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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04789070




Registration number
NCT04789070
Ethics application status
Date submitted
15/02/2021
Date registered
9/03/2021
Date last updated
13/04/2023

Titles & IDs
Public title
Phase III Trial of Sirolimus in IBM
Scientific title
A Double-Blind Randomised Controlled Trial (dbRCT) Phase III Trial Investigating the Effect of Sirolimus on Disease Progression in Patients With Inclusion Body Myositis (IBM) as Measured by the IBM Functional Rating Scale (IBM-FRS)
Secondary ID [1] 0 0
Optimism in IBM
Universal Trial Number (UTN)
Trial acronym
Linked study record

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

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Sirolimus
Treatment: Drugs - Placebo

Active Comparator: Sirolimus - 2mg capsules once daily

Placebo Comparator: Placebo - 2mg capsules once daily


Treatment: Drugs: Sirolimus
Sirolimus is a currently licensed drug primarily used for immunosuppression post-kidney transplantation to prevent organ rejection. Sirolimus was initially considered as a treatment in IBM for its immunosuppressive action and beneficial effects in an experimental myositis mouse model.(11) Transfer of effector T cells from affected to healthy animals resulted in myositis, but the presence of Treg cells were protective against development of myositis. As Sirolimus, which acts to deplete effector T cells but preserving the Treg cells, was effective in this mouse model of myositis, it was therefore postulated that it may also be effective in IBM, not only for its effects on effector T cells and Treg cells, but also for its additional effects on protein degradation.

Treatment: Drugs: Placebo
Placebo
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Change in IBM Functional Rating Scale (IBM-FRS) from Baseline to Week 84
Timepoint [1] 0 0
Baseline, Week 84
Secondary outcome [1] 0 0
Change in 6 Minute Walk Test (6MWT) from Baseline to Week 84
Timepoint [1] 0 0
Baseline, Week 84
Secondary outcome [2] 0 0
Change in Modified Timed Up and Go (mTUG) from Baseline to Week 84
Timepoint [2] 0 0
Baseline, Week 84
Secondary outcome [3] 0 0
Change in Manual Muscle Testing (MMT) from Baseline to Week 84
Timepoint [3] 0 0
Baseline, Week 84

Eligibility
Key inclusion criteria
1. Adults able to read and understand the Participant Information Sheet, and who freely
provide written Informed Consent for the study;

2. Males or females aged 45 years or older;

3. Diagnosis of IBM according to the criteria proposed by the ENMC criteria 2011;

4. Able to walk a minimum distance of 200m within 6 minutes (walking aids, including
frames, may be used);

5. Evidence of disease progression over the previous 12 months, as determined by a
neuromuscular specialist through patient history, physical examination, MMT, IBM-FRS
or other metrics.
Minimum age
45 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Inability to complete a 6MWT with a minimum distance of 200m achieved;

2. Inability to complete a mTUG or any other study procedure, including inability to
swallow study drug, or clinical suspicion that the participant will become unable to
swallow the study drug during the study period;

3. Unwillingness or inability to comply with study interventions or study schedule;

4. Hypersensitivity to Sirolimus, Everolimus or any compound of the oral solution;

5. Any prior exposure to Sirolimus or Everolimus within the last 6 months;

6. 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;

7. Clinical suspicion of moderate or severe respiratory insufficiency based on history,
clinical examination or respiratory function tests with an FVC < 50% of predicted;
Nocturnal NIV is allowed for sleep-disordered breathing;

8. Severe chronic kidney disease or renal insufficiency with proteinuria (e.g Estimated
Glomerular Filtration Rate < 30 ml/min and/or proteinuria as defined by spot urine
protein/creatinine ratio > 100mg/mmol;

9. Chronic liver disease (cirrhosis and/or ALT/AST > 3 times the upper limit of normal
(ULN)) , excluding cases in which raised ALT/AST are deemed to be due to underlying
muscle disease. Patients can be re-screened within the window if a one-off measurement
is elevated due to an acute injury such as a viral infection;

10. History of cancer (Except localised skin cancers including BCC/SCC) during the past 5
years;

11. Systemic autoimmune or rheumatological disease not in remission and/or necessitating
specific treatment during the last 12 months. This includes significant organ-specific
autoimmune disorder (e.g Grave's disease) not in remission and/or necessitating
specific treatment during the past 12 months;

