Clinical trial NCT04789070: Phase III Trial of Sirolimus in IBM
Official 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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Inclusion Body Myositis
Lead sponsor: University of Kansas Medical Center
Sponsor class: OTHER
Collaborators: name: The Perron Institute
First posted: 2021-03-09
Enrollment: 140
Sex: ALL
Minimum age (years): 45
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Change in IBM Functional Rating Scale (IBM-FRS) from Baseline to Week 84
timeFrame: Baseline, Week 84
Secondary outcomes:
measure: Change in 6 Minute Walk Test (6MWT) from Baseline to Week 84
timeFrame: Baseline, Week 84
measure: Change in Modified Timed Up and Go (mTUG) from Baseline to Week 84
timeFrame: Baseline, Week 84
measure: Change in Manual Muscle Testing (MMT) from Baseline to Week 84
timeFrame: Baseline, Week 84
Other outcomes:
Locations:
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Sydney
country: Australia
facility: Concord Repatriation Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Royal Northshore Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Melbourne
country: Australia
facility: Austin Health
state: Victoria
city: Melbourne
country: Australia
facility: St Vincent's Hospital
state: Victoria
city: Perth
country: Australia
facility: Perron Institute
state: Washington
Study officials:
affiliation: University of Kansas Medical Center
name: Mazen Dimachkie
role: PRINCIPAL_INVESTIGATOR
References: