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

• ClinicalTrials.gov Identifier: NCT03578497
• Recruitment Status: Completed
• First Posted: July 6, 2018
• Last Update Posted: January 27, 2021
• Sponsor: University Hospital, Basel, Switzerland
• Information provided by (Responsible Party): University Hospital, Basel, Switzerland

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Polycystic Ovary Syndrome	Drug: IL-1 receptor antagonist Anakinra	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: August 31, 2018
• Actual Primary Completion Date: July 30, 2020
• Actual Study Completion Date: July 30, 2020

Arms and Interventions

Arm

Intervention/treatment

Experimental: IL-1 receptor antagonist Anakinra 100 mg; 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; 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.; Other Name: Kineret

Outcome Measures

Primary Outcome Measures :

1. Absolute change in fasting serum androstenedione level (nmol/l) from start (baseline, day 1) to one week after treatment start with Anakinra. [ Time Frame: 7 days ]
   Absolute change in fasting serum androstenedione level (nmol/l) from start (baseline, day 1) to one week after treatment start with Anakinra.

Secondary Outcome Measures :

1. Ferriman-Gallwey-score [ Time Frame: Day 1 and 28 ]
   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
2. Sebum production measures [ Time Frame: At day 1 and 28 ]
   Effect of Anakinra/Kineret® on sebum production will be assessed with Sebumeter® SM 815, Courage + Khazaka electronic Gesellschaft mit beschränkter Haftung (GmbH)
3. Self-reported frequency of hair removal (times/week) [ Time Frame: At day 1 and 28 ]
   Effect of Anakinra/Kineret® on hirsutism will be assessed
4. Plewig-Kligman-score [ Time Frame: At day 1 and 28 ]
   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.
5. Ovulation and menstruation rates [%] [ Time Frame: Between day 1 and day 35 ]
   Effect of Anakinra/Kineret® on ovulation and menstruation rates will be assessed
6. 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) [ Time Frame: Day 1, 7, 14, 21, 28 and 35 ]
   Effect of Anakinra/Kineret® on peripheral (sexual) hormones will be assessed
7. Fasting glucose (mmol/l), homeostatic model of assessment of insulin resistance (HOMA-IR) [ Time Frame: At day 1, 7, 14, 21, 28 and 35 ]
   Effect of Anakinra/Kineret® on glucose metabolism will be assessed
8. Pituitary hormones (luteinizing hormone (LH), follicle stimulating hormone (FSH), adrenocorticotropic hormone (ACTH) [IU/L]) [ Time Frame: Day 1, 7, 14, 21, 28 and 35 ]
   Effect of Anakinra/Kineret® on the pituitary-gonadal axis will be assessed
9. Treatment response according to a Dexamethasone suppression test [ Time Frame: At days 35 and 36 ]
   Dexamethasone suppression test will be evaluated as a predictor for treatment response
10. inflammatory marker white blood cell count [x109/l], [ Time Frame: Day 1, 7, 14, 21, 28 and 35 ]
    Time course of inflammatory marker white blood cell count [x109/l] will be assessed
11. inflammatory marker C reactive protein (CRP) [mg/l] [ Time Frame: Day 1, 7, 14, 21, 28 and 35 ]
    Time course of inflammatory marker CRP [mg/l] will be assessed
12. inflammatory marker IL-6 [pg/ml] [ Time Frame: Day 1 and 28 ]
    Time course of inflammatory marker IL-6 [pg/ml] will be assessed
13. inflammatory marker IL-1Ra [pg/ml] [ Time Frame: Day 1, 7, 14, 21, 28 and 35 ]
    Time course of inflammatory marker IL-1Ra [pg/ml] will be assessed
14. Change in androstenedione level (nmol/l) from start (baseline, day 1) to days 14, 21, 28, and 35 after treatment start with Anakinra. [ Time Frame: 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.
15. 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 [ Time Frame: 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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

Switzerland

University Hospital Basel Endocrinology, Diabetes and Metabolism

Basel, Switzerland, 4031

Sponsors and Collaborators

University Hospital, Basel, Switzerland

Investigators

• Principal Investigator: Mirjam Christ-Crain, Prof. Dr. MD; University Hospital Basel, Dep. of Endocrinology, Diabetes and Metabolism

More Information

• Responsible Party: University Hospital, Basel, Switzerland
• ClinicalTrials.gov Identifier: NCT03578497
• Other Study ID Numbers: 2018-00780; me16CC6
• First Posted: July 6, 2018
• Last Update Posted: January 27, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by University Hospital, Basel, Switzerland:

Interleukin-1 receptor antagonism; Kineret/Anakinra; testosteron; hyperandrogenemia; androstenedione

Additional relevant MeSH terms:

Polycystic Ovary Syndrome; Syndrome; Disease; Pathologic Processes; Ovarian Cysts; Cysts; Neoplasms; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine System Diseases; Interleukin 1 Receptor Antagonist Protein; Antirheumatic Agents