A Futility Trial of Sirolimus in Multiple System Atrophy

• ClinicalTrials.gov Identifier: NCT03589976
• Recruitment Status: Terminated
• First Posted: July 18, 2018
• Results First Posted: December 7, 2021
• Last Update Posted: December 7, 2021
• Sponsor: NYU Langone Health
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS)
• Information provided by (Responsible Party): NYU Langone Health

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Multiple System Atrophy	Drug: Sirolimus 2 MG; Other: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 47 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Single Center Randomized,Double Blind, Placebo-controlled Futility Trial to Determine if Sirolimus is of Sufficient Promise to Slow the Progression of Multiple System Atrophy
• Actual Study Start Date: September 1, 2018
• Actual Primary Completion Date: November 20, 2020
• Actual Study Completion Date: January 1, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Sirolimus; 2 mg/day (one 2-mg tablet/day). The dose of sirolimus will be adjusted throughout the trial based on sirolimus plasma levels and the presence of drug-related adverse events. The maximum dose of sirolimus will be6 mg/day (three 2-mg tablets/day).	Drug: Sirolimus 2 MG; 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.
Placebo Comparator: Placebo; 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.	Other: Placebo; 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.

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline to 48 Weeks in United Multiple System Atrophy Rating Score (UMSARS) Total Score [ Time Frame: Baseline, 48 Weeks ]

   UMSARS is a validated, disease-specific scale representing the diverse signs and symptoms in MSA.

   USMARS has an Activities of Daily Living score (UMSARS-1, 12 questions) that evaluates motor including autonomic activities and the Motor Examination score (UMSARS-2, 14 questions). UMSARS-3 measures supine/standing BP and UMSARS-4 is a disability scale.

   The total range of score is 1-109; Higher scores on the UMSARS scales mean poorer health.

Secondary Outcome Measures :

1. Change From Baseline to 48 Weeks in UMSARS-1 [ Time Frame: Baseline, 48 Weeks ]

   The Activities of Daily Living score (UMSARS-1, 12 questions) evaluates impact of symptoms, including autonomic, on activities of daily living.

   12 functional situations are rated between 0-4. The total range of score is 0-48; the higher the score, the more problems conducting activities of daily living.

Eligibility Criteria

• Ages Eligible for Study: 30 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, New York

New York University School of Medicine

New York, New York, United States, 10016

Sponsors and Collaborators

NYU Langone Health

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Jose-Alberto Palma, MD, PhD; NYU Langone Health

  Study Documents (Full-Text)

Documents provided by NYU Langone Health:

Study Protocol and Statistical Analysis Plan  [PDF] June 4, 2020

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Palma JA, Martinez J, Millar Vernetti P, Ma T, Perez MA, Zhong J, Qian Y, Dutta S, Maina KN, Siddique I, Bitan G, Ades-Aron B, Shepherd TM, Kang UJ, Kaufmann H. mTOR Inhibition with Sirolimus in Multiple System Atrophy: A Randomized, Double-Blind, Placebo-Controlled Futility Trial and 1-Year Biomarker Longitudinal Analysis. Mov Disord. 2022 Apr;37(4):778-789. doi: 10.1002/mds.28923. Epub 2022 Jan 18.

• Responsible Party: NYU Langone Health
• ClinicalTrials.gov Identifier: NCT03589976
• Other Study ID Numbers: 17-01392
• First Posted: July 18, 2018
• Results First Posted: December 7, 2021
• Last Update Posted: December 7, 2021
• Last Verified: November 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).
• Supporting Materials: Study Protocol
• Time Frame: Beginning 3 months and ending 5 years following article publication.
• Access Criteria: Researchers who provide a methodologically sound proposal that has been approved by a local Institutional Review Board.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Multiple System Atrophy; Shy-Drager Syndrome; Atrophy; Pathological Conditions, Anatomical; Primary Dysautonomias; Autonomic Nervous System Diseases; Nervous System Diseases; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Hypotension; Vascular Diseases; Cardiovascular Diseases; Sirolimus; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Antifungal Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs