52 Week RCT to Investigate the Effect of Testosterone Undecanoate vs Placebo on Intrahepatic Fat Content in Obese/Overweight Men With T2DM/Prediabetes and Hypogonadism and Subsequent 108 Week Open Label Phase to Investigate Effects on Cardiometabolic Parameters
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 发起方
- 入组人数
- 32
- 试验地点
- 1
- 主要终点
- Liver fat
研究概览
简要总结
The epidemics of obesity, MeTSy, T2DM and CVD are increasing worldwide. Non-alcoholic fatty liver disease (NAFLD) is becoming recognized as a condition possibly involved in the pathogenesis of these diseases. The prevailing hypothesis for NAFLD pathogenesis is the 'two-hit' model, with insulin resistance and hyperinsulinemia playing essential roles, which have a plethora of effects on hepatic lipid metabolism and can lead to accumulation of triglycerides in hepatocytes. Accepted treatment for NAFLD is lifestyle modifications. Sex hormones might be relevant in T2DM development and treatment. Low testosterone (T) has deteriorating effects on glucose levels, and aggravates in obesity as aromatization of T is enhanced. T deficiency is related to increases of visceral fat accumulation and associated with development of NAFLD. T replacement might be a successful way in hypogonadism to treat obesity and counteract progression of MEtSy,T2DM or CVD driven by visceral fat accumulation or NAFLD.
Primary Objective To investigate the effects on hepatic lipid content reduction of a therapy with Testosterone undecanoate 1000mg compared to placebo given for 52 weeks in patients with type 2 diabetes mellitus and hypogonadism.
详细描述
Background The epidemics of obesity, metabolic syndrome, type 2 diabetes, and atherosclerosis are increasing worldwide. Non-alcoholic fatty liver disease (NAFLD), for a long time unnoted in the metabolic field, is becoming recognized as a condition possibly involved in the pathogenesis of these diseases. Support for this hypothesis emerges from studies revealing that NAFLD precedes the manifestation of the metabolic derangements. NAFLD includes the whole spectrum from non-evolutive simple steatosis to progressive non-alcoholic steatohepatitis (NASH) with/without cirrhosis and hepatocellular carcinoma in individuals without relevant alcohol consumption. NAFLD is a relevant issue in public health owing to its' epidemiologic burden. It represents the most common chronic liver disease in the general population and is expected to increase in the future as a result of an ageing population, the improving control of other major causes of chronic liver disease and the epidemics of obesity and diabetes. The prevalence of NAFLD varies according to age, gender and ethnicity. In the general population, the prevalence of NAFLD is about 25% and the incidence is of two new cases/100 people/year. 2-3% of individuals in the general population will suffer from NASH. Furthermore, up to 15-20% of patients with NASH may develop cirrhosis and 30-40%of these patients who develop cirrhosis may suffer from liver-related mortality. NAFLD is tightly associated with the metabolic syndrome. The metabolic syndrome is a condition characterized by a cluster of alterations including glucose intolerance/ insulin resistance, abdominal obesity, atherogenic dyslipidemia (low concentrations of high density lipoprotein- cholesterol and high concentrations of triglycerides), elevated blood pressure, a proinflammatory and a prothrombotic state. It increases morbidity and mortality, especially due to cardiovascular disease. The prevailing hypothesis for NAFLD pathogenesis is the 'two-hit' model, with insulin resistance and hyperinsulinemia playing essential roles. Insulin resistance and hyperinsulinemia have a plethora of effects on hepatic lipid metabolism and can lead to accumulation of excess triglycerides in hepatocytes. The progression to NASH entails a 'second hit', which is believed to be due to oxidative stress, upregulation of inflammatory mediators, and dysregulated apoptosis, resulting in inflammation (producing NASH) and fibrosis. Currently, the only accepted treatment for NAFLD regardless of stage is lifestyle modifications. These include weight loss by a combination of decreased caloric intake and increased physical activity.
Study rationale Many patients worldwide are suffering from type 2 diabetes with steeply rising numbers predicted for the next decades. Although much progress can be seen in the field of diabetic research and new treatment modalities, new approaches have to be found to cure the disease and underlying risk factors. As men and women show sex specific differences especially in risk factors of T2DM, a sex- and gender-sensitive approach might be considered. Sex hormones might play an important role in the development and possibly the treatment of T2DM. In women higher but in men lower than normal testosterone concentrations predispose for a higher diabetes risk making evident that sex hormones and sex hormone equilibrium are relevant in disease progression. Especially in men low testosterone levels have deteriorating effects on glucose levels, which is aggravated in obesity as aromatization of testosterone to estrogen is enhanced. Due to this mechanism changes in energy homeostasis are reported which lead to changes in lipid accumulation, as described for visceral obesity. Testosterone deficiency is related to increases of visceral fat accumulation. Furthermore testosterone deficiency is associated with the development of non alcoholic fatty liver disease (NAFLD), a well known risk factor for progression of metabolic syndrome (MEtSy), T2DM and cardiovascular disease. Thus, testosterone replacement might be a successful way in hypogonadal men to treat obesity and counteract the further progression of MEtSy, T2DM or cardiovascular disease mainly driven by visceral fat accumulation and NAFLD and are able to improve quality of life.
Testosterone and changes in metabolism:
Whether low testosterone levels have direct effects on hyperglycaemia or testosterone deficiency is caused by chronic diseases such as type 2 diabetes is not yet fully understood and needs further clarification.
