Testosterone supplementation combined with exercise program to improve muscle condition in men affected by inclusion body myositis.

INTERVENTION: This is a double‐blinded, two‐arm crossover RCT to test whether testosterone on a background of exercise training (see below) will improve measures of muscle strength and performance, and physical activity, in N=20 men with IBM, over 26 weeks (2 treatment‐periods of 12 weeks separated by a 2 week wash‐out period). The participants will be randomly assigned to a group receiving either testosterone or a placebo during the first treatment period, and then after washout, swapped to the alternate treatment during the second period.. Drugs applied Active name: testosterone Trade name: AndroForte 5, strength 5.0% w/v, dosage form 2 ml transdermal cream applied once daily by the patient over a 12‐week period Placebo: The placebo contains exactly the same ingredients as the active (minus the testosterone). Inactive ingredients: cetomacrogol 1000, cetostearyl alcohol, carbopol 940, almond oil, dl‐a‐tocopheryl acetate (Vitamin E acetate), triethanolamine, Phenonip, butylated hydroxytoluene, anhydrous citric acid, purified water Trade name N/A, dosage form 2 ml transdermal cream applied once daily by the patient over a 12‐week period The transdermal cream will be applied on an area of the torso with low subcutaneous fat, and then covered. Procedures: Medical assessments will be performed at IIID (Murdoch University) by Professor Needham or Professor Bu Yeap (Neurologist and Endocrinologist, respectively). Participants will be given the option to participate in a muscle biopsy sub‐study to evaluate the effects of the intervention directly on the muscle. Muscle biopsies will be performed by Prof Phillipa Lamont (Neurologist) or Professor Needham at IIID. All these clinicians have at least 10 years experience. Exercise training: Exercise training will be a combination of light‐moderate resistance training, balance training and aerobic exercise, tailored to each individual and supervised by investigators (with at least 10 years experience) from the School of Psychology and Exercise Science, Murdoch University. The Home‐based progressive exercise will comprise of resistance, aerobic/mobility, and balance exercises. All exercises will comprise of either resistance bands (therabands) or body weight movements. Resistance bands will largely be single‐joint exercises while body weight movements will target whole body muscles involved in mobility and function however focus on extensors of knee and flexors of the wrist and fingers (i.e. leg extension, arm row, bicep curl). This will be supplemented with aerobic/mobility and functional exercises (i.e. walking, sitting and rising) and balance exercises (i.e. narrow stance, tandem stance). The duration of the exercise program will be approximately 30 minutes which will be completed three times a week and may progress to 45 minutes per session. The intensity of the exercise (moderate‐light) will be determined using the RPE Borg scale. A rate of perceived exertion will be attained for every exercise prescribed for each participant and this information will be used to establish an appropriate intensity and regress or progress the exercise accordingly. The home‐based exercise program will be completed only at home by participants for the intervention period. The program will be supervised via telephone and home visits. A one‐off induction physical training session will be completed as part of the physical assessments at pre‐intervention which will be conducted at the university. The participants will be asked to keep a record on a diary of their drug application, exercise and falls. Procedure timeline: (week 0 being when drug/placebo application begins and data collection starts) Medical assessments: week 0, 12, 26 Blood & urine collections: week 0, 12, 26 Exercise training will be tailored as follows: The progressive exercise program will be individually prescribed and progressed to accommodate the large variance in functional capabilities of each participant expected at baseline and in their individual exercise‐response. This includes the specific exercises given (mode), the duration and frequency in which they are completed (depending on post‐exercise pain and recovery scores) and the prescribed intensity of the exercise. Resistance exercise will largely be conducted using single joint exercises of the lower and upper limbs using elastic bands (Therabands); with varying levels of resistance providing the different intensities (different colour bands). Multi‐joint compound exercises will be body‐weight based. The initial exercise prescription will occur following baseline assessment. Progression of exercises and intensity will be based on RPE scores provided during fortnightly telephone calls and supervisory visits. Muscle biopsies (optional): week ‐3, 12 Exercise and physical strength and performance assessments (under 2 hours): week 0, 12, 26 Exercise program (home based): daily Physical measures: daily and continuous (actigraph ‐o CONDITION: Inclusion Body Myositis PRIMARY OUTCOME: A battery of functional tasks related to activities of daily living have been adopted for this trial. ; Specifically: ; ‐ 2‐minute walk test (2MWT) ; ‐ Timed up‐and‐go ; ‐ Sit‐to‐stand ; ‐ Quantitative gait assessment using Gaitrite ; ‐ Berg Balance Scale ; ‐ Activities‐specific balance confidence ; ‐ 4‐stage balance test ; ‐ Functional reach test. ; ‐ More specific questions related to ADLs are then obtained via the Short Form Health Survey SF‐36; 10‐point IBM Functional Rating Scale (IBMFRS). ; ; The set of data generated upon these assessments forms a composite primary outcome. ; ; ; Changes in muscle strength in quadriceps will be tested. (isokinetic strength). ; ; Testing will be conducted at 60 degrees and 180 degrees per second on a HUMACNORM isokinetic dynamometer. Left and Right legs will be tested, with order standardised and following a standardised warm‐up protocol. The participants will be requested to record on a diary their daily training as a composite set of information (exercises executed, number of repetitions and sets, exercising duration). SECONDARY OUTCOME: Engagement in activities (broadly ADLs) will be captured using Medical actigraph vs Fitbit activity trackers ; ; This secondary outcome includes a composite set of daily measures including: ; ‐ number of steps ; ‐ energy expenditure ; ‐ floors climbed ; ‐ minutes of activity ; ‐ sleep quality ; ; The research team will set the activity trackers for the participants and will have access to all these data. Measure of inflammation in blood samples is a composite set of data that include creatine kinase, pro‐inflammatory cytokines and chemokines. ; ; ; Measures of protein carbonyls in urine samples will be used to quantify oxidative stress. The degree of inflammation in muscles will be addressed using composite measures: ; ; Inflammation and damages in the muscle will be observed: ; ‐ by histological analysis of muscle biopsies (leukocyte recruitment, HLA molecule upregulation on muscle fibres and presence of rimmed vacuoles) ; ‐ by measuring gene expression levels of pro‐inflammatory cytokines and chemokines. ; ; Biopsies are optional; participants may opt‐out of this procedure This is a 4th primary outcome. ; ; Engagement in activities of daily living (broadly ADLs) and noticed changes will be recorded by the participants in an activity diary. These data entries will include falls. ; This record of ADLs, noticed ADL changes and falls form a composite secondary outcome. ; INCLUSION CRITERIA: Adult men with a diagnosis of IBM in accordance with the ENMC criteria 2011 who are able to provide informed consent.