A Clincial Study Testing Tirzepatide on Reproductive Function and Metabolic Health in Women With PCOS Who Are Overweight or Obese

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.

General Inclusion Criteria

• Written informed consent to participate in this clinical trial in accordance with local regulations and the ethical review board governing this clinical trial
• 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.

Indication-specific Inclusion Criteria

• Females aged 18 - 45 years of childbearing potential
• At least 3 years post-menarche and premenopausal
• BMI ≥ 27 kg/m²
• Previous diagnosis of PCOS, defined by Rotterdam criteria
• Oligomenorrhea or secondary amenorrhea with irregular periods (defined as cycle length less than 21 or more than 35 days or < 8 cycles per year); within the last 10 years (if currently receiving hormonal contraceptive treatment) OR over the last year in the absence of hormonal contraceptive treatment
• Biochemical signs of hyperandrogenism with total testosterone in upper 95th Percentile AND free androgen index (FAI) > ULN and/or clinical signs of hyperandrogenism
• Hormonal contraceptive naïve or not on hormonal contraceptives six months prior to screening, willing to be without hormonal contraceptives for the duration of the clinical trial and to perform safe alternate contraception (barrier methods) during the 72-week IMP intake period and 30 days after the last dose of IMP

General Exclusion Criteria

• 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
• Simultaneous participation in another clinical trial, or participation in a clinical trial taking an investiga-tional product, up to 30 days after last IMP intake in that clinical trial
• Known or persistent abuse of medication, drugs or alcohol
• History of an active or untreated malignancy or being in remission from a clinically significant malig-nancy for less than 5 years

o Excluding basal- or squamous-cell skin cancer or in situ carcinomas of the cervix

• Prior diagnosis of severe renal impairment or measured as estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m² during screening
• Acute or chronic hepatitis, signs and symptoms of any other liver disease other than non-alcoholic fatty liver disease, or alanine aminotransferase (ALT) level > 3.0 X the upper limit of normal, as deter-mined by the laboratory during screening
• History of gastric emptying abnormality (e.g., gastroparesis, gastric outlet obstruction or chronic de-pendence on drugs that significantly affect gastric emptying)
• Current (positive pregnancy test, e.g., ß-HCG test in urine / serum) or planned pregnancy during the 72-week treatment period from randomization, or nursing women

Indication-specific Exclusion Criteria

• Prior diagnosis of diabetes mellitus other forms than type 2

o Note: Excluding prior history of gestational diabetes

• In case of diabetes mellitus type 2, exclusion of subjects

• on DPP-4 inhibitors, GLP-1R agonist and/or a dual/triple incretin agonist (up to 6 months prior to screening)
• on sulfonylureas or insulin (basal and/or bolus)
• with uncontrolled diabetes (HbA1c > 8.5%)
• with non-proliferative diabetic retinopathy requiring acute treatment
• with diabetic maculopathy
• Note: use of metformin or SGLT-2-inhibitor (if needed for glycemic control in type-2-diabetes) is allowed
• Current or prior treatment (up to 6 months prior to screening) with GLP-1R agonist or a dual incretin agonist for obesity or other indications
• Use of inositol formulations (up to 6 months prior to screening)
• Congenital adrenal hyperplasia (CAH, classic and non-classic forms)
• Thyroid, pituitary, and/or adrenal disease (if not appropriately treated)

o Note: Excluding stable disease and/or stable drug dose 12 weeks before screening

• Hyperprolactinaemia
• Known history of benign intrauterine lesions
• Hysterectomy
• Known history of hypersensitivity against tirzepatide or excipients
• Known history of hypersensitivity against medroxyprogesterone acetate or dydrogesterone or any other ingredients of the Auxiliary Medicinal Products
• Known personal or family history of medullary thyroid cancer or subjects with Multiple Endocrine Ne-oplasia syndrome type 2 (MEN 2)
• Elevated calcitonin levels as determined by the laboratory during screening

• ≥ 20 ng/L, if eGFR ≥ 60 mL/min/1.73 m2
• ≥ 35 ng/L, if eGFR < 60 mL/min/1.73 m2
• Known secondary cause of obesity (i.e., Cushing syndrome) or monogenetic or syndromic forms of obesity (i.e., melanocortin 4 receptor deficiency or Prader Willi Syndrome)
• Known history of acute or chronic pancreatitis
• Previous or planned bariatric surgery or endoscopic and/or device-based therapy for obesity

o Note: excluding liposuction or abdominoplasty if performed > 1 year prior to screening

• Vaginal bleeding of unknown cause
• Known thromboembolic events or active thrombophlebitis