A Futility Trial of Sirolimus in Multiple System Atrophy

Single-center, randomized, placebo-controlled, phase-II, futility clinical trial to determine if oral sirolimus is of sufficient promise to slow disease progression in MSA, prior to embarking on a large-scale and costly phase III study to assess its efficacy. A futility design under the null hypothesis assumes that sirolimus will slow the progression of the disease, whereas the alternative hypothesis assumes no benefit of sirolimus. If the null hypothesis is rejected (i.e., futility of sirolimus to slow progression of MSA), a major phase III study will be discouraged, whereas non-futility will offer strong support for a phase III trial to detect clinical efficacy.


Eligibility Criteria:
Inclusion Criteria:

* Participants aged 30-80 years old with a diagnosis of MSA based on clinical criteria and standardized autonomic testing. This approach allows for identification of patients with MSA with very high specificity and is yet sensitive enough to allow for enrollment of patients at a disease stage at which an intervention on the natural disease course has a meaningful impact on patient outcome. Patients therefore have to fulfill current consensus criteria (1) for probable MSA of the parkinsonian subtype (MSA-P) or cerebellar subtype (MSA-C) and have findings on autonomic function testing suggestive of MSA.
* Participants who are less than 4 years from the time of documented MSA diagnosis.
* Participants who are still able to walk with or without assistance.
* Participants with an anticipated survival of at least 3 years in the opinion of the investigator.
* Participants who are willing and able to give informed consent.
* Montreal Cognitive Assessment (MoCA) \> 20.
* Ability to take oral medication and be willing to adhere to the study drug regimen
* For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation and for an additional 8 weeks after the end of study drug administration
* For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner
* Agreement to adhere to Lifestyle Considerations (see section 5.3) throughout study duration

Exclusion Criteria:

* Women of childbearing potential who do not practice an acceptable method of birth control. Acceptable methods of birth control in this study are: surgical sterilization, intrauterine devices, partner's vasectomy, a double-protection method (condom or diaphragm with spermicide), hormonal contraceptive drug (i.e., oral contraceptive, contraceptive patch, long-acting injectable contraceptive) with a required second mode of contraception.
* Participants with a clinically significant or unstable medical or surgical condition that, in the opinion of the investigator, might preclude safe completion of the study or might affect the results of the study. These include conditions causing significant central nervous system (CNS) or autonomic dysfunction, including congestive heart failure, recent (\<6 months) myocardial infarct, cardiopulmonary disease, severe, uncontrolled hypertension, thrombocytopenia (\< 50 x 10(9)/L), severe anemia (\< 8g/dl), immunocompromised state, liver or kidney disease (creatinine \> 1.5 mg/dl or proteinuria \> 20 mg/dl), uncontrolled diabetes mellitus (HbA1c \>10g%), alcoholism, amyloidosis, uncontrolled hypothyroidism, sympathectomy, unstable peripheral neuropathies, concurrent infections, orthopedic problems that compromise mobility and activity of daily living, cerebrovascular accidents, neurotoxin or neuroactive drug exposure, parkinsonism due to drugs (including neuroleptics, alpha-methyldopa, reserpine, metoclopramide).
* Participants with high LDL cholesterol levels (LDL \> 160 mg/dL) and/or high triglycerides levels (\> 200 mg/dL).
* Participants with latent tuberculosis infection as defined as positive interferon-gamma release-assay (QUANTIferon®).
* Participants with history of tuberculosis
* Participants with a history of active, acute or chronic, or latent hepatitis B or hepatitis C.
* Participants with human immunodeficiency virus (HIV) infection, or other congenital or acquired causes of immunosuppression.
* Participants with active malignant neoplasms or history of malignant neoplasm in the last 5 years.
* Movement disorders other than MSA; e.g., Parkinson disease, dementia with Lewy bodies, essential tremor, progressive supranuclear palsy, spinocerebellar ataxia, spastic paraparesis, corticobasal degeneration, or vascular, pharmacological or post-encephalitic parkinsonism.
* Dementia (DSM-V criteria).
* History of electroconvulsive therapy.
* History of deep brain stimulation surgery.
* Patients with contraindication for MRI scanning, including those with MRI-incompatible pacemaker
* History of organ transplant
* Participants who have taken any investigational products within 60 days prior to baseline.
* Treatment with cyclosporine, corticosteroids, methotrexate, rituximab within 3 months prior to baseline.
* Treatment with inhibitors of CYP3A4 (which may decrease the metabolism of sirolimus and increase sirolimus levels): nicardipine, verapamil, clotrimazole, fluconazole, itraconazole, clarithromycin, erythromycin, troleandomycin, cisapride, metoclopramide, bromocriptine, cimetidine, danazol, HIV-protease inhibitors (e.g., ritonavir, indinavir); grapefruit.
* Treatment with inducers of CYP3A4 (which may increase the metabolism of sirolimus and decrease sirolimus levels): carbamazepine, phenobarbital, phenytoin, rifabutin, rifapentine.
* Inability or unwillingness of subject or legal guardian/representative to give written informed consent.