Efficacy of Testosterone Gel to Restore Normal Serum Values of Testosterone During the Acute Phase of Critical Illness in Adult ICU Patients

Study Overview
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Brief Summary
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Critically ill patients experience major insults that lead to increased protein catabolism. Hypermetabolism occurs early and rapidly during the first week of critical illness to provide amino acids for the production of energy via gluconeogenesis, and also for the synthesis of acute phase proteins and repair of tissue damage. During acute phase, neuroendocrine and inflammatory responses promote protein breakdown and amino acid release. Under stress conditions, protein synthesis cannot match the increased rate of muscle proteolysis because of a state of anabolism resistance, which limits uptake of amino acids into muscles. Hypermetabolism results in a significant loss of lean body mass with an impact on weaning from the ventilator and muscle recovery. Functional disability may be long term sometimes with no full return to normal. In critically ill patients, severe and persistent testosterone deficiency is very common and is observed early after ICU admission. This acquired hypogonadism promotes the persistent loss of skeletal muscle protein and is related to poor outcome. Administration of testosterone induces skeletal muscle fiber hypertrophy, decreases protein breakdown in healthy young men and burned patients. It has been repeatedly shown that testosterone treatment enhances muscle mass and strength in young and older hypogonadal men and women and can improve physical performance.

Detailed Description
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Type of trial TestICUs-1 is a single center open-label parallel randomized controlled study phase II assessing the efficacy of testosterone gel to correct low testosterone serum levels associated with ICU acquired hypogonadism in mechanically ventilated patients with shock. TestICUs-1 will be conducted in the 10-bed medical ICU of the university hospital of Clermont-Ferrand. Study drug is Androgel® 1.62 mg/L approved by the ANSM for the treatment of hypogonadism in men containing 1.62% of testosterone. Category of research Research involving human subjects aimed at assessing the efficacy of and safety to drug. Study phase II/ Feasibility Technology Readiness Level : 7 B A study assessing the efficacy of a multimodal strategy including treatment with testosterone gel, (75 mg/day in men and 25 mg/day in women) in improving physical activity in hemodialysis patients is in progress (Americano PHRC N 2012, AE Heng).

Official Title
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Efficacy of Testosterone Gel to Restore Normal Serum Values of Testosterone During the Acute Phase of Critical Illness in Adult ICU Patients

Conditions
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Hypermetabolism in ICU, Loss of Muscle Mass, Functional Disability After ICU, ICU Acquired Hypogonadism, Treatment With Testosterone Gel in ICU

Intervention / Treatment
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* Drug: AndroGel 16.2 mg/L


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Males and females aged over 18 years receiving invasive mechanical ventilation Invasive mechanical ventilation expected to be required for more than 48 hours Treatment with vasoactive drugs Written informed consent obtained from the legal representative Social security cover Exclusion Criteria: - History of prostate or breast cancer, prostatic specific antigen (PSA) ≥ 4 ng/ml ICU length of stay > 72 h before enrollment Moribund defined as having a score SAPS II > 75 12 hours after admission Pre-existing illness with a life expectancy of <6 months Cardiac arrest Preexistent cognitive impairment or language barrier Acute intracranial or spinal cord injury Acute hemorrhagic or ischemic stroke Neuromuscular disease (Guillain-Barré, myasthenia) Inability to walk without assistance prior to acute ICU illness (use of a cane or walkers not excluded) Documented allergy to testosterone Age > 80 years Pregnancy or breast feeding Patient on judicial protection

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intervention<br>AndroGel® AndroGel 16.2 mg/L will be applied to upper arms or shoulders once a day at 9:00 am to dry and intact skin for a period of 28 days or until ICU discharge. The daily dose 101.25 mg in men and 20.25 mg in women | Drug: AndroGel 16.2 mg/L<br>* Testosterone gel 1.62 % will be applied to upper arms or shoulders once a day at 9:00 am to dry and intact skin for a period of 28 days or until ICU discharge. The daily dose 101.25 mg in men and 20.25 mg in women.<br>|
| No Intervention: Control<br>In the control group, AndroGel will not be administered. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pourcentage of patients with normal median value of serum total testosterone | Pourcentage of patients with median value of serum total testosterone collected from blood samples at day 4, 7, 10, 14 higher than 280 ng/dl in men and 12 ng/dl in women. | day 4 to day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with normal median free testosterone serum values | Proportion of patients with median free testosterone serum values at day 4, 7, 10, 14 higher than 58 pg/ml in men and 0,9 ng/ml in women | day 4 to day 14 | 
| Proportion of patients with normal median serum values of bioavailable testosterone | Proportion of patients with median serum values of bioavailable testosterone at day 4, 7, 10, 14 higher than 75 ng/dl in men 0.8 ng/dl in women | day 4 to day 14 | 
| Nitrogen balance | Daily and cumulative nitrogen balance from day 1 to extubation | daily from day 1 to day 14 | 
| Physical performance | Physical performance by Six-minute walk test (6MWT) | day 14, 1month and 3 months after ICU discharge | 
| Muscle strength | Muscle strength by MRC (Medical Research Scale) | at ICU discharge, 1month and 3 months after ICU discharge | 
| Near Infrared Spectroscopy | Near Infrared Spectroscopy by NIRS test | at 14 days | 
| Muscular mass | Muscular mass by L3 computed tomography | at ICU discharge and 1month after ICU discharge | 
| Lung function | Lung function by spirometry | at 1 and 3 months after ICU discharge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hypermetabolism, hypogonadism, testosterone