Phase III Trial of Sirolimus in IBM

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.