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

Critical Illness Clinical Trial

— TestICUs  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05825092
• Other study ID #: PHRC N 2018 BACHOUMAS
• Status: Recruiting
• Phase: Phase 2
• Start date: July 21, 2023
• Est. completion date: April 1, 2027

Study information

• Verified date: April 2023
• Source: University Hospital, Clermont-Ferrand
• Contact: Lise LACLAUTRE
• Phone: +33473754963
• Email: promo_interne_drci[@]chu-clermontferrand.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 600
• Est. completion date: April 1, 2027
• Est. primary completion date: September 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 79 Years

Eligibility

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

Related Conditions & MeSH terms

• Critical Illness

Intervention

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
• 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
• 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)
• Muscular mass
Muscular mass at 3, 6 months and 1 year after ICU admission Mid-arm muscle circumference (MAMC)
• 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)
• 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

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Clermont-Ferrand

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	the 6-minute-walk distance test (6MWD)	Physical performance 3 months after ICU admission assessed by the 6-minute-walk distance test (6MWD) in metres. Absolute values will be compared to show a minimum absolute difference of 30 meters	3 months after ICU admission
Secondary	the 6-minute-walk	Percentage of patients with 6 MWD at 6 months > 60% the distance walked in an age-matched and sex-matched control population	6 months
Secondary	the 6-minute-walk	Percentage of patients with 6 MWD at 1 year > 65% the distance walked in an age-matched and sex-matched control population	1 year after ICU admission
Secondary	Functional status with Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL)	11 items of Activities of Daily Living (ADL) and Instrumental; Activities of Daily Living (IADL):	at 3, 6 months and 1 year after ICU admission
Secondary	Oxygen muscular consumption with NIRS test (Near Infrared Spectroscopy)	Low muscle oxidative capacity is associated with muscle dysfunction and exercise intolerance in COPD patients and may contribute to reduce physical activity and quality of life in these patients. Muscle maximal oxidative capacity can be evaluated by oxygen muscular consumption which will be measured by Near Infrared Spectroscopy (NIRS), during a series of short arterial occlusions in muscle quadriceps. Studies performed in healthy subjects showed a good agreement with high-resolution respirometry and phosphorus magnetic resonance spectroscopy (P-MRS) for assessing mitochondrial respiratory capacity. In COPD patients, NIRS technique was feasible and well tolerated.	48 hours after intensive care unit (ICU) admission and 3 months after ICU admission
Secondary	Muscular mass with MAMC (Mid-arm muscle circumference):	Mid-arm muscle circumference (MAMC) : MAMC (Mid-arm muscle circumference): MAMC is calculated using the following formula: MAMC = mid-arm circumference - (3.14 × triceps skinfold thickness). The mid-arm circumference is measured using a standard flexible measuring tape on the left upper arm, at the mid-point between the olecranon process of the shoulder and the acromion, with the subject in a seated position. The triceps skinfold thickness is measured using a calibrated skinfold caliper (range 0.00- 50.00 mm; minimum graduation 0.2 mm) (85).	at 3, 6 months and 1 year after ICU admission
Secondary	the Short Physical Performance Battery (SPPB)	Percentage of patients with Short Physical Performance Battery < 10 at 3 months: The SPPB represents the sum of results from three component tests of functional relevance: standing balance, 4-meter gait speed (4MGS), and fiverepetition sit-to-stand motion (5STS). Each component is scored based on a subscale, and the three subscores are added to obtain a summary score. The SPPB is a high-level physical function outcome as it examines gait speed, balance control and sit-to-stand repetitions. It has been commonly used in COPD patients. In critical ill patients, the SPPB may be more appropriate as a measure in the post ICU setting in the acute hospital wards or post hospital discharge.	3, 6 months and 1 year after ICU admission
Secondary	Physical component of Medical Outcomes Study 36 Item Short Form Health (SF36)	Physical component of SF 36 (Medical Outcomes Study 36 Item Short Form Health): The physical component of SF 36 is a commonly used and well validated instrument in critical ill patients. The SF 36 has demonstrated reliability, validity and responsiveness and is recommended in ICU populations.	3, 6 months and 1 year after ICU admission
Secondary	Muscle strength by Handgrip test	Kg and percent of the predicted force: Hand-grip strength (HGS) is a manual muscle test that enables measurement of force using a calibrated device. It is reliable, rapid and simple and can serve as a surrogate for global strength. Normative data are available. HGS has been commonly used in critical ill patients.	48 hours after ICU admission, at 3, 6 months and 1 year after ICU admission
Secondary	Muscle strength by Medical Research Council (MRC) score	MRC has been routinely used in critical care research to screen for muscle weakness. It classifies muscle contraction on a 0-5 point ordinal scale. Six muscle groups will be assessed bilaterally.	at 3, 6 months and 1 year after ICU admission
Secondary	Ventilation free days	Number of day without ventilation	at day 28
Secondary	Length of stay in the ICU	Number of date between ICU admission and ICU discharge	48 hours after ICU admission
Secondary	Length of stay in hospital	Number of date between ICU admission and hospital discharge	at hospital discharge, an average of 1 month
Secondary	Mortality rate at day 28	rate of patient included in the study and died at day 28	at day 28
Secondary	Mortality rate at day 90	rate of patient included in the study and died at day 90	at day 90
Secondary	ICU mortality rate	rate of patient included in the study and died at ICU discharge	48 hours after ICU admission
Secondary	Hospital mortality rate	rate of patient included in the study and died at hospital discharge	at hospital discharge, an average of 1 month
Secondary	Nombers of adverses events	Safety of testosterone gel	from day 1 to day 28