Effects of IL-1 Beta on the Hypothalamic-pituitary-gonadal (HPG) Axis in Men With Obesity and Metabolic Syndrome - The TestIL Trial
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 70
- 试验地点
- 2
- 主要终点
- Total morning testosterone (nmol/l)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Informed consent as documented by signature,
- •Men at the age between 18 and 75 years,
- •BMI >30 kg/m2 and at least 1 manifestation of the metabolic syndrome (i.e. prediabetes, diabetes, hypertension, dyslipidemia),
- •Total testosterone level <12 nmol/l.
排除标准
- •Previous or current medication with testosterone,
- •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,
- •Clinical signs of infection in the week before inclusion or history of a severe infection during the last 2 months,
- •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),
- •Hematologic disease (leukocyte count < 1.5 x 109/l, hemoglobin < 11 g/dl, platelets <100 x 103/µl),
- •Other clinically significant concomitant disease states (e.g., renal failure [Creatinine-Clearance < 30 ml/min], hepatic dysfunction [transaminases >3x upper normal range], active carcinoma,
- •History of tuberculosis,
- •Known or suspected non-compliance, drug or alcohol abuse,
- •Contraindications to the class of drugs under study, e.g. known hypersensitivity or allergy to anakinra/Kineret®,
- •Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant,
- •Previous enrolment into the current study.
研究组 & 干预措施
Anakinra
Anakinra//Kineret® 100mg s.c. bid
干预措施: Anakinra (Drug)
Placebo
Sodium Chloride 0.9% s.c. bid
干预措施: Sodium Chloride 0.9% (Drug)
结局指标
主要结局
Total morning testosterone (nmol/l)
时间窗: 4 weeks
次要结局
- Interleukin-1, Interleukin-6 (pg/ml)(1 week, 4 weeks and 3 months)
- Total morning testosterone (nmol/l)(1 week and 3 months)
- Free testosterone (nmol/l)(1 week, 4 weeks and 3 months)
- Bioavailable testosterone (nmol/l)(1 week, 4 weeks and 3 months)
- Cortisol basal (nmol/l)(1 week, 4 weeks and 3 months)
- C-reactive protein (mg/l)(1 week, 4 weeks and 3 months)
- free T4 (pmol/l)(1 week, 4 weeks and 3 months)
- T3 (nmol/l)(1 week, 4 weeks and 3 months)
- IGF-1 (nmol/l)(1 week, 4 weeks and 3 months)
- Erectile dysfunction as assessed by International Index of Erectile Function (IIEF) score(1 week, 4 weeks and 3 months)
- Clinical severity of hypogonadism as assessed by quantitative Androgen Deficiency in the Aging Male (qADAM) questionnaire(1 week, 4 weeks and 3 months)
- Proportion of muscle mass as assessed by bioelectrical impedance Analysis(1 week, 4 weeks and 3 months)
- Proportion of fat mass as assessed by bioelectrical impedance Analysis(1 week, 4 weeks and 3 months)
- HbA1c (%)(1 week, 4 weeks and 3 months)
- LH and FSH (IU/l)(1 week, 4 weeks and 3 months)
- Inhibin B, ACTH (pg/ml)(1 week, 4 weeks and 3 months)
- Prolactin, TSH, Insulin (mIU/l)(1 week, 4 weeks and 3 months)
- GH (mU/l)(1 week, 4 weeks and 3 months)
- Androstendione (μg/l)(1 week, 4 weeks and 3 months)
- DHEAS (μmol/l)(1 week, 4 weeks and 3 months)
- Oestradiol (pmol/l)(1 week, 4 weeks and 3 months)
- Oestron (ng/l)(1 week, 4 weeks and 3 months)
- 17-OH-progesterone (nmol/l)(1 week, 4 weeks and 3 months)
- Copeptin (pmol/l)(1 week, 4 weeks and 3 months)
- Sex hormone-binding globulin (SHBG)(1 week, 4 weeks and 3 months)
- Muscle strength as assessed by grip strength test(1 week, 4 weeks and 3 months)
- Waist-hip-ratio(1 week, 4 weeks and 3 months)
- BMI in kg/m2(1 week, 4 weeks and 3 months)
- Insulin sensitivity as assessed by homeostasis model assessment insulin resistance (HOMA-IR)(1 week, 4 weeks and 3 months)
- Total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides (mmol/l)(1 week, 4 weeks and 3 months)
- Leptin (μg/l)(1 week, 4 weeks and 3 months)