ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12620001226998

Ethics application status

Approved

Date submitted

9/09/2020

Date registered

17/11/2020

Date last updated

27/06/2024

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]

Protocol Number MDP200623

Secondary ID [2]

NHMRC APP1199753

Secondary ID [3]

ClinicalTrials.gov Identifier: NCT04789070

Universal Trial Number (UTN)

U1111-1258-1354

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Inclusion Body Myositis

Condition category

Condition code

Neurological

Other neurological disorders

Inflammatory and Immune System

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]

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]

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]

The IBM-FRS will be assessed at Baseline, Week 12, 24, 52, 76 and 84 (Primary timepoint).

Secondary outcome [1]

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]

Adverse Events will be recorded at all study timepoints (Baseline, Week 4, 12, 24, 36, 52, 64, 76, 84, 88).

Secondary outcome [2]

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]

The 6MWT will be completed at Screening (for inclusion), Baseline, Week 4, 12, 24, 52, 76 and 84.

Secondary outcome [3]

3. To measure, as part of the 6MWT, the distance walked in 2 minutes (2MWT), to correlate with the 6MWT distance.

Timepoint [3]

The 2MWT will be measured at Baseline, Week 4, 12, 24, 52, 76 and 84.

Secondary outcome [4]

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]

The mTUG will be performed at Screening (inclusion), Baseline, Week 4, 12, 24, 52, 76 and 84.

Secondary outcome [5]

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]

PROs will be collected at Baseline, Week 4, 12, 24, 52, 76 and 84.

Secondary outcome [6]

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]

PhGA score will be assessed at Baseline, Week 4, 12, 24, 52, 76 and 84.

Secondary outcome [7]

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]

Quantitative Muscle Testing (QMT) will be assessed at Baseline, Week 4, 12, 24, 52, 76 and 84.

Secondary outcome [8]

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]

Manual Muscle Testing (MMT) will be assessed at Baseline, Week 4, 12, 24, 52, 76 and 84.

Secondary outcome [9]

9. To compare the sensitivity to change of the IMACS MMT8 vs IBM-modified MMT12 from Baseline to Week 84.

Timepoint [9]

Manual Muscle Testing (MMT) will be assessed at Baseline, Week 4, 12, 24, 52, 76 and 84.

Secondary outcome [10]

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]

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]

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]

PROs will be collected at Baseline, Week 4, 12, 24, 52, 76 and 84.

Secondary outcome [12]

To assess the efficacy of Sirolimus through measurement of the changes in Patient-Reported Outcomes (PROs): sIFA from Baseline to Week 84.

Timepoint [12]

PROs will be collected at Baseline, Week 4, 12, 24, 52, 76 and 84.

Secondary outcome [13]

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]

PROs will be collected at Baseline, Week 4, 12, 24, 52, 76 and 84.

Secondary outcome [14]

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]

PROs will be collected at Baseline, Week 4, 12, 24, 52, 76 and 84.

Secondary outcome [15]

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]

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 and maximum of 500m within 6 minutes (walking aids, including frames, may be used)

Minimum age

45 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

• Inability to complete a 6MWT with a minimum distance of 200m and maximum of 500m 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

Recruiting

Date of first participant enrolment

Anticipated

31/08/2021

Actual

15/06/2022

Date of last participant enrolment

Anticipated

31/12/2024

Actual

Date of last data collection

Anticipated

1/07/2026

Actual

Sample size

Target

140

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW,QLD,SA,WA,VIC

Recruitment hospital [1]

Brain and Mind Centre - University of Sydney - Camperdown

Recruitment postcode(s) [1]

2050 - Camperdown

Recruitment outside Australia

Country [1]

United States of America

State/province [1]

Kansas

Country [2]

United States of America

State/province [2]

Baltimore

Country [3]

Netherlands

State/province [3]

Leiden

Country [4]

Netherlands

State/province [4]

Amsterdam

Country [5]

United Kingdom

State/province [5]

Oxfordshire, London

Country [6]

Germany

State/province [6]

Gottingen

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council

Address [1]

National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Other collaborator category [1]

University

Name [1]

University of Notre Dame, Australia (Fremantle)

Address [1]

32 Mouat St, Fremantle WA 6160

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

St Vincent's Hospital Melbourne (SVHM) Human Research Ethics Committee

Ethics committee address [1]

41 Victoria Parade Fitzroy VIC 3065

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

04/12/2020

Approval date [1]

19/02/2021

Ethics approval number [1]

SVHM HREC Ref: HREC-D 311/20

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

Prof Merrilee Needham

Address

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

Australia

Phone

+61 8 6457 0200

Fax

[email protected]

Contact person for public queries

Name

Kelly Beer

Address

The Perron Institute for Neurological and Translational Science
Ground Floor, RR Block, QE II Medical Centre
8 Verdun St, Nedlands, WA 6009

Country

Australia

Phone

+61 8 9360 1365

Fax

[email protected]

Contact person for scientific queries

Name

Merrilee Needham

Address

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

Australia

Phone

+61 8 6457 0200

Fax

[email protected]

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: [email protected]

What supporting documents are/will be available?

Doc. No.	Type	Email	Other Details
9112	Study protocol	[email protected]	Will be published once approved by ethics, and als... [More Details]
9113	Clinical study report		Will be published once approved by ethics, and als... [More Details]
9115	Informed consent form		Will be available via the Study Sponsor's website ... [More Details]

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	CHALLENGES IN RARE DISEASES AND THE CASE FOR OPTIMISM IN IBM: AN MSG STUDY.	2023

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically