Effects of Interleukin-1 Receptor Antagonism on Hyperandrogenemia in Women With Polycystic Ovary Syndrome

Study Overview
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Brief Summary
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A prospective, interventional, open-label, single-arm, proof-of-concept study: 18 women with Polycystic Ovary Syndrome (PCOS) will be treated with 100 mg of Anakinra/Kineret® for 4 weeks. 1 week after last injection patients will have a follow-up and a dexamethasone visit after a dexamethasone suppression test. Goal of this study is to investigate the effect of the Interleukin 1( IL-1) receptor antagonist Anakinra/Kineret® on laboratory and clinical features in women with PCOS.

Official Title
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Effects of Interleukin-1 Receptor Antagonism on Hyperandrogenemia in Women With Polycystic Ovary Syndrome - a Prospective, Interventional, Single-arm, Open-label, Proof-of-concept Study

Conditions
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Polycystic Ovary Syndrome

Intervention / Treatment
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* Drug: IL-1 receptor antagonist Anakinra


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed Consent as documented by signature Premenopausal women aged 18 years or older Onset of menarche ≥5 years ago Diagnosis of PCOS defined by the Rotterdam criteria High sensitivity C-reactive protein level ≥1 mg/l Follicular phase of menstrual cycle as evident by Serum estradiol level <200 pmol/l AND Serum progesterone level <8 ng/ml Willingness to use non-hormonal contraceptive measures adequate to prevent becoming pregnant during the study Exclusion Criteria: Intake of any testosterone level modifying drugs in the 8 weeks prior to study inclusion, Contraindications to the class of drugs under study, e.g. known hypersensitivity or allergy to Anakinra/Kineret, Women who are pregnant or breast feeding, Female participants who are ovariectomized or hysterectomised or post-menopausal Known or suspected non-compliance, drug or alcohol abuse, Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant, Participation in another study with investigational drug within the 30 days preceding and during the present study, Previous enrolment into the current study, Enrolment of the investigator, his/her family members, employees and other dependent persons, Clinical signs of infection in the week before inclusion or history of a severe infection during the last 2 months, Potentially severe immunosuppression or intake of other immunosuppressive drugs Severe hematologic disease Other clinically significant concomitant disease states (e.g., renal failure, hepatic dysfunction, active carcinoma), History of or suspected tuberculosis and/or hepatitis B/C