12. Any unhealed wounds or active infections at the time of screening;

13. If patient has received a live vaccine within the last 12 weeks;

14. Participants must be HIV negative, and Hepatitis C Virus Ribonucleic Acid (HCVRNA)
Polymerase Chain Reaction (PCR) negative, and Hep B surface antigen negative and Hep B
core antibody negative;

15. One or more the following blood test results at screening:

1. Total cholesterol > 8 mmol/l (304mg/dl)

2. Triglycerides > 5 mmol/l (>194 mg/dl)

3. Haemoglobin < 110 g/L (11g/dl)

4. Platelet count < 100 x 109/L

5. Neutrophils < 1.5 x 109/L

6. Lymphocytes < 1.0 x 109/L

16. Presence at screening of any medically significant cardiac, neurological, pulmonary,
gastrointestinal, musculoskeletal or psychiatric illness (including uncontrolled
anxiety and/or depression) that in the Investigator's opinion might interfere with the
patient's ability to comply with study procedures or that might confound the
interpretation of clinical safety or IBM-FRS;

17. Has taken any investigational study drug within 30 days or five half-lives of the
prior agent (whichever is longer) prior to the Baseline visit;

18. Patient taking any other immunosuppressive or immunomodulatory medication (including
but not limited to prior high dose prednisolone (>10mg/day) in the last 4 weeks,
Intravenous Immunoglobulin (IVIG) within the last 3 months, methotrexate,
mycophenolate, Sirolimus, Everolimus, calcineurin inhibitors, (cyclosporine or
tacrolimus) or azathioprine within the last 6 months, and rituximab, alemtuzumab or
other biologics within the last 12 months);

19. Other medications or products that may affect the metabolism of Sirolimus (See
concomitant medications in Section 27) such as the following at time of screening:

1. Strong inhibitors of CYP3A4 and/or P-gp (eg ketoconazole, voriconazole,
itraconazole, telithromycin, erythromycin or clarithromycin)

2. Strong inducers of CYP3A4 and/or P-gp (eg rifampicin, rifabutin, Phenytoin,
Phenobarbitol, St John's Wort);

20. Use of any investigational drug other than study medication;

21. Pregnancy or planning a pregnancy:

1. Women of child-bearing potential (WOCBP) must have a negative serum pregnancy
test prior to randomisation, and must have a negative urine pregnancy test within
24 hours prior to the start of study drug. WOCBP must agree to use 'highly
effective' contraception (MHRA guidelines, 2014) for the duration of the study
and for 12 weeks post-treatment completion.

2. Men who are sexually active with a WOCBP must agree to use barrier contraception
(condom) for the duration of treatment with study drug and for 30 days
post-treatment completion.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/07/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/02/2024
Actual
Sample size
Target
140
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC,WA
Recruitment hospital [1] 0 0
Concord Repatriation Hospital - Sydney
Recruitment hospital [2] 0 0
Royal Northshore Hospital - Sydney
Recruitment hospital [3] 0 0
Royal Brisbane and Women's Hospital - Brisbane
Recruitment hospital [4] 0 0
Royal Adelaide Hospital - Adelaide
Recruitment hospital [5] 0 0
Austin Health - Melbourne
Recruitment hospital [6] 0 0
St Vincent's Hospital - Melbourne
Recruitment hospital [7] 0 0
Perron Institute - Perth
Recruitment postcode(s) [1] 0 0
- Sydney
Recruitment postcode(s) [2] 0 0
- Brisbane
Recruitment postcode(s) [3] 0 0
- Adelaide
Recruitment postcode(s) [4] 0 0
- Melbourne
Recruitment postcode(s) [5] 0 0
- Perth
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Kansas
Country [2] 0 0
United States of America
State/province [2] 0 0
Maryland

Funding & Sponsors
Primary sponsor type
Other
Name
University of Kansas Medical Center
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
The Perron Institute
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
The hypothesis is that Sirolimus, (Rapamycin (R)) which is currently used in organ
transplantation and works by blocking the activity of T effector cells but preserving T
regulatory cells, as well as by inducing autophagy (protein degradation), will be effective
in IBM to slow or stabilize disease progression, helping to maintain patient function and
independence. This phase III trial will confirm pilot data showing statistically significant
clinical outcomes.
Trial website
https://clinicaltrials.gov/ct2/show/NCT04789070
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Mazen Dimachkie
Address 0 0
University of Kansas Medical Center
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Andrew J Heim
Address 0 0
Country 0 0
Phone 0 0
9139459926
Fax 0 0
Email 0 0
aheim2@kumc.edu
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT04789070