Evaluation of Testosterone Gel on Physical Performance in Patients Requiring Prolonged Invasive Mechanical Ventilation: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to demonstrate that daily administration of **testosterone** gel, 101.25 mg in men and 20.25 mg in women, during the acute phase of critical illness, is more effective than placebo in improving physical performance 3 months after ICU admission. This is clinically relevant as it addresses the potential for testosterone therapy to enhance recovery and physical rehabilitation in critically ill patients, potentially reducing long-term morbidity associated with prolonged ICU stays.

Secondary objectives include:

• Demonstrating the effectiveness of testosterone gel in improving physical performance 6 months and 1 year after ICU admission.
• Assessing its impact on increasing muscle strength at ICU discharge and at 3, 6 months, and 1 year post-admission.
• Evaluating improvements in functional status at 3, 6 months, and 1 year after ICU admission.
• Investigating the enhancement of oxygen muscular consumption at ICU discharge and at 3 months.
• Evaluating the impact on the duration of invasive mechanical ventilation, length of stay in the ICU and hospital, and mortality rates at 28 and 90 days post-ICU admission, as well as hospital and ICU mortality rates.
• Assessing the safety of testosterone gel in critically ill patients.

The clinical trial involves a study population comprising both **male** and **female** participants aged over 18 years. The trial does not specifically target a vulnerable population. Participants are expected to require **invasive mechanical ventilation** for more than 48 hours, which is a significant medical condition under investigation. The trial aims to assess the efficacy of daily administration of testosterone gel in improving physical performance three months after ICU admission. The sponsor has not provided information regarding the total number of participants. Participants were selected based on criteria such as age, gender, and the requirement for mechanical ventilation, with additional considerations for females of childbearing potential, including a negative pregnancy test and the use of contraception. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study includes individuals with or without COVID-19, and informed consent is a prerequisite for participation.

The clinical trial is designed as a **randomized, double-blind, controlled** study to evaluate the effects of early administration of **testosterone** gel on physical performance in critically ill patients. The trial aims to demonstrate that daily administration of testosterone gel, at a dose of 101.25 mg for men and 20.25 mg for women, is more effective than a placebo in improving physical performance three months after ICU admission. The study will involve participants who are expected to require invasive mechanical ventilation for more than 48 hours. The trial is set to run from July 21, 2023, with an estimated end date of July 31, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age over 18 years, a negative pregnancy test for females of childbearing potential, and written informed consent. The trial will include follow-up visits at 3, 6 months, and 1 year after ICU admission to assess primary and secondary endpoints, including physical performance measured by the 6-minute-walk distance test, muscle strength, muscle mass, functional status, and safety of the testosterone gel. The end-of-study visit will occur at the conclusion of the participant's involvement, which is expected to last up to 28 days for the treatment period, with additional follow-up assessments extending up to one year.

Participant involvement may be terminated early if they experience adverse events related to the treatment, withdraw consent, or if the investigator deems it necessary for safety reasons. The trial will ensure that all procedures adhere to ethical standards and regulatory requirements, maintaining the integrity and scientific validity of the study. The trial's primary endpoint is the improvement in physical performance, specifically a minimum absolute difference of 30 meters in the 6-minute-walk distance test three months post-ICU admission. Secondary endpoints include assessments of muscle strength, muscle mass, functional status, and safety parameters such as cardiovascular events and changes in hematological profiles.

The clinical trial involves the administration of **ANDROGEL 16.2 mg/g**, a gel formulation containing the active substance **testosterone**. This pharmaceutical product is manufactured by Laboratoires Besins International and is authorized for use in France. The gel is applied cutaneously, with a maximum daily dose of 101.25 mg for men and 20.25 mg for women, and a total maximum dose of 2835 mg over a treatment period of 28 days. The primary objective is to assess the efficacy of testosterone gel in improving physical performance in critically ill patients three months post-ICU admission. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

The study also includes a **placebo** control, formulated as a gel and produced by CHU Clermont Ferrand. The placebo is structurally diverse and does not contain active testosterone. It is administered cutaneously in the same manner and dosage as the experimental testosterone gel, ensuring blinding and comparability between treatment groups. The placebo serves as a comparator to evaluate the true effect of testosterone on the study's primary outcome. Participant compliance with the placebo administration is similarly monitored to maintain the integrity of the trial results.

Efficacy in this clinical trial will be assessed primarily through the evaluation of physical performance 3 months after ICU admission. The primary endpoint is the 6-minute-walk distance test (6MWD), measured in meters, with a focus on demonstrating a minimum absolute difference of 30 meters between the treatment and placebo groups. Secondary endpoints include additional assessments of physical performance at 3, 6 months, and 1 year post-ICU admission, using the 6MWD, the Short Physical Performance Battery, and the physical component of the SF-36 survey.

Muscle strength will be evaluated at ICU discharge and at subsequent intervals of 3, 6 months, and 1 year, using handgrip strength in kilograms and the Medical Research Council (MRC) scale. Muscle mass will be assessed through mid-arm muscle circumference (MAMC) at the same timepoints. Functional status will be measured using a composite score of 11 items of Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL). Additional parameters include oxygen muscular consumption at ICU discharge and 3 months post-admission, ventilation-free days at day 28, and various mortality rates.

Safety assessments will monitor potential adverse effects of the testosterone gel, including hypertension, cardiovascular events, obstructive sleep apnea, and changes in hematological parameters, among others. The trial will also track the length of stay in the ICU and hospital. These efficacy and safety parameters will be collected and analyzed at specified intervals to determine the overall effectiveness of the testosterone gel treatment compared to placebo.