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Trial registered on ANZCTR


Registration number
ACTRN12618000755235
Ethics application status
Approved
Date submitted
3/04/2018
Date registered
4/05/2018
Date last updated
30/07/2019
Date data sharing statement initially provided
30/07/2019
Date results information initially provided
30/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Testosterone supplementation combined with exercise program to improve muscle condition in men affected by inclusion body myositis.
Scientific title
Testosterone plus exercise to improve muscle strength and performance in men affected by inclusion body myositis (IBM).
Secondary ID [1] 294456 0
None
Universal Trial Number (UTN)
U1111-1211-3860
Trial acronym
TEX-IBM
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Inclusion Body Myositis 307205 0
Condition category
Condition code
Musculoskeletal 306317 306317 0 0
Other muscular and skeletal disorders
Inflammatory and Immune System 306318 306318 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.

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.

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
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 -over two 7 day-periods- / activity trackers -worn continuously-)
DEXA scan: week 0, 12, 26

Location:
- Medical assessment and examination: Institute for Immunology and Infectious Diseases (IIID), Murdoch University, Murdoch, Western Australia 6150
- Physical training and assessment: School of Psychology and Exercise Science, Murdoch University
- Exercise program: home-based

After completion of the initial 26 week phase of the study (completion of the 2 x 12 week treatment periods + 2 week wash-out), participants will be invited to join an Open Label Extension Study. This study aims to provide additional data on the safety and tolerability of testosterone in IBM, as well as tracking any changes in muscle strength during the extension study period.

The established trial endpoints remain unchanged, with the addition of a secondary endpoint as follows:

• Investigate safety and tolerability of transdermal testosterone in IBM over a 12 month period.

This outcome will be measured by 3 monthly safety blood draws and 3 monthly medication dispensing visits, as well as review of compliance with medication administration and exercise via the medication/exercise diary and analysis of Fitbit data at 3 month intervals.

Established endpoints will be measured at 6 month and 12 month timepoints. Visits at these timepoints will replicate Week 12 and Week 26 visits from the initial study phase.

All patients who complete the initial phase of the study will be invited to take part in the extension study as soon as possible following their completion of the initial study phase.

A detailed study schedule for the Open Label Extension Study is provided within the PICF for the Extension project.

This extension has been considered as an amendment to the project by the Murdoch HREC and was granted approval on 29/03/2019.
Intervention code [1] 300768 0
Treatment: Drugs
Intervention code [2] 300769 0
Treatment: Other
Intervention code [3] 300770 0
Lifestyle
Comparator / control treatment
This is a double-blinded two-arm crossover RC where participants will be randomly assigned to a group receiving placebo during either the first or the second treatment period. Exercise training will be performed during both periods, regardless of the treatment received.

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 participants over a 12-week period.
Control group
Placebo

Outcomes
Primary outcome [1] 305365 0
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.
Timepoint [1] 305365 0
Muscle strength will be measured at the end of each treatment period (week 12 and 26) during physical assessment at Murdoch University


Primary outcome [2] 305427 0
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.


Timepoint [2] 305427 0
Muscle functional capacity will be discussed at the end of each treatment period (week 12 and 26) during physical assessment at Murdoch University

Primary outcome [3] 305616 0
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).
Timepoint [3] 305616 0
Engagement in training activity will be recorded by the participants in an activity diary daily during each of the two 12-week treatment periods.




Secondary outcome [1] 344966 0
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.
Timepoint [1] 344966 0
Continuous activity of daily living will be measured and recorded in real-time using wrist-worn activity trackers / actigraphs

Fitbits will be worn 24/7 over the whole duration of the trial
Actigraphs will be worn during a 7 day-period within the first two weeks of enrollment into the study (i.e., week one OR week two) of each treatment period.
Secondary outcome [2] 344967 0
Measure of inflammation in blood samples is a composite set of data that include creatine kinase, pro-inflammatory cytokines and chemokines.


