scores mean a better outcome.
Time frame: Baseline and Week 72
Patient Global Impression of Severity (PGI-S) at Week 72
The PGI-S is a single-item question asking the patient to rate the severity of their condition. It uses a 5-point scale: 1 (None), 2 (Mild), 3 (Moderate), 4 (Severe), 5 (Very Severe). A decrease in score indicates an improvement in condition.
Time frame: Baseline and Week 72
Wiebke Fenske K. Head of Department at BG Universitätsklinikum Bochum, Professor
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