Phase III Trial of Sirolimus in IBM

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)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Inclusion Body Myositis
• Intervention / Treatment: Drug: Placebo; Drug: Sirolimus

• Study Type: Interventional
• Enrollment (Estimated): 140
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia
      • Concord Repatriation Hospital
    • Sydney, New South Wales, Australia
      • Royal Northshore Hospital
  • Queensland
    • Brisbane, Queensland, Australia
      • Royal Brisbane and Women's Hospital
  • South Australia
    • Adelaide, South Australia, Australia
      • Royal Adelaide Hospital
  • Victoria
    • Melbourne, Victoria, Australia
      • Austin Health
    • Melbourne, Victoria, Australia
      • St Vincent's Hospital
  • Washington
    • Perth, Washington, Australia
      • Perron Institute
• Netherlands
  • Leiden, Netherlands
    • Leiden University Medical Center
• United States
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21218
      • Johns Hopkins University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Sirolimus; 2mg capsules once daily	Drug: 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.; Other Names: Rapamune
Placebo Comparator: Placebo; 2mg capsules once daily	Drug: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in IBM Functional Rating Scale (IBM-FRS) from Baseline to Week 84	The IBM-FRS is a concise and quick (~10 minute), clinician-administered ordinal rating scale used to determine participants' assessment of their capability and independence. It includes 10 measures (swallowing, handwriting, cutting food and handling utensils, fine motor tasks, dressing, hygiene, turning in bed and adjusting covers, changing position from sitting to standing, walking, and climbing stairs), graded on a Likert scale from 0 (being unable to perform) to 4 (normal). The sum of the 10 items gives a value between 0 and 40, with a higher score representing less functional limitation.	Baseline, Week 84

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 6 Minute Walk Test (6MWT) from Baseline to Week 84	The 6MWT measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The 6MWT is a sub-maximal exercise test used to assess aerobic capacity and endurance in patients with cardiopulmonary disease. It is now a commonly used and validated test to estimate the functional walking capacity in patients with a range of chronic diseases including IBM.	Baseline, Week 84
Change in Modified Timed Up and Go (mTUG) from Baseline to Week 84	The Timed Up and Go (mTUG) was initially developed as a tool to determine falls risk, mobility, balance and walking ability in an elderly population. It has since been adopted as an outcome measure in a broader clinical setting including myositis.	Baseline, Week 84
Change in Manual Muscle Testing (MMT) from Baseline to Week 84	Manual Muscle Testing (MMT) is a relatively simple method of assessing a patient's strength in a muscle or group of muscles. There is however a degree of subjectivity when assigning a score. MMT will be used to assess change in strength throughout the study period. This method is routinely performed in a clinical setting and has been shown to be reliable. This tool assesses muscle strength using a 0 - 10 point scale.	Baseline, Week 84

Collaborators and Investigators

• Sponsor: University of Kansas Medical Center
• Collaborators: The Perron Institute
• Investigators: Principal Investigator: Mazen Dimachkie, University of Kansas Medical Center

Publications and helpful links

General Publications

• Badrising UA, Henderson R, Reddel S, Corbett A, Liang C, Reardon K, Ghaoui R, Bulsara M, Brady S, Brusch A, Chan D, Coudert JD, Fairchild T, Jain G, Kiernan MC, Leonard D, Lloyd T, Schmidt J, McDermott MP, Sanders L, Lowe C, van der Kooi AJ, Weihl C, Mohassel P, Simpson M, Carroll A, Cooper I, Beer K, Hiscock K, Walters S, Panicker A, Doverty A, Heim A, van Heur-Neuman M, Benveniste O, Dimachkie MM, Needham M. Optimism in inclusion body myositis: a double-blind randomised controlled phase III trial investigating the effect of sirolimus on disease progression in patients with IBM as measured by the IBM Functional Rating Scale. Clin Exp Rheumatol. 2025 Feb;43(2):316-325. doi: 10.55563/clinexprheumatol/zvffa0. Epub 2025 Feb 26.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2022
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: February 15, 2021
• First Submitted That Met QC Criteria: March 4, 2021
• First Posted (Actual): March 9, 2021

Study Record Updates

• Last Update Posted (Estimated): January 14, 2026
• Last Update Submitted That Met QC Criteria: January 13, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Neuromuscular Diseases; Myositis; Myositis, Inclusion Body; Organic Chemicals; Macrolides; Lactones; Sirolimus
• Other Study ID Numbers: Optimism in IBM

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No