Study of Rifampicin in Multiple System Atrophy (MSA)

This study has been terminated.
(DSMB recommended stopping the study after an interim analysis of the primary endpoint revealed that futility criteria were met.)
Sponsor:
Collaborators:
Vanderbilt University
Rare Disease Research Network Autonomic Consortium
Information provided by (Responsible Party):
Phillip Low, Mayo Clinic
ClinicalTrials.gov Identifier:
NCT01287221
First received: January 28, 2011
Last updated: February 11, 2014
Last verified: February 2014
  Purpose

The purpose of this study was to determine whether Rifampicin was effective in slowing or reversing the progression of multiple system atrophy (MSA). Research studies indicate that there is an abnormality in protein synthesis and structure in parts of the brain responsible for MSA (protein misfolding) and the drug Rifampicin could potentially prevent or reverse this protein alteration. The study was done on participants with early MSA. The study consisted of taking the drug 2 times a day for 12 months. Participants underwent an evaluation of symptoms and function and will underwent a neurologic examination at the beginning of the study, at 6 months and at 12 months. They were also be contacted at 3 and 9 months by telephone. Studies were done at 10 participating sites.


Condition Intervention Phase
Multiple System Atrophy
Drug: Rifampicin
Drug: placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Double-Blind, Placebo-Controlled Study of Rifampicin in Multiple System Atrophy

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • Rate of Change From Baseline to 12 Months in the Total Unified Multiple System Atrophy Rating Scale (UMSARS) Part I Score (Minus Question 11) [ Time Frame: baseline, 12 months ] [ Designated as safety issue: No ]

    UMSARS is a scale measuring disease progression that comprises 4 parts; only Parts I and II were used in this study. Part I scores symptoms of neurological and autonomic dysfunction. Part II is a motor examination. Part I has 12 questions with a rating scale ranging from 0 (normal) to 4 (extreme dysfunction). Therefore the total score for Part I could range from 0 (normal) to 48 (extreme dysfunction).

    Participant-specific rate of change in points per month was estimated using slope estimate from least square regression where for each participant, their UMSARS I scores were plotted over time measured in months.



Secondary Outcome Measures:
  • Change From Baseline to 12 Months in UMSARS Part I Score (Minus Question 11) [ Time Frame: baseline, 12 months ] [ Designated as safety issue: No ]
    UMSARS is a scale measuring disease progression that comprises 4 parts, only Parts I and II were used in this study. Part I scores symptoms of neurological and autonomic dysfunction. Part II is a motor examination. Part I has 12 questions with a rating scale ranging from 0 (normal) to 4 (extreme dysfunction). Therefore the total score for Part I could range from 0 (normal) to 48 (extreme dysfunction).

  • Change From Baseline to 12 Months in UMSARS Part II [ Time Frame: baseline, 12 months ] [ Designated as safety issue: No ]
    UMSARS is a scale measuring disease progression that comprises 4 parts; only Parts I and II were used in this study. Part I scores symptoms of neurological and autonomic dysfunction. Part II is a motor examination. Part II has 14 items with a rating scale ranging from 0 (normal) to 4 (extreme dysfunction). Therefore the total score for Part II could range from 0 (normal) to 56 (extreme dysfunction).

  • Change From Baseline to 12 Months in Total UMSARS (i.e., UMSARS Part I Minus Question 11 + UMSARS Part II) [ Time Frame: baseline, 12 months ] [ Designated as safety issue: No ]
    UMSARS is a scale measuring disease progression that comprises 4 parts; only Parts I and II were used in this study. Part I scores symptoms of neurological and autonomic dysfunction. Part II is a motor examination. Part I has 12 questions with a rating scale ranging from 0 (normal) to 4 (extreme dysfunction). Part II has 14 items with a rating scale ranging from 0 (normal) to 4 (extreme dysfunction). Therefore the total score for total UMSARS Parts I minus Question 11 + Part II could range from 0 (normal) to 104 (extreme dysfunction).

  • Rate of Change From Baseline to 12 Months in Total UMSARS (i.e., UMSARS Part I Minus Question 11 + UMSARS Part II) Using Slope Estimate [ Time Frame: baseline, 12 months ] [ Designated as safety issue: No ]

    UMSARS is a scale measuring disease progression that comprises 4 parts; only Parts I and II were used in this study. Part I scores symptoms of neurological and autonomic dysfunction. Part II is a motor examination. Part I has 12 questions with a rating scale ranging from 0 (normal) to 4 (extreme dysfunction). Part II has 14 items with a rating scale ranging from 0 (normal) to 4 (extreme dysfunction). Therefore