Clinical trial NCT05825092: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Critical Illness
Keywords: Critical ill patient
Physical performance
Testosterone
Lead sponsor: University Hospital, Clermont-Ferrand
Sponsor class: OTHER
First posted: 2023-04-24
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a prospective, phase II, multi-centre, double blind, randomised, controlled, parallel group study.
Primary purpose: TREATMENT

Brief summary: 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.


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

Primary outcomes:
measure: the 6-minute-walk distance test (6MWD)
timeFrame: 3 months after ICU admission
Secondary outcomes:
measure: the 6-minute-walk
timeFrame: 6 months
measure: the 6-minute-walk
timeFrame: 1 year after ICU admission
measure: Functional status with Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL)
timeFrame: at 3, 6 months and 1 year after ICU admission
measure: Oxygen muscular consumption with NIRS test (Near Infrared Spectroscopy)
timeFrame: 48 hours after intensive care unit (ICU) admission and 3 months after ICU admission
measure: Muscular mass with MAMC (Mid-arm muscle circumference):
timeFrame: at 3, 6 months and 1 year after ICU admission
measure: the Short Physical Performance Battery (SPPB)
timeFrame: 3, 6 months and 1 year after ICU admission
measure: Physical component of Medical Outcomes Study 36 Item Short Form Health (SF36)
timeFrame: 3, 6 months and 1 year after ICU admission
measure: Muscle strength by Handgrip test
timeFrame: 48 hours after ICU admission, at 3, 6 months and 1 year after ICU admission
measure: Muscle strength by Medical Research Council (MRC) score
timeFrame: at 3, 6 months and 1 year after ICU admission
measure: Ventilation free days
timeFrame: at day 28
measure: Length of stay in the ICU
timeFrame: 48 hours after ICU admission
measure: Length of stay in hospital
timeFrame: at hospital discharge, an average of 1 month
measure: Mortality rate at day 28
timeFrame: at day 28
measure: Mortality rate at day 90
timeFrame: at day 90
measure: ICU mortality rate
timeFrame: 48 hours after ICU admission
measure: Hospital mortality rate
timeFrame: at hospital discharge, an average of 1 month
measure: Nombers of adverses events
timeFrame: from day 1 to day 28
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: Service de Medecine Intensive et Réanimation CHU de Bordeaux Hopital Pellegrin
city: Clermont-Ferrand
country: France
facility: Service d'Anesthésie et Réanimation Centre Jean-Perrin
city: Clermont-Ferrand
country: France
facility: Service de Médecine Intensive et Réanimation (MIR), CHU Clermont-Ferrand
city: La Roche-sur-Yon
country: France
facility: Service de Médecine Intensive et de Réanimation CHD La Roche sur Yon
city: Nantes
country: France
facility: Service de Médecine Intensive et Réanimation CHU Nantes, Hôtel Dieux
Study officials:
affiliation: Hospital, La Roche sur Yon
name: Konstantinos BACHOUMAS, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Clermont-Ferrand
name: Bertrand SOUWEINE, MD, PhD
role: STUDY_DIRECTOR
References: