Clinical trial NCT02672592: Effects of Interleukin-1 Beta on Low Testosterone Levels in Men With Obesity and Metabolic Syndrome
Official title: Effects of IL-1 Beta on the Hypothalamic-pituitary-gonadal (HPG) Axis in Men With Obesity and Metabolic Syndrome - The TestIL Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hypogonadism
Metabolic Syndrome X
Obesity
Keywords: Metabolic syndrome X
Hypogonadism
Testosterone
Inflammation
Obesity
Lead sponsor: University Hospital, Basel, Switzerland
Sponsor class: OTHER
First posted: 2016-02-03
Enrollment: 70
Sex: MALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Total morning testosterone (nmol/l)
timeFrame: 4 weeks
Secondary outcomes:
measure: Total morning testosterone (nmol/l)
timeFrame: 1 week and 3 months
measure: Free testosterone (nmol/l)
timeFrame: 1 week, 4 weeks and 3 months
measure: Bioavailable testosterone (nmol/l)
timeFrame: 1 week, 4 weeks and 3 months
measure: Erectile dysfunction as assessed by International Index of Erectile Function (IIEF) score
timeFrame: 1 week, 4 weeks and 3 months
measure: Clinical severity of hypogonadism as assessed by quantitative Androgen Deficiency in the Aging Male (qADAM) questionnaire
timeFrame: 1 week, 4 weeks and 3 months
measure: Proportion of muscle mass as assessed by bioelectrical impedance Analysis
timeFrame: 1 week, 4 weeks and 3 months
measure: Proportion of fat mass as assessed by bioelectrical impedance Analysis
timeFrame: 1 week, 4 weeks and 3 months
measure: HbA1c (%)
timeFrame: 1 week, 4 weeks and 3 months
measure: LH and FSH (IU/l)
timeFrame: 1 week, 4 weeks and 3 months
measure: Inhibin B, ACTH (pg/ml)
timeFrame: 1 week, 4 weeks and 3 months
measure: Prolactin, TSH, Insulin (mIU/l)
timeFrame: 1 week, 4 weeks and 3 months
measure: Interleukin-1, Interleukin-6 (pg/ml)
timeFrame: 1 week, 4 weeks and 3 months
measure: Cortisol basal (nmol/l)
timeFrame: 1 week, 4 weeks and 3 months
measure: C-reactive protein (mg/l)
timeFrame: 1 week, 4 weeks and 3 months
measure: free T4 (pmol/l)
timeFrame: 1 week, 4 weeks and 3 months
measure: T3 (nmol/l)
timeFrame: 1 week, 4 weeks and 3 months
measure: IGF-1 (nmol/l)
timeFrame: 1 week, 4 weeks and 3 months
measure: GH (mU/l)
timeFrame: 1 week, 4 weeks and 3 months
measure: Androstendione (μg/l)
timeFrame: 1 week, 4 weeks and 3 months
measure: DHEAS (μmol/l)
timeFrame: 1 week, 4 weeks and 3 months
measure: Oestradiol (pmol/l)
timeFrame: 1 week, 4 weeks and 3 months
measure: Oestron (ng/l)
timeFrame: 1 week, 4 weeks and 3 months
measure: 17-OH-progesterone (nmol/l)
timeFrame: 1 week, 4 weeks and 3 months
measure: Copeptin (pmol/l)
timeFrame: 1 week, 4 weeks and 3 months
measure: Sex hormone-binding globulin (SHBG)
timeFrame: 1 week, 4 weeks and 3 months
measure: Muscle strength as assessed by grip strength test
timeFrame: 1 week, 4 weeks and 3 months
measure: Waist-hip-ratio
timeFrame: 1 week, 4 weeks and 3 months
measure: BMI in kg/m2
timeFrame: 1 week, 4 weeks and 3 months
measure: Insulin sensitivity as assessed by homeostasis model assessment insulin resistance (HOMA-IR)
timeFrame: 1 week, 4 weeks and 3 months
measure: Total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides (mmol/l)
timeFrame: 1 week, 4 weeks and 3 months
measure: Leptin (μg/l)
timeFrame: 1 week, 4 weeks and 3 months
Other outcomes:
Locations:
city: Aarau
country: Switzerland
facility: University Department of Medicine, Kantonsspital Aarau
city: Basel
country: Switzerland
facility: University Hospital Basel
Study officials:
affiliation: Endocrinology, Diabetes and Metabolism; University Hospital Basel
name: Mirjam Christ-Crain, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: University Department of Medicine; Kantonsspital Aarau
name: Beat Müller, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ebrahimi F, Urwyler SA, Betz MJ, Christ ER, Schuetz P, Mueller B, Donath MY, Christ-Crain M. Effects of interleukin-1 antagonism and corticosteroids on fibroblast growth factor-21 in patients with metabolic syndrome. Sci Rep. 2021 Apr 12;11(1):7911. doi: 10.1038/s41598-021-87207-w.
citation: Urwyler SA, Ebrahimi F, Burkard T, Schuetz P, Poglitsch M, Mueller B, Donath MY, Christ-Crain M. IL (Interleukin)-1 Receptor Antagonist Increases Ang (Angiotensin [1-7]) and Decreases Blood Pressure in Obese Individuals. Hypertension. 2020 Jun;75(6):1455-1463. doi: 10.1161/HYPERTENSIONAHA.119.13982. Epub 2020 Apr 10.
citation: Ebrahimi F, Urwyler SA, Schuetz P, Mueller B, Bernasconi L, Neyer P, Donath MY, Christ-Crain M. Effects of interleukin-1 antagonism on cortisol levels in individuals with obesity: a randomized clinical trial. Endocr Connect. 2019 Jun 1;8(6):701-708. doi: 10.1530/EC-19-0201.
citation: Ebrahimi F, Urwyler SA, Straumann S, Doerpfeld S, Bernasconi L, Neyer P, Schuetz P, Mueller B, Donath MY, Christ-Crain M. IL-1 Antagonism in Men With Metabolic Syndrome and Low Testosterone: A Randomized Clinical Trial. J Clin Endocrinol Metab. 2018 Sep 1;103(9):3466-3476. doi: 10.1210/jc.2018-00739.