Timepoint [2] 344967 0
Blood measures: weeks 0, 12 and 26

Secondary outcome [3] 346227 0
Measures of protein carbonyls in urine samples will be used to quantify oxidative stress.
Timepoint [3] 346227 0
Urine samples collected for analysis on weeks 0, 12 and 26
Secondary outcome [4] 346228 0
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
Timepoint [4] 346228 0
The 1st muscle biopsy will be performed on week -3 relative to the onset of the first treatment period, the 2nd biopsy on week 12 .
Secondary outcome [5] 346342 0
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.
Timepoint [5] 346342 0
The participants will be requested to record in a diary this primary outcome daily during the two 12-week periods of both study arms.
Secondary outcome [6] 373271 0
Within the Open-Label extension phase of the protocol, we have an additional outcome measure as follows:

• Investigate safety and tolerability of transdermal testosterone in IBM over a 12 month period.

This outcome will be measured by 3 monthly safety blood draws and 3 monthly medication dispensing visits, as well as review of compliance with medication administration and exercise via the medication/exercise diary and analysis of Fitbit data at 3 month intervals.
Timepoint [6] 373271 0
This outcome will be measured by 3 monthly safety blood draws and 3 monthly medication dispensing visits, as well as review of compliance with medication administration and exercise via the medication/exercise diary and analysis of Fitbit data at 3 month intervals.

Eligibility
Key inclusion criteria
Adult men with a diagnosis of IBM in accordance with the ENMC criteria 2011 who are
able to provide informed consent.

Inclusion criterion for the extension study:
*Completion of the first 26 week phase of the study.
Minimum age
18 Years
Maximum age
No limit
Gender
Males
Can healthy volunteers participate?
No
Key exclusion criteria
- Active cardiovascular disease (unstable angina, myocardial infarction, stroke, transient
ischaemic attack, or revascularisation procedure within the past 12 months)

- History of prostate cancer or other major medical comorbidity (e.g. advanced lung disease or cancer)

- Men on anti-androgen drugs for benign prostatic hyperplasia (BPH)

- Elevated blood pressure ( >160 mmHg systolic and > 100 mmHg diastolic)

- Abnormal prostate examinations suspicious for malignancy

- Total cholesterol > 6.5 mmol/L or LDL > 4.0 mmol/L

- eGFR <45 ml/min

- Testosterone concentration must be in the 5-14 nmol/L range with non-elevated haematocrit and PSA. Men with Testosterone concentration <5 nmol/L would be referred for endocrine assessment, and can participate if no pituitary or testicular disease is found.

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)
Sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
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
Crossover
Other design features
After completion of the first 26 week phase of the study, participants will be offered a 12 month Open Label Extension Study.
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
This pilot project includes a limited number of participants (n=20); we do not expect that the outcomes will be sufficient to generate a whole set of statistically significant data. Rather, this project aims at providing critical information that will enable us to establish reliable foundations for a future bigger study that will include a greater number of participants at the national level and more in depth study.

Mean values of normally distributed data collected between groups will be compared using parametric Student t test. Alternatively, median values of non-normally distributed data collected between groups will be compared using nonparametric Mann-Whitney U test.

Strength of association between two variables will be assessed when applicable. Correlation coefficients will be determined using Pearson r test when variables are assumed to be normally distributed, alternatively Spearman rank correlation will be used as a non-parametric test.

