A Futility Trial of Sirolimus in Multiple System Atrophy

NCT03589976 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: 17-01392
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 1

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.

Conditions

Multiple System Atrophy

Outcome Measures

Primary Outcomes (1)

• Change From Baseline to 48 Weeks in United Multiple System Atrophy Rating Score (UMSARS) Total Score

  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.

  Baseline, 48 Weeks

Secondary Outcomes (1)

• Change From Baseline to 48 Weeks in UMSARS-1

  Baseline, 48 Weeks

Study Arms (2)

Sirolimus

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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

Interventions

Sirolimus 2 MG DRUG

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.

Sirolimus

Placebo OTHER

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.

Placebo

Eligibility Criteria

• Age: 30 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• NYU Langone Health: lead
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator

Study Sites (1)

New York University School of Medicine

New York, New York, 10016, United States

Location

Related Publications (1)

• 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.

  PMID: 35040506 DERIVED

MeSH Terms

Conditions

Multiple System Atrophy

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

Primary Dysautonomias; Autonomic Nervous System Diseases; Nervous System Diseases; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Jose-Alberto Palma, MD, PhD
• Organization: NYU Langone Health

JoseAlberto.PalmaCarazo@nyulangone.org

212-263-7225

Study Officials

• Jose-Alberto Palma, MD, PhD

  NYU Langone Health

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 5, 2018
• First Posted: July 18, 2018
• Study Start: September 1, 2018
• Primary Completion: November 20, 2020
• Study Completion: January 1, 2021
• Last Updated: December 7, 2021
• Results First Posted: December 7, 2021

Record last verified: 2021-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: 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.

Locations

US (1)