Effects of Interleukin-1 Beta on Low Testosterone Levels in Men With Obesity and Metabolic Syndrome

Overview

Obesity and the metabolic syndrome in men are associated with a high prevalence of hypogonadism of up to 50%. Increased fat mass leads to augmented release of adipocytokines and pro-inflammatory cytokines such as IL-1-beta, IL-6 and tumor necrosis factor-alpha which in turn suppress the hypothalamic-pituitary-gonadal (HPG) axis, leading to hypogonadism. This pathophysiological interplay is termed hypogonadal-obesity-adipocytokine hypothesis. TestIL is a prospective, multicenter, randomized, double-blinded, placebo-controlled trial to test the hypothesis that inhibition of IL-1-activity diminishes the inhibitory effects on HPG axis and increases testosterone levels in men with metabolic syndrome.

Full Title of Study: “Effects of IL-1 Beta on the Hypothalamic-pituitary-gonadal (HPG) Axis in Men With Obesity and Metabolic Syndrome – The TestIL Trial”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: June 2017

Detailed Description

Obesity and the metabolic syndrome are considered as chronic low-grade inflammatory states. Elevated pro-inflammatory mediators in obesity and metabolic syndrome have an inhibitory effect on the hypothalamic-pituitary-gonadal axis (HPG axis) leading to hypogonadism. Decreased testosterone production in obese men in turn promotes additional fat deposition, contributing to a vicious cycle of fat accumulation. This complex pathophysiological interplay is termed hypogonadal-obesity-adipocytokine hypothesis, describing a bidirectional relationship between low levels of testosterone and the metabolic syndrome. TestIL is a prospective, multicenter, randomized, double-blinded, placebo-controlled trial to test the hypothesis that inhibition of IL-1-activity diminishes the inhibitory effects on HPG axis and increases testosterone levels in men with metabolic syndrome.

Interventions

  • Drug: Anakinra
    • Anakinra 100mg s.c. bid
  • Drug: Sodium Chloride 0.9%
    • Sodium Chloride 0.9% s.c. bid

Arms, Groups and Cohorts

  • Active Comparator: Anakinra
    • Anakinra//Kineret® 100mg s.c. bid
  • Placebo Comparator: Placebo
    • Sodium Chloride 0.9% s.c. bid

Clinical Trial Outcome Measures

Primary Measures

  • Total morning testosterone (nmol/l)
    • Time Frame: 4 weeks

Secondary Measures

  • Total morning testosterone (nmol/l)
    • Time Frame: 1 week and 3 months
  • Free testosterone (nmol/l)
    • Time Frame: 1 week, 4 weeks and 3 months
    • Assessed by equilibrium dialysis
  • Bioavailable testosterone (nmol/l)
    • Time Frame: 1 week, 4 weeks and 3 months
    • Assessed by equilibrium dialysis
  • Erectile dysfunction as assessed by International Index of Erectile Function (IIEF) score
    • Time Frame: 1 week, 4 weeks and 3 months
  • Clinical severity of hypogonadism as assessed by quantitative Androgen Deficiency in the Aging Male (qADAM) questionnaire
    • Time Frame: 1 week, 4 weeks and 3 months
  • Proportion of muscle mass as assessed by bioelectrical impedance Analysis
    • Time Frame: 1 week, 4 weeks and 3 months
  • Proportion of fat mass as assessed by bioelectrical impedance Analysis
    • Time Frame: 1 week, 4 weeks and 3 months
  • HbA1c (%)
    • Time Frame: 1 week, 4 weeks and 3 months
  • LH and FSH (IU/l)
    • Time Frame: 1 week, 4 weeks and 3 months
  • Inhibin B, ACTH (pg/ml)
    • Time Frame: 1 week, 4 weeks and 3 months
  • Prolactin, TSH, Insulin (mIU/l)
    • Time Frame: 1 week, 4 weeks and 3 months
  • Interleukin-1, Interleukin-6 (pg/ml)
    • Time Frame: 1 week, 4 weeks and 3 months
  • Cortisol basal (nmol/l)
    • Time Frame: 1 week, 4 weeks and 3 months
  • C-reactive protein (mg/l)
    • Time Frame: 1 week, 4 weeks and 3 months
  • free T4 (pmol/l)
    • Time Frame: 1 week, 4 weeks and 3 months
  • T3 (nmol/l)
    • Time Frame: 1 week, 4 weeks and 3 months
  • IGF-1 (nmol/l)
    • Time Frame: 1 week, 4 weeks and 3 months
  • GH (mU/l)
    • Time Frame: 1 week, 4 weeks and 3 months
  • Androstendione (μg/l)
    • Time Frame: 1 week, 4 weeks and 3 months
  • DHEAS (μmol/l)
    • Time Frame: 1 week, 4 weeks and 3 months
  • Oestradiol (pmol/l)
    • Time Frame: 1 week, 4 weeks and 3 months
  • Oestron (ng/l)
    • Time Frame: 1 week, 4 weeks and 3 months
  • 17-OH-progesterone (nmol/l)
    • Time Frame: 1 week, 4 weeks and 3 months
  • Copeptin (pmol/l)
    • Time Frame: 1 week, 4 weeks and 3 months
  • Sex hormone-binding globulin (SHBG)
    • Time Frame: 1 week, 4 weeks and 3 months
  • Muscle strength as assessed by grip strength test
    • Time Frame: 1 week, 4 weeks and 3 months
  • Waist-hip-ratio
    • Time Frame: 1 week, 4 weeks and 3 months
  • BMI in kg/m2
    • Time Frame: 1 week, 4 weeks and 3 months
  • Insulin sensitivity as assessed by homeostasis model assessment insulin resistance (HOMA-IR)
    • Time Frame: 1 week, 4 weeks and 3 months
  • Total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides (mmol/l)
    • Time Frame: 1 week, 4 weeks and 3 months
  • Leptin (μg/l)
    • Time Frame: 1 week, 4 weeks and 3 months

Participating in This Clinical Trial

Inclusion Criteria

1. Informed consent as documented by signature, 2. Men at the age between 18 and 75 years, 3. BMI >30 kg/m2 and at least 1 manifestation of the metabolic syndrome (i.e. prediabetes, diabetes, hypertension, dyslipidemia), 4. Total testosterone level <12 nmol/l. Exclusion Criteria:

1. Previous or current medication with testosterone, 2. Testosterone deficiency of other cause, i.e. primary hypogonadism caused e.g. by Klinefelters syndrome, cryptorchidism, condition following orchiectomy. Known secondary hypogonadism caused by pituitary adenoma. Patients on antiandrogen medication, 3. Clinical signs of infection in the week before inclusion or history of a severe infection during the last 2 months, 4. Severe immunosuppression (e.g. patients with previously known infection with human immunodeficiency virus and a cluster of differentiation 4 (CD4) count below 350 x 109/L, patients on immunosuppressive therapy after solid organ transplantation and neutropenic patients with neutrophil count < 500 x 109/L and patients under chemotherapy with neutrophils 500-1000 x 109/L with an expected decrease to values < 500 x 109/L), 5. Hematologic disease (leukocyte count < 1.5 x 109/l, hemoglobin < 11 g/dl, platelets <100 x 103/µl), 6. Other clinically significant concomitant disease states (e.g., renal failure [Creatinine-Clearance < 30 ml/min], hepatic dysfunction [transaminases >3x upper normal range], active carcinoma, 7. History of tuberculosis, 8. Known or suspected non-compliance, drug or alcohol abuse, 9. Contraindications to the class of drugs under study, e.g. known hypersensitivity or allergy to anakinra/Kineret®, 10. Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant, 11. Previous enrolment into the current study.

Gender Eligibility: Male

Minimum Age: 18 Years

Maximum Age: 75 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University Hospital, Basel, Switzerland
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Mirjam Christ-Crain, Professor, Principal Investigator, Endocrinology, Diabetes and Metabolism; University Hospital Basel
    • Beat Müller, Professor, Principal Investigator, University Department of Medicine; Kantonsspital Aarau

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