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Trial registered on ANZCTR


Registration number
ACTRN12620001226998p
Ethics application status
Not yet submitted
Date submitted
9/09/2020
Date registered
17/11/2020
Date last updated
17/11/2020
Date data sharing statement initially provided
17/11/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Sirolimus in Inclusion Body Myositis (IBM)
Scientific title
Optimism in IBM: A Double-Blind Randomised Controlled Trial (dbRCT) Phase III trial of Sirolimus in patients with Inclusion Body Myositis (IBM), to slow or stabilise disease progression, as measured by the IBM Functional Rating Scale (IBM-FRS)
Secondary ID [1] 302272 0
Protocol Number MDP200623
Secondary ID [2] 302273 0
NHMRC APP1199753
Universal Trial Number (UTN)
U1111-1258-1354
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Inclusion Body Myositis 319003 0
Condition category
Condition code
Neurological 316969 316969 0 0
Other neurological disorders
Inflammatory and Immune System 317316 317316 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be randomised 1:1 to either Sirolimus or Placebo.
Adherence will be monitored through compliance checks via drug packaging/container checks at study visits, weekly study diaries to monitor missed dosages, and measurement of serum Sirolimus levels at 3 month intervals.

Sirolimus arm: Sirolimus 2mg daily (2 x 1mg oral tablet), for 84 weeks.


Intervention code [1] 318562 0
Treatment: Drugs
Comparator / control treatment
Matched placebo daily (2 x matched oral capsules), for 84 weeks.
The IP will be blinded using over-encapsulation (Lonza Capsugel DB Capsules), and placebo will comprise of the same capsules, with a suitable filler in both active and placebo capsules.
Control group
Placebo