Statistical analysis will be performed with the assistance of a biostatistician at IIID.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 10528 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [2] 10529 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [3] 10530 0
Royal Perth Hospital - Perth
Recruitment postcode(s) [1] 22246 0
6150 - Murdoch
Recruitment postcode(s) [2] 22247 0
6009 - Nedlands
Recruitment postcode(s) [3] 22248 0
6000 - Perth

Funding & Sponsors
Funding source category [1] 299080 0
Other
Name [1] 299080 0
Perron Institute for Neurological and Translational Science
Address [1] 299080 0
RR block
QEII Medical Centre
8 Verdun Street
Nedlands WA 6009
Country [1] 299080 0
Australia
Primary sponsor type
Other
Name
Perron Institute for Neurological and Translational Science
Address
RR block
QEII Medical Centre
8 Verdun Street
Nedlands WA 6009
Country
Australia
Secondary sponsor category [1] 298322 0
Commercial sector/Industry
Name [1] 298322 0
Lawley Pharmaceuticals Pty Ltd
Address [1] 298322 0
2/15A Harrogate Street
West Leederville
WA 6007
Country [1] 298322 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300016 0
Human Research Ethics Committee - Murdoch University
Ethics committee address [1] 300016 0
Murdoch University
Chancellery Building Room 1.006
South Street, Murdoch
Western Australia 6150
Ethics committee country [1] 300016 0
Australia
Date submitted for ethics approval [1] 300016 0
22/02/2018
Approval date [1] 300016 0
26/02/2018
Ethics approval number [1] 300016 0
2017/262

Summary
Brief summary
Inclusion body myositis (IBM) is the most commonly acquired skeletal muscle disease associated with aging. The cause is not known, and it affects men more often than women. The condition is progressive, resulting in muscle weakness and wasting including the muscles used for breathing and swallowing. There is no known cure and the impact on health-related quality of life is considerable.

Exercise helps to prevent loss of muscle mass and maintain strength; and in healthy men the combination of testosterone and exercise has been shown to further increase muscle strength, performance and physical activity overall.

In this study we propose to examine whether testosterone treatment, used in combination with exercise improves muscle strength and rates of physical activity in men affected by IBM.

The study will be done in the context of a double-blind, randomised, clinical trial. The study investigators have expertise in neurology, endocrinology, immunology and physical sciences.

In March 2019, a 12 month Open Label Extension study was approved.
Trial website
Trial related presentations / publications
Public notes
The participants to this study will receive an Information sheet that include information relative to:
Purpose of the study
Screening period
Sample collection
Blood, urine at weeks 0, 12, 16
Muscle biopsy (optional) at weeks -3, 12
Drug information sheet (AndroForte / Placebo)
Administration of the drug
Exercise program
Actigraphy (activity read-out efficacy of commercial activity trackers (FitBit) will be compared to actigraphs approved for medical purpose)
Body composition analysis (Dual Energy X-ray Absorptiometry)
Samples analysis and biobanking
Confidentiality
Potential risks and side effects

Contacts
Principal investigator
Name 82270 0
Prof Merrilee Needham
Address 82270 0
Institute for Immunology and Infectious Diseases
Murdoch University
Building 390 Discovery Way
Murdoch WA 6150
Country 82270 0
Australia
Phone 82270 0
+61 8 9360 1334
Fax 82270 0
+61 8 9360 1380
Email 82270 0
Merrilee.Needham@health.wa.gov.au
Contact person for public queries
Name 82271 0
Mrs Kelly Beer
Address 82271 0
Institute for Immunology and Infectious Diseases
Murdoch University
Building 390 Discovery Way
Murdoch WA 6150
Country 82271 0
Australia
Phone 82271 0
+61 8 9360 1365
Fax 82271 0
Email 82271 0
k.beer@iiid.murdoch.edu.au
Contact person for scientific queries
Name 82272 0
Dr Jerome Coudert
Address 82272 0
Institute for Immunology and Infectious Diseases
Murdoch University
Building 390 Discovery Way
Murdoch WA 6150
Country 82272 0
Australia
Phone 82272 0
+61 8 9360 1366
Fax 82272 0
+61 8 9360 1380
Email 82272 0
j.coudert@iiid.murdoch.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The data set is kept on local secure servers. Data sharing requests can be submitted to the research team.
It is not intended to share IPD for the trial. Results will be made available as per open access requirements.
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary