Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000729628
Ethics application status
Approved
Date submitted
18/05/2023
Date registered
5/07/2023
Date last updated
5/07/2023
Date data sharing statement initially provided
5/07/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Muscle growth and anabolism in intensive care survivors
Scientific title
Nandrolone versus placebo for muscle weakness in Intensive Care Survivors: a randomised controlled trial
Secondary ID [1] 309682 0
None
Universal Trial Number (UTN)
Trial acronym
GAINS 2.0
Linked study record
This is the full RCT of the pilot ACTRN12616000835448

Health condition
Health condition(s) or problem(s) studied:
Intensive Care 330052 0
Critical illness myopathy 330053 0
Critical illness nutrition 330054 0
Condition category
Condition code
Physical Medicine / Rehabilitation 326955 326955 0 0
Other physical medicine / rehabilitation
Diet and Nutrition 326956 326956 0 0
Other diet and nutrition disorders
Musculoskeletal 326957 326957 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Randomised controlled trial

placebo versus nandrolone administration.

Intervention arm: Nandrolone intramuscular injection (IMI) administered weekly for 3 weeks.
Dose 50mg females, 100mg males

Intervention will be administered by blinded investigators to inpatients so adherence will not be a problem.
Intervention code [1] 326126 0
Treatment: Drugs
Comparator / control treatment
Sterile water for injection IMI.

Both placebo and study drug will be prepared in masked syringes so contents not apparent to person administering.
Control group
Placebo

Outcomes
Primary outcome [1] 334791 0
Time to walking with one person assisting (using the ICU mobility scale (IMS) - from physiotherapy assessment)
Timepoint [1] 334791 0
Days from admission to ICU
Primary outcome [2] 334792 0
Hospital length of stay (from medical records)
Timepoint [2] 334792 0
At hospital discharge
Secondary outcome [1] 422102 0
Change in muscle strength as measured by the medical research council muscle strength (MRC) sum score -
Timepoint [1] 422102 0
Weekly from enrolment to hospital discharge
Secondary outcome [2] 422103 0
Grip strength measured by dynanometry
Timepoint [2] 422103 0
Weekly from enrolment to hospital discharge
Secondary outcome [3] 422104 0
Functional activity at hospital discharge, measured by Chelsea critical care assessment tool.
Timepoint [3] 422104 0
Hospital discharge
Secondary outcome [4] 422105 0
Functional assessment using SF 36
Timepoint [4] 422105 0
3 months following discharge
Secondary outcome [5] 422106 0
ICU length of stay
Timepoint [5] 422106 0
ICU discharge
Secondary outcome [6] 422107 0
Time to return to work (for those working pre hospital)
Timepoint [6] 422107 0
Date of return to work (measured in days following hospital discharge)
Secondary outcome [7] 422440 0
Economic evaluation: Calculating difference between resource use and costs of total hospital stay from hospital medical records (including ICU length of stay)
Timepoint [7] 422440 0
At hospital discharge

Eligibility
Key inclusion criteria
1.) At least 21 years of age
2.) Admitted to participating ICU/HDU
3.) Receiving nutrition at estimated goals for at least 24 hours
4.) ICU/HDU length of stay => 5 days
OR
Significant weakness as deemed by treating clinician below patient’s baseline as a result of the ICU stay
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1.) Intercurrent septic shock (fevers, broad spectrum anti-microbials, and needing vasopressors)
2. Active cardiac disease (such as STEMI/NSTEMI in last 2 weeks) or EF <35%
3. Prostate or breast cancer
4. Ongoing reason for catabolic state (active malignancy, HIV & opportunistic infection last 2 months)
5. Unable to engage in rehabilitation (due to significant neurological or orthopaedic issues)
6. Normal age-related level of serum testosterone in males (measured in early morning 6-9am)
7. Pregnancy or breast-feeding
8. Any known allergies to nandrolone components – including peanuts and soya and latex.
9. Elevated LFTs (ALT > 5x normal) and impaired bilirubin excretion
10. Polycythaemia (Hb > 165 males, > 150 females)
11. Nephrotic syndrome.
12. Athletes competing in international/national events.
13. Expected death within the next week

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation concealment by centralised computer randomisation
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computerised sequence randomisation - block randomisation (4)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
The investigational pharmacist will not be blinded, but will not be involved in administering, assessing outcomes or analysis
Phase
Phase 2 / Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Efficacy of intervention will be analysed on an intention to treat basis. The analysis population is the intention to treat population defined as all study participants except for those who do not consent to use of data. There will be no imputation for missing data. A per protocol analysis will also be conducted including all participants with adherence to study medication of >80% of total study duration.

Normally and non-normally distributed data will be presented as mean and standard deviation (SD), and median and interquartile range (IQR), respectively. Between-group comparison of parametric data will be provided as mean difference and confidence interval and analysed using Student’s t test. Between-group comparison of non-parametric data will be presented at median difference and analysed using the Mann-Whitney U test. For dichotomous data, frequencies and percentages will be presented and between-group analysis will use Fischer’s Exact or Chi-squared test as appropriate. The numbers at risk in each group and the number and proportion of events observed will be reported, as well as the equivalent absolute risk difference, relative risk ratio and corresponding 95% confidence intervals. Survival time from randomisation until day 60, according to treatment group will be displayed as Kaplan-Meier curves and analysed using a log-rank test. Estimates of hazard ratios for survival, with corresponding 95% CI and P values, will be obtained from the Cox proportional hazards models incorporating treatment group alone, and independent covariates used in the multivariate models. Secondary analysis will also be conducted adjusting the primary outcome variable for prespecified baseline covariates (age, gender, APACHE-II score, BMI) in a transformed multivariable linear regression model including baseline univariate variables with a p<0.25. For all outcome analyses a two-sided P value of <0.05 will be considered significant.
Baseline variables recorded to demonstrate that the groups are comparable; if this is not demonstrated, post-hoc adjustments to correct for differences will be applied.
Sample size calculation: 60.
This is based on several different assumptions and outcome measures:
1. Hospital length of stay, as sample of n=24 per group has 80% power to detect a median difference of 3 days LOS (26 vs 23 days) with IQR 5.4 between independent groups (this is a conservative estimate as in the pilot, LOS results were 26 vs 36 days).
2. Time to walking with one-assist (ICU mobility scale). A sample of 24 per group has 80% power to detect a difference in proportions of 40 between the intervention and control groups, of patients walking with one assist at discharge (from a baseline of 27% in pilot).
To allow for loss to follow-up, the sample size number increased to 60.
Subgroup analysis: due to potential heterogeneity in patients, stratification based on MRC score, >= 48 (48 is an accepted cut off for ICU acquired weakness).

Economic evaluation:
An economic evaluation will be performed. Cost offsets from any reduction in LoS will be estimated separately for ICU stay and total hospital stay, and costed using hospital-specific per day costs. We will estimate QALYs using the SF-36 data converted to SF-6D using Australian population weights.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
5/07/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
60
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 24757 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [2] 24758 0
Royal Perth Hospital - Perth
Recruitment hospital [3] 24759 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 40390 0
6000 - Perth
Recruitment postcode(s) [2] 40389 0
6009 - Nedlands
Recruitment postcode(s) [3] 40391 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 313876 0
Charities/Societies/Foundations
Name [1] 313876 0
Charlies Foundation for Research
Country [1] 313876 0
Australia
Primary sponsor type
Hospital
Name
Sir Charles Gairdner Hospital
Address
Hospital Avenue
Nedlands 6009 WA
Country
Australia
Secondary sponsor category [1] 315722 0
None
Name [1] 315722 0
Address [1] 315722 0
Country [1] 315722 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313023 0
Sir Charles Gairdner and Osborne Park Hospital
Ethics committee address [1] 313023 0
Hospital Avenue
Nedlands 6009
Ethics committee country [1] 313023 0
Australia
Date submitted for ethics approval [1] 313023 0
Approval date [1] 313023 0
29/03/2023
Ethics approval number [1] 313023 0
RGS 4839

Summary
Brief summary
Intensive care patients can face significant health issues that extend beyond their Intensive Care Unit (ICU) stay. Despite recent advances it is estimated that one-quarter to one-half of long-stay intensive care survivors live with significant weakness as a consequence of their illness, resulting in impaired mobility and function.
The loss of muscle mass in critical illness is related to immobility and a complicated process that causes muscle and nerve dysfunction called critical illness polymyoneuropathy. Another contributory factor is low levels of anabolic (muscle building) hormones such as testosterone – with testosterone levels in critically ill patients are extremely low, even in the recovery phase from acute illness. One potential treatment may be to provide anabolic support in the recovery phase from prolonged critical illness.
This project aims to test whether giving a synthetic testosterone (nandrolone), will improve muscle strength in ICU survivors, when compared to placebo. Previous research has already established that early physiotherapy in the ICU can reduce length of stay and improve patients outcomes. In this study, both groups will receive standard care, which includes early physiotherapy. Nandrolone or placebo will be administered intramuscularly weekly for up to 3 weeks. Outcome measures will include hospital length of stay, time until the patient walks with assistance, muscle strength (globally and grip strength) as well as the patient’s physical functioning at 3 months following enrolment.
The study design will be a double blinded randomised controlled trial.
The teams involved are multi-disciplinary, involving physiotherapy, dietitians, pharmacy as well as medical specialists. The investigators have already successfully conducted a pilot feasibility trial of a nandrolone versus placebo, showing that the intervention is safe and feasible
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 126718 0
A/Prof Matthew Anstey
Address 126718 0
Sir Charles Gairdner Hospital
Hospital Avenue
Nedlands 6009 WA
Country 126718 0
Australia
Phone 126718 0
+61 409124876
Fax 126718 0
Email 126718 0
matthew.anstey@health.wa.gov.au
Contact person for public queries
Name 126719 0
A/Prof Matthew Anstey
Address 126719 0
Sir Charles Gairdner Hospital
Hospital Avenue
Nedlands WA 6009
Country 126719 0
Australia
Phone 126719 0
+61 409124876
Fax 126719 0
Email 126719 0
matthew.anstey@health.wa.gov.au
Contact person for scientific queries
Name 126720 0
A/Prof Matthew Anstey
Address 126720 0
Sir Charles Gairdner Hospital
Hospital Avenue
Nedlands WA 6009
Country 126720 0
Australia
Phone 126720 0
+61 409124876
Fax 126720 0
Email 126720 0
matthew.anstey@health.wa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
May be available following reasonable request of PI and amendment to ethics.
De-identified dataset.
When will data be available (start and end dates)?
After publication of the study, until 5 years later.
Available to whom?
Researchers
Available for what types of analyses?
De-identified analysis for meta-analyses
How or where can data be obtained?
Following reasonable request to the PI (matthew.anstey@health.wa.gov.au), and requiring an ethics amendment.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.