Outcomes
Primary outcome [1] 325078 0
To assess the efficacy of Sirolimus compared to placebo in slowing or stabilising the progression of IBM, as measured by the mean change in patient function using the IBM Functional Rating Scale (IBM-FRS) from Baseline to Week 84.
Timepoint [1] 325078 0
The IBM-FRS will be assessed at Baseline, Week 12, 24, 52, 76 and 84 (Primary timepoint).
Secondary outcome [1] 386766 0
1. To assess the safety and tolerability of Sirolimus when administered to participants with IBM through comparison of the number and type of adverse events (AE) in both groups. AEs will be assessed via weekly study diaries, through eliciting questions at study visits and clinical examination as well as laboratory results.
Timepoint [1] 386766 0
Adverse Events will be recorded at all study timepoints (Baseline, Week 4, 12, 24, 36, 52, 64, 76, 84, 88).
Secondary outcome [2] 386769 0
2. To assess the efficacy of Sirolimus compared to placebo in slowing or stabilising progression of IBM by measuring the distance walked in the standardised 6 Minute Walk Test (6MWT) from Baseline to Week 84.
Timepoint [2] 386769 0
The 6MWT will be completed at Screening (for inclusion), Baseline, Week 4, 12, 24, 52, 76 and 84.
Secondary outcome [3] 386770 0
3. To measure, as part of the 6MWT, the distance walked in 2 minutes (2MWT), to correlate with the 6MWT distance.
Timepoint [3] 386770 0
The 2MWT will be measured at Baseline, Week 4, 12, 24, 52, 76 and 84.
Secondary outcome [4] 386771 0
4. To assess the efficacy of Sirolimus compared to placebo in slowing or stabilising progression of IBM by measuring the standardised modified Timed up-and-go test (mTUG) from Baseline to Week 84.
Timepoint [4] 386771 0
The mTUG will be performed at Screening (inclusion), Baseline, Week 4, 12, 24, 52, 76 and 84.
Secondary outcome [5] 386774 0
5. To assess the efficacy of Sirolimus through measurement of the changes in Patient-Reported Outcomes (PROs): EAT-10 from Baseline to Week 84.
Timepoint [5] 386774 0
PROs will be collected at Baseline, Week 4, 12, 24, 52, 76 and 84.
Secondary outcome [6] 386775 0
6. To assess the efficacy of Sirolimus through measurement of the changes in the Physician Global Activity (PhGA) score from Baseline to Week 84.
Timepoint [6] 386775 0
PhGA score will be assessed at Baseline, Week 4, 12, 24, 52, 76 and 84.
Secondary outcome [7] 386776 0
7. To measure the efficacy of Sirolimus in slowing or stabilising disease progression through a composite score comprising measurement of changes in maximal voluntary isometric strength in quadriceps, hand grip and pinch grip, as assessed using hand-held dynamometer (Citec Hand-Held Dynamometer or equivalent) from Baseline to Week 84.
Timepoint [7] 386776 0
Quantitative Muscle Testing (QMT) will be assessed at Baseline, Week 4, 12, 24, 52, 76 and 84.
Secondary outcome [8] 386777 0
8. To assess the efficacy of Sirolimus in slowing or stabilising disease progression through measurement of changes seen in muscle strength using Manual Muscle Testing (MMT) in 12 muscle groups (MMT12) (IMACS MMT8 plus an additional 4 muscle groups affected in IBM including the Flexor Pollicis Longus, wrist flexors, elbow extensors and hip flexors)
Timepoint [8] 386777 0
Manual Muscle Testing (MMT) will be assessed at Baseline, Week 4, 12, 24, 52, 76 and 84.
Secondary outcome [9] 386778 0
9. To compare the sensitivity to change of the IMACS MMT8 vs IBM-modified MMT12 from Baseline to Week 84.
Timepoint [9] 386778 0
Manual Muscle Testing (MMT) will be assessed at Baseline, Week 4, 12, 24, 52, 76 and 84.
Secondary outcome [10] 386779 0
10. To assess the suitability of current standard outcome measures in IBM. This will be assessed through retrospective analysis of the study data, combined with participant information via questionnaire or semi-structured interview (subject to ethical approval). This questionnaire has not yet been developed.
Timepoint [10] 386779 0
Suitability of current standard outcome measures in IBM will be investigated on the participant's completion of the study via a single questionnaire or semi-structured interview.
Secondary outcome [11] 388876 0
To assess the efficacy of Sirolimus through measurement of the changes in Patient-Reported Outcomes (PROs): SF-36, from Baseline to Week 84.
Timepoint [11] 388876 0
PROs will be collected at Baseline, Week 4, 12, 24, 52, 76 and 84.
Secondary outcome [12] 388877 0
To assess the efficacy of Sirolimus through measurement of the changes in Patient-Reported Outcomes (PROs): sIFA from Baseline to Week 84.
Timepoint [12] 388877 0
PROs will be collected at Baseline, Week 4, 12, 24, 52, 76 and 84.
Secondary outcome [13] 388878 0
To assess the efficacy of Sirolimus through measurement of the changes in Patient-Reported Outcomes (PROs): HAQ-1 from Baseline to Week 84.
Timepoint [13] 388878 0
PROs will be collected at Baseline, Week 4, 12, 24, 52, 76 and 84.
Secondary outcome [14] 388879 0
To assess the efficacy of Sirolimus through measurement of the changes in Patient-Reported Outcomes (PROs): PROMIS Fatigue Short Form 7a from Baseline to Week 84.
Timepoint [14] 388879 0
PROs will be collected at Baseline, Week 4, 12, 24, 52, 76 and 84.
Secondary outcome [15] 388880 0
To assess the efficacy of Sirolimus through measurement of the changes in Patient-Reported Outcomes (PROs): Patient Global Activity (PaGA) from Baseline to Week 84.
Timepoint [15] 388880 0
PROs will be collected at Baseline, Week 4, 12, 24, 52, 76 and 84.

Eligibility
Key inclusion criteria
• Adults able to read and understand the Participant Information Sheet, and who freely provide Informed Consent for the study;
• Males or females aged 45 years or older;
• Diagnosis of IBM according to the criteria proposed by the European Neuromuscular Centre (ENMC) criteria 2011.
• Able to walk a minimum distance of 200m within 6 minutes (walking aids, including frames, may be used)
Minimum age
45 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Inability to complete a 6MWT with a minimum distance of 200m achieved
• Inability to complete a mTUG or any other study procedure;
• Unwillingness or inability to comply with study interventions or study schedule, including inability to swallow the study medication;
• Hypersensitivity to Sirolimus, Everolimus or any compound of the oral solution
• Any prior exposure to Sirolimus within the last 6 months;
• Current use or exposure to Everolimus within the last 6 months;
• Presence of any other clinically significant disease that might interfere with patients ability to comply with study procedures, or places the patient at greater risk for SAEs;
• Patient taking any other immunosuppressive or immunomodulatory medication;
• Other medications or products that may significantly affect the metabolism of Sirolimus at screening;
• Pregnancy or planning a pregnancy.

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 via sequentially numbered treatment kits at sites.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation sequence determined by central pharmacy. Randomisation stratified by site.
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
Phase
Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
A maximum of 140 participants will be randomised to the trial, to achieve a sample size of 108 participants completing all study interventions (assuming a 20% drop-out rate).
Analysis of demographics, baseline characteristics and derived variables from study endpoints will be performed. Data manipulation, tabulation of descriptive statistics, regression modelling and graphical representations will be performed primarily using SPSS v25 and Stata v15 for Windows. Descriptive and inferential statistical tests will be two-sided and any resultant p-value of less than or equal to 0.05 will be considered statistically significant.
The number of participants at each time point, and the compliance and completion rates will be summarised and reported. An intention-to-treat and per-protocol analysis will be conducted for all randomised participants. Formal testing for a treatment effect using linear mixed-effects models will be used to compare the treatment effect on the IBM-FRS. Any missing or partial data will be presented in the participant data listing. The use of multiple imputation methods will be considered.

Recruitment
Recruitment status
Not yet 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)
NSW,QLD,SA,WA,VIC
Recruitment outside Australia
Country [1] 22967 0
United States of America
State/province [1] 22967 0
Kansas
Country [2] 22968 0
United States of America
State/province [2] 22968 0
Baltimore
Country [3] 22969 0
Netherlands
State/province [3] 22969 0
Leiden
Country [4] 22970 0
Netherlands
State/province [4] 22970 0
Amsterdam
Country [5] 22971 0
United Kingdom
State/province [5] 22971 0
Oxfordshire
Country [6] 22972 0
Germany
State/province [6] 22972 0
Gottingen
Country [7] 22973 0
Sweden
State/province [7] 22973 0
Uppsala

Funding & Sponsors
Funding source category [1] 306698 0
Government body
Name [1] 306698 0
National Health and Medical Research Council
Address [1] 306698 0
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
Country [1] 306698 0
Australia
Primary sponsor type
Other
Name
The Perron Institute for Neurological and Translational Science
Address
Ground Floor, RR Block, QE II Medical Centre
8 Verdun St, Nedlands, WA 6009
Country
Australia
Secondary sponsor category [1] 307246 0
None
Name [1] 307246 0
Address [1] 307246 0
Country [1] 307246 0
Other collaborator category [1] 281481 0
University
Name [1] 281481 0
University of Notre Dame, Australia (Fremantle)
Address [1] 281481 0
32 Mouat St, Fremantle WA 6160
Country [1] 281481 0
Australia

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 306871 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 306871 0
123 Glen Osmond Rd, Eastwood SA 5063
Ethics committee country [1] 306871 0
Australia
Date submitted for ethics approval [1] 306871 0
04/12/2020
Approval date [1] 306871 0
Ethics approval number [1] 306871 0

