A 52-Week Randomized Controlled Trial of Intramuscular Testosterone Undecanoate on Intrahepatic Fat in Obese Hypogonadal Men with Type 2 Diabetes or Prediabetes

Trial ID: 2023-509819-87-00
Sponsor: Medical University Of Vienna

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Diseases & Conditions

Type 2 diabetes mellitus Obesity Hypogonadism male

Objectives

The primary objective of this study is to evaluate the effects of **testosterone undecanoate** supplementation on intrahepatic fat content in obese men with uncontrolled type 2 diabetes (T2DM) or prediabetes who are also suffering from hypogonadism. This is assessed by measuring the change in intrahepatic fat content from baseline to follow-up. The clinical relevance of this objective lies in addressing the potential therapeutic benefits of testosterone supplementation in reducing liver fat, which is a significant concern in patients with T2DM and hypogonadism, potentially impacting overall metabolic health and reducing the risk of liver-related complications.

Participants

The clinical trial involves a study population of **male** participants aged between 18 and 75 years, specifically targeting individuals diagnosed with **hypogonadism** and either type 2 diabetes or prediabetes. The trial does not include female subjects, and the participants are not considered a vulnerable population. The sponsor has not provided the total number of participants. Participants were selected based on specific health criteria, including a body mass index (BMI) of 25 kg/m² or higher, and stable doses of certain diabetes medications such as metformin, SGLT2 inhibitors, DPP4 inhibitors, GLP1 agonists, and long-acting insulin. Additionally, participants are required to maintain their current diet and physical activity levels throughout the study. The trial aims to assess the effects of testosterone supplementation on intrahepatic fat content in this specific population.

Plans and Procedures

The clinical trial is a **randomized**, **controlled** study designed to evaluate the effects of **testosterone undecanoate** supplementation compared to placebo on intrahepatic fat content in obese men with uncontrolled type 2 diabetes and hypogonadism. The trial consists of a 52-week double-blind phase followed by a 108-week open-label phase, making the total duration approximately 160 weeks. Participants will be randomly assigned to receive either the active treatment, Nebido 1000 mg/4 ml solution for injection, or a placebo, administered via **intramuscular use**. The primary objective is to assess changes in liver fat content from baseline to week 52 using magnetic resonance spectroscopy (MRS).

Study visits are structured to ensure comprehensive monitoring and data collection. The initial inclusion visit, or screening, will determine eligibility based on criteria such as male sex, age between 18 and 75 years, a body mass index (BMI) of 25 kg/m² or higher, and confirmed hypogonadism. Participants must also have stable doses of specific diabetes medications. Follow-up visits will occur at regular intervals to monitor safety, efficacy, and adherence to the study protocol. The end-of-study visit will conclude the participant's involvement, with a final assessment of the primary and secondary endpoints.

Participant involvement is expected to last for the entire duration of the trial, approximately 160 weeks, unless early termination is warranted. Conditions for early withdrawal include adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial is conducted in accordance with ethical standards and regulatory requirements, ensuring the safety and well-being of all participants throughout the study period.

Treatment

The clinical trial involves the administration of **testosterone undecanoate** as the experimental medication. The product, marketed under the name Nebido 1000 mg/4 ml Injektionslösung, is a **solution for injection**. The active substance, testosterone undecanoate, is of chemical origin. The medication is administered via **intramuscular use**. The dosage form is a solution, with a maximum daily dose of 3.58 mg/ml and a total maximum dose of 250 mg/ml. The treatment period is set for 52 weeks. The pharmaceutical product is manufactured by Grünenthal Ges. M.B.H. in Austria, and it is not a paediatric formulation. Participant compliance with the dosing schedule will be monitored throughout the study.

The study also includes a **placebo** comparator, referred to as Placebo to Nebido. This placebo is designed to match the experimental medication in appearance but does not contain any active substance. The placebo is used to ensure the validity of the study by providing a control group for comparison against the effects of testosterone undecanoate. The placebo is not associated with any specific pharmaceutical form or active substance, and it is not a paediatric formulation. The administration route for the placebo is not specified, but it is implied to be consistent with the experimental medication for blinding purposes.

Efficacy

Efficacy in this clinical trial will be assessed by evaluating the primary endpoint, which is the change in liver fat content. This will be measured using magnetic resonance spectroscopy (MRS) from baseline to week 52. The trial is designed to investigate the effects of intramuscular **testosterone undecanoate** supplementation compared to placebo in obese men with uncontrolled type 2 diabetes and hypogonadism. The primary objective is to identify the effects of testosterone supplementation on intrahepatic fat content, assessed as a change from baseline to follow-up.

Inclusion and Exclusion Criteria

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Inclusion Criteria

T2DM or prediabetes, male sex, 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: two measurements below lower limit of normal total testosterone levels (< 4,04ng/ml (=14nmol/l) according to guideline Wittert et al. Lancet Diabetes Endocrinol. 2021), Metformin >=8 weeks stable dose, SGLT2 inhibitors >=3 months stable dose, DPP4 inhibitors or GLP1 agonist >= 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 enrolement in study, consent and able to give informed consent.

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Exclusion Criteria

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 • Epilepsy • Migraine • 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 • 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. • Any subject who is the investigator or any subinvestigator, research assistant, 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)