Studies are showing that the link between hypogonadism and the metabolic syndrome is bidirectional. On the one hand MetSy and obesity are associated with a higher risk of hypogonadism in the future but on the other hand low testosterone levels and SHBG levels are strong predictors for the development of MetSy and T2DM. It is further hypothesized that hypoandrogenism is an early marker for disturbances in glucose metabolism. Many studies proved that low testosterone levels may aggravate hyperglycaemia and also may deteriorate other metabolic parameters such as insulin levels and sensitivity, lipid levels, hepatic, myocardial and visceral fat content or body composition in general. Just recently the ADA recommends to test for testosterone deficiency (morning testosterone levels) in all men with T2DM with symptoms or signs of hypogonadism, which are decreased sexual desire or erectile dysfunction.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 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
- •prediabetes/T2DM
- •HbA1c >=5.7% -9.0% or fasting glucose >=100mg/dl or postprandial glucose>= 140mg/dl
- •Age >=18 -75 years
- •BMI>=25kg/m²
- •Hypogonadism assessed by laboratory testing (testosterone < 4,04ng/ml (=14nmol/l) Metformin 8 weeks stable dose, SGLT2 inhibitors 3 months stable dose, DPP4 inhibitors 3 months stable dose, GLP1 RA 3 months stable dose and long acting insulin (basal insulin) 8 weeks stable dose
- •able and willing to not change diet and physical activity during enrollment in study
- •consent and able to give informed consent.
排除标准
- •Current testosterone treatment or testosterone replacement within the last 12 month
- •Serum creatinine>1,5mg/dl
- •Liver enzymes above 3 fold normal range
- •PSA>4.0μg/l
- •Hematocrit>50%
- •Known intolerance to testosterone undecanoate or any of its ingredients
- •Myocardial infarction within the last 12month
- •Stroke within the last 12 month
- •Untreated congestive heart disease
- •malignancy within the last 5 years before randomization
- •Prostate cancer or any suspicion thereof
- •Breast cancer
- •Liver tumor/cancer
- •Presence of any absolute or relative contraindication for the conduct of an MRI investigation, such as cardiac pacemakers, ferromagnetic haemostatic clips in the central nervous system, metallic splinters in the eye, ferromagnetic or electronically operated active devices like automatic cardioverter defibrillators, cochlear implants, insulin pumps and nerve stimulators, prosthetic heart valves etc.
- •patients on antidiabetic medication like Sulfonylurea or Glitazones.
- •Any other clinical condition that would jeopardize patients safety while participating in this clinical trial
- •Known autoimmune disease or chronic inflammatory condition
- •Other liver disease including chronic viral hepatitis (B or C), alcohol abuse, hemochromatosis, alpha-1 antitrypsin deficiency, autoimmune hepatitis, Wilson's disease, primary sclerosing cholangitis or primary biliary cirrhosis, or liver cirrhosis of any etiology
- •Alcohol or drug abuse within the 3 months prior to informed consent that would interfere with trial participation or any ongoing condition leading to a decreased compliance to study procedures or study drug intake
- •History of bariatric surgery
- •Treatment with anti-obesity drugs (e.g. sibutramine, orlistat) 3 months prior to informed consent or any other treatment at the time of screening (i.e. surgery, aggressive diet regimen, etc.) leading to unstable body weight
- •Subjects receiving antihypertensive medication and/or thyroid hormones, the dose(s) of which have not been stable for at least 6 weeks prior to baseline
- •Uncontrolled/ untreated hypertension
- •Current treatment with systemic steroids at time of informed consent. (Treatment with local and inhaled steroids is allowed)
- •Donation of blood (> 400 mL) during the previous 3 months prior to the screening visit or during the duration of the study
- •Participation in another trial with an investigational drug within 30 days prior to informed consent.
- •Pharmacist, study coordinator, other staff thereof, directly involved in the conduct of the protocol.
- •contraindication for intramuscular injection (e.g patient receiving anticoagulants on a regular basis such as NOAKs or VKAs, or DAPT).
- •COPD Gold IV or recurrent acute or allergic asthma (for MPI)
- •Contraindications for cardiac stress test as acute myocardial infarction, instable angina, severe hypertension, myocarditis, life threatening rhythmic disorders without physical activity.
研究组 & 干预措施
Testosterone undecanoate
intramuscular Testosterone undecanoate 1000mg/4ml
干预措施: Testosterone Undecanoate (Drug)
Testosterone like Placebo
intramuscular Testosterone undecanoate like Placebo
干预措施: Placebo (Drug)
结局指标
主要结局
Liver fat
时间窗: baseline to week 52, and after 2 years follow up
Change in Liver fat content
次要结局
- quality of live questionnaire(baseline to week 52, and after 2 years follow up)
- waist, hip and neck circumference(baseline to week 52, and after 2 years follow up)
- insulin sensitivity(baseline to week 52, and after 2 years follow up)
- Concentration of lipids(baseline to week 52, and after 2 years follow up)
- body weight(baseline to week 52, and after 2 years follow up)
- Level of HbA1c(baseline to week 52, and after 2 years follow up)
- blood pressure(baseline to week 52, and after 2 years follow up)
- sexual function questionnaire(baseline to week 52, and after 2 years follow up)
- diabetes management satisfaction questionnaire(baseline to week 52, and after 2 years follow up)
研究者
Alexandra Kautzky-Willer
Head of Department of Endocrinology, Principal Investigator
Medical University of Vienna