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IL-1 receptor antagonist Anakinra 100 mg<br>Anakinra (Kineret®; r-metHuIL-1ra, Swedish Orphan Biovitrum AB) is a recombinant, non-glycosylated form of the human IL-1Ra in a 100 mg/ 0.67 ml solution for subcutaneous injection. Anakinra/Kineret® is supplied in single use prefilled glass syringes with 27 gauge needles as a sterile, clear, colorless-to-white, preservative free solution for daily s.c. administration over a time period of 28 days. | Drug: IL-1 receptor antagonist Anakinra<br>* IL-1 receptor antagonist Anakinra is a recombinant, non-glycosylated form of the human IL-1Ra in a 100 mg/ 0.67 ml solution for subcutaneous injection. Standard dosage licensed by the FDA and European Medicines Agency (EMA) is 100 mg Anakinra daily. It is supplied in single use prefilled glass syringes with 27 gauge needles as a sterile, clear, colourless-to-white, preservative free solution for daily s.c. administration.<br>* Other names: Kineret;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute change in fasting serum androstenedione level (nmol/l) from start (baseline, day 1) to one week after treatment start with Anakinra. | Absolute change in fasting serum androstenedione level (nmol/l) from start (baseline, day 1) to one week after treatment start with Anakinra. | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ferriman-Gallwey-score | Effect of Anakinra/Kineret® on hirsutism by Ferriman-Gallwey-score (representation of hair growth in a male pattern on a woman shown in four different degrees of severity ( 0= no hair growth; 1= light hair growth; 2= moderate hair growth; 4= severe hair growth) in 11 different body parts; namely the upper lip, chin, chest, upper back, lower back, upper abdomen, lower abdomen, arm, forearm, thigh, and lower leg) will be assessed | Day 1 and 28 | 
| Sebum production measures | Effect of Anakinra/Kineret® on sebum production will be assessed with Sebumeter® SM 815, Courage + Khazaka electronic Gesellschaft mit beschränkter Haftung (GmbH) | At day 1 and 28 | 
| Self-reported frequency of hair removal (times/week) | Effect of Anakinra/Kineret® on hirsutism will be assessed | At day 1 and 28 | 
| Plewig-Kligman-score | Effect of Anakinra/Kineret® on acne severity, assessed with Plewig-Kligman score (presentation of comedonal and inflammatory acne severity, separately graded based on the number of lesions and type; lesion counting done at right side of the face, excluding other side, chest and back. | At day 1 and 28 | 
| Ovulation and menstruation rates [%] | Effect of Anakinra/Kineret® on ovulation and menstruation rates will be assessed | Between day 1 and day 35 | 
| Estradiol (pmol/l), free testosterone (nmol/l), total testosterone (nmol/l), sex hormone-binding globulin (SHBG) [nmol/l], Anti-Muellerian Hormone [pmol/l], dehydroepiandrosterone (DHEA) [nmol/l]), basal cortisol (nmol/l) | Effect of Anakinra/Kineret® on peripheral (sexual) hormones will be assessed | Day 1, 7, 14, 21, 28 and 35 | 
| Fasting glucose (mmol/l), homeostatic model of assessment of insulin resistance (HOMA-IR) | Effect of Anakinra/Kineret® on glucose metabolism will be assessed | At day 1, 7, 14, 21, 28 and 35 | 
| Pituitary hormones (luteinizing hormone (LH), follicle stimulating hormone (FSH), adrenocorticotropic hormone (ACTH) [IU/L]) | Effect of Anakinra/Kineret® on the pituitary-gonadal axis will be assessed | Day 1, 7, 14, 21, 28 and 35 | 
| Treatment response according to a Dexamethasone suppression test | Dexamethasone suppression test will be evaluated as a predictor for treatment response | At days 35 and 36 | 
| inflammatory marker white blood cell count [x109/l], | Time course of inflammatory marker white blood cell count [x109/l] will be assessed | Day 1, 7, 14, 21, 28 and 35 | 
| inflammatory marker C reactive protein (CRP) [mg/l] | Time course of inflammatory marker CRP [mg/l] will be assessed | Day 1, 7, 14, 21, 28 and 35 | 
| inflammatory marker IL-6 [pg/ml] | Time course of inflammatory marker IL-6 [pg/ml] will be assessed | Day 1 and 28 | 
| inflammatory marker IL-1Ra [pg/ml] | Time course of inflammatory marker IL-1Ra [pg/ml] will be assessed | Day 1, 7, 14, 21, 28 and 35 | 
| Change in androstenedione level (nmol/l) from start (baseline, day 1) to days 14, 21, 28, and 35 after treatment start with Anakinra. | Change in androstenedione level (nmol/l) from start (baseline, day 1) to days 14, 21, 28, and 35 after treatment start with Anakinra. | Days 14, 21, 28, and 35 after treatment start with Anakinra | 
| Change in 11-oxygenated androgens (e.g. 11-ketotestosterone, 11-ketoandrostenedione, 11β-hydroxytestosterone, 11β-hydroxyandrostenedione [nmol/l]) on days 7, 14, 28, and 35 after treatment start with Anakinra | Change in 11-oxygenated androgens (e.g. 11-ketotestosterone, 11-ketoandrostenedione, 11β-hydroxytestosterone, 11β-hydroxyandrostenedione [nmol/l]) on days 7, 14, 28, and 35 after treatment start with Anakinra | Days 7, 14, 28, and 35 after treatment start with Anakinra | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Interleukin-1 receptor antagonism, Kineret/Anakinra, testosteron, hyperandrogenemia, androstenedione