Summary
Brief summary
Currently an estimated 1,250 Australians are living with Inclusion Body Myositis (IBM), a rare, chronic and incurable neuromuscular disease. IBM causes progressive muscle weakness and disability, compelling major life changes for patients and their families. There are no current disease-modifying treatments available for IBM.
We are planning a clinical trial of a re-purposed drug (Sirolimus), to stabilise or slow progression of IBM, allowing patients to retain mobility, independence and quality of life for longer, as well as reducing healthcare costs. Sirolimus (Rapamycin) has been identified in pre-clinical studies as a strong treatment candidate based on its known mechanisms of action and our understanding of the pathogenesis of IBM. A small monocentric pilot study in France of Sirolimus in IBM demonstrated disease stabilisation in a cohort of 44 patients.
This is an international, investigator-led Phase III trial of Sirolimus in 140 IBM patients. The trial will be led from Australia, and conducted as a double-blind, randomised, controlled Phase III trial (dbRCT). The study team includes leading IBM specialists across the globe, facilitating rapid translation into clinical care worldwide.
Trial website
Trial related presentations / publications
https://www.notredame.edu.au/news-items/new-treatment-trial-for-rare-disease-offers-hope-to-thousands-of-sufferers-worldwide
Public notes

Contacts
Principal investigator
Name 105294 0
Prof Merrilee Needham
Address 105294 0
Myositis Discovery Programme Lead
The Perron Institute for Neurological and Translational Science
Ground Floor, RR Block, QE II Medical Centre
8 Verdun St, Nedlands, WA 6009
Country 105294 0
Australia
Phone 105294 0
+61 8 6457 0200
Fax 105294 0
Email 105294 0
merrilee.needham@health.wa.gov.au
Contact person for public queries
Name 105295 0
Mrs Kelly Beer
Address 105295 0
The Perron Institute for Neurological and Translational Science
Ground Floor, RR Block, QE II Medical Centre
8 Verdun St, Nedlands, WA 6009
Country 105295 0
Australia
Phone 105295 0
+61 8 9360 1365
Fax 105295 0
Email 105295 0
k.beer@iiid.murdoch.edu.au
Contact person for scientific queries
Name 105296 0
Prof Merrilee Needham
Address 105296 0
Myositis Discovery Programme Lead
The Perron Institute for Neurological and Translational Science
Ground Floor, RR Block, QE II Medical Centre
8 Verdun St, Nedlands, WA 6009
Country 105296 0
Australia
Phone 105296 0
+61 8 6457 0200
Fax 105296 0
Email 105296 0
merrilee.needham@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?
Individual participant data that underlie the results reported in this main results publication, after de-identification (text, tables, figures, and appendices). The study protocol is also planned to be published.
When will data be available (start and end dates)?
Beginning 9 months and ending 36 months following main result publication.
Available to whom?
Investigators/researchers whose proposed use of the data has been approved by an independent human research ethics committee identified for this purpose.
Available for what types of analyses?
For individual participant data meta-analysis.
How or where can data be obtained?
Proposals may be submitted to the Principal Investigator up to 36 months following main result publication. After 36 months the data will be available in the study Sponsor's data warehouse but without investigator support other than deposited metadata. Information regarding
submitting proposals and accessing data may be obtained via the Study Coordinator: kelly.beer@murdoch.edu.au
What supporting documents are/will be available?
Study protocol
Informed consent form
Clinical study report
How or where can supporting documents be obtained?
Type [1] 9112 0
Study protocol
Citation [1] 9112 0
Link [1] 9112 0
Email [1] 9112 0
k.beer@iiid.murdoch.edu.au
Other [1] 9112 0
Will be published once approved by ethics, and also available on publication of main study results or via email request to the study team, via the Study Coordinator: kelly.beer@murdoch.edu.au
Attachment [1] 9112 0
Type [2] 9113 0
Clinical study report
Citation [2] 9113 0
Link [2] 9113 0
Email [2] 9113 0
Other [2] 9113 0
Will be published once approved by ethics, and also available on publication of main study results or via email request to the study team, via the Study Coordinator: kelly.beer@murdoch.edu.au
Attachment [2] 9113 0
Type [3] 9115 0
Informed consent form
Citation [3] 9115 0
Link [3] 9115 0
Email [3] 9115 0
Other [3] 9115 0
Will be available via the Study Sponsor's website (link to be established), or via email request to the study team via the Study Coordinator: kelly.beer@murdoch.edu.au
Attachment [3] 9115 0
Summary results
No Results