Effects of Early Testosterone Gel Administration on Physical Performance in the Critically Ill

Official title

Effects of Early Testosterone Gel Administration on Physical Performance in the Critically Ill: a Randomised Double Blind Clinical Trial

Overview

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 can 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 Intensive Care Unit (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 and decreases protein breakdown in healthy young men. It has been repeatedly shown that testosterone treatment enhances muscle mass and strength in hypogonadal men and women and can improve physical performance. Testosterone administration in burned patients reduces protein breakdown and increases protein synthesis efficiency. Oxandrolone, a synthetic testosterone analogue, reduces body mass and nitrogen loss and accelerates healing in burned patients. Trials in critically ill unburned patients failed to demonstrate any effect on clinical outcome but the studies were underpowered to detect a difference. Transdermal gel testosterone is the preferred route of administration for achieving steady serum testosterone concentrations as compared to oral and intramuscular formulations. Intramuscular injection induces strong fluctuations of testosterone plasma concentrations and can cause haematoma in patients with coagulation disorders, a common condition in ICUs. Several studies have raised the concern that testosterone administration could increase the risk of cardiovascular disease events. However, in a recent meta-analysis, no significant effects on cardiovascular risk were observed with either injected or transdermal testosterone supplementation in men, and the French National Agency for Medicines (ANSM) recently reported that drugs containing testosterone were not associated with an increased risk of cardiovascular events.

Interventions

• Drug Androgel Topical Product
  AndroGel® will be applied daily to the upper arms/shoulders at 9:00 am. The daily dose will be 101.25 mg in men and 20.25 mg in women. AndroGel® will be administered within 24 hours after inclusion for a period of 28 days or until hospital discharge. For patients discharged from ICU before day 28, AndroGel® will be administered in hospital wards to complete the 28 days of treatment or until hospital discharge
• Drug Placebo
  Placebo gel will be applied daily to the upper arms/shoulders at 9:00 am. The daily dose will be 101.25 mg in men and 20.25 mg in women. Placebo gel will be administered within 24 hours after inclusion for a period of 28 days or until hospital discharge. For patients discharged from ICU before day 28, Placebo gel will be administered in hospital wards to complete the 28 days of
• Diagnostic test Physical performance
  Physical performance at 3, 6 months and 1 year after ICU admission 6 minute walk distance 3 months after ICU admission, at 6 months and at 1 year Percentage of patients with Short Physical Performance Battery \< 10 at 3, 6 months and 1 year Physical component of SF 36 (Medical Outcomes Study 36 Item Short Form Health Survey) at 3, 6 months and 1 year
• Diagnostic test Muscle strength
  Muscle strength at ICU discharge at 3, 6 months and 1 year after ICU admission Handgrip: Kg and percent of the predicted force Medical Research Council testing (MRC)
• Diagnostic test Muscular mass
  Muscular mass at 3, 6 months and 1 year after ICU admission Mid-arm muscle circumference (MAMC)
• Diagnostic test Test: Functional status
  Functional status at 3, 6 months and 1 year after ICU admission • Composite score of 11 items of Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL)
• Diagnostic test Oxygen muscular consumption
  Oxygen muscular consumption at ICU discharge and at 3 months after ICU admission Ventilation free days at day 28 Length of stay in ICU Length of stay in hospital Mortality rate at day 28 Mortality rate at day 90 ICU mortality rate Hospital mortality rate

Primary outcome measures

• the 6-minute-walk distance test (6MWD) [Time frame: 3 months after ICU admission]

Secondary outcome measures (12)

• the 6-minute-walk [Time frame: 6 months]
• the 6-minute-walk [Time frame: 1 year after ICU admission]
• Functional status with Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) [Time frame: at 3, 6 months and 1 year after ICU admission]
• Oxygen muscular consumption with NIRS test (Near Infrared Spectroscopy) [Time frame: 48 hours after intensive care unit (ICU) admission and 3 months after ICU admission]
• Muscular mass with MAMC (Mid-arm muscle circumference): [Time frame: at 3, 6 months and 1 year after ICU admission]
• the Short Physical Performance Battery (SPPB) [Time frame: 3, 6 months and 1 year after ICU admission]
• Physical component of Medical Outcomes Study 36 Item Short Form Health (SF36) [Time frame: 3, 6 months and 1 year after ICU admission]
• Muscle strength by Handgrip test [Time frame: 48 hours after ICU admission, at 3, 6 months and 1 year after ICU admission]
• Muscle strength by Medical Research Council (MRC) score [Time frame: at 3, 6 months and 1 year after ICU admission]
• Ventilation free days [Time frame: at day 28]
• Length of stay in the ICU [Time frame: 48 hours after ICU admission]
• Length of stay in hospital [Time frame: at hospital discharge, an average of 1 month]

Eligibility criteria

Inclusion criteria

• Males and females aged over 18 years
• Negative pregnancy test (b-HCG) in female patient of childbearing potential
• Invasive mechanical ventilation expected to be required for more than 48 hours
• Written informed consent obtained from the patient or his/her legal representative
• Social security cover
• Contraception
• Female patient of childbearing potential (entering the study after a menstrual period and who has a negative pregnancy test), who agrees to use a highly effective method of contraception and an effective method of contraception by her male partner during treatment and for 7 months after the last treatment intake
• Male patient with a female partner of childbearing potential who agrees to use a highly effective method of contraception and an effective method of contraception by his female partner during treatment and for 4 months after the last treatment intake OR who agrees to use an effective method of contraception and a highly effective method of contraception by his female partner during the study and for 4 months after the last treatment intake

Exclusion criteria

• History of prostate cancer
• History of breast cancer
• Prostate cancer suspected or confirmed
• Breast cancer suspected or confirmed
• PSA (prostatic specific antigen) ≥ 4 ng/ml
• ICU length of stay > 120 h before enrollment
• Moribund
• Pre-existing illness with a life expectancy of <6 months
• Recent intracranial or spinal cord injury (< 1 month)
• Recent haemorrhagic or ischemic stroke (< 1 month)
• Neuromuscular disease
• Cardiac arrest in non-shockable rhythm
• Preexistent cognitive impairment or language barrier
• 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
• Breast feeding

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

France · 5 centers

• Service de Medecine Intensive et Réanimation CHU de Bordeaux Hopital Pellegrin — Bordeaux
• Service d'Anesthésie et Réanimation Centre Jean-Perrin — Clermont-Ferrand
• Service de Médecine Intensive et Réanimation (MIR), CHU Clermont-Ferrand — Clermont-Ferrand
• Service de Médecine Intensive et de Réanimation CHD La Roche sur Yon — La Roche-sur-Yon
• Service de Médecine Intensive et Réanimation CHU Nantes, Hôtel Dieux — Nantes

Identifiers

NCT: NCT05825092 · PHRC N 2018 BACHOUMAS

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