A Futility Trial of Sirolimus in Multiple System Atrophy
Condition: Multiple System Atrophy
MeSH terms: Multiple System Atrophy; Shy-Drager Syndrome; Atrophy
Intervention: Sirolimus 2 MG; Placebo
Intervention description: Dose will be adjusted throughout this trial based on sirolimus plasma levels and the presence of drug-related adverse events. The maximum dose will be 6mg/day.; Patients receiving placebo will undergo analog sham level measurements and the number of tablets will be also adjusted to maintain the blinding of the trial.
Intervention MeSH terms: Sirolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Double (Participant, Investigator)
Enrollment: 47.0
Sex: All
Minimum age: 30 Years
Maximum age: 80 Years
Healthy volunteers: No

Summary:

      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.