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A Futility Trial of Sirolimus in Multiple System Atrophy

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ClinicalTrials.gov Identifier: NCT03589976
Recruitment Status : Terminated (Interim analysis showed early evidence of futility of sirolimus. Trial stopped per DSMB recommendation.)
First Posted : July 18, 2018
Results First Posted : December 7, 2021
Last Update Posted : December 7, 2021
Sponsor:
Collaborator:
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
NYU Langone Health

Tracking Information
First Submitted Date  ICMJE July 5, 2018
First Posted Date  ICMJE July 18, 2018
Results First Submitted Date  ICMJE November 8, 2021
Results First Posted Date  ICMJE December 7, 2021
Last Update Posted Date December 7, 2021
Actual Study Start Date  ICMJE September 1, 2018
Actual Primary Completion Date November 20, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 8, 2021)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: July 5, 2018)
  • Change from baseline to 48 weeks in United Multiple System Atrophy Rating Score (UMSARS) total score in patients taking sirolimus [ Time Frame: 48 Weeks ]
    UMSARS is a validated, disease-specific scale representing the diverse signs and symptoms in MSA. Higher scores on the UMSARS scales mean poorer health. 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.
  • Change from baseline to 48 weeks in United Multiple System Atrophy Rating Score (UMSARS) total score in historical controls [ Time Frame: 48 Weeks ]
    UMSARS is a validated, disease-specific scale representing the diverse signs and symptoms in MSA. Higher scores on the UMSARS scales mean poorer health. 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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 8, 2021)
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.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 5, 2018)
  • Change from baseline to 48 weeks in United Multiple System Atrophy Rating Score (UMSARS) subscores (UMSARS-1 and UMSARS-2) in patients taking sirolimus [ Time Frame: 48 Weeks ]
    UMSARS-2 score (neurological examination) progression at week 48 compared to baseline; the UMSARS-1 score (activity of daily living) progression at week 48 compared to baseline.
  • Change from baseline to 48 weeks in United Multiple System Atrophy Rating Score (UMSARS) subscores (UMSARS-1 and UMSARS-2) in historical controls [ Time Frame: 48 Weeks ]
    UMSARS-2 score (neurological examination) progression at week 48 compared to baseline; the UMSARS-1 score (activity of daily living) progression at week 48 compared to baseline.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Futility Trial of Sirolimus in Multiple System Atrophy
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Multiple System Atrophy
Intervention  ICMJE
  • 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.
  • 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.
Study Arms  ICMJE
  • 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).
    Intervention: Drug: Sirolimus 2 MG
  • 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.
    Intervention: Other: Placebo
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: March 23, 2021)
47
Original Estimated Enrollment  ICMJE
 (submitted: July 5, 2018)
56
Actual Study Completion Date  ICMJE January 1, 2021
Actual Primary Completion Date November 20, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 30 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03589976
Other Study ID Numbers  ICMJE 17-01392
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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.
Current Responsible Party NYU Langone Health
Original Responsible Party Same as current
Current Study Sponsor  ICMJE NYU Langone Health
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE National Institute of Neurological Disorders and Stroke (NINDS)
Investigators  ICMJE
Principal Investigator: Jose-Alberto Palma, MD, PhD NYU Langone Health
PRS Account NYU Langone Health
Verification Date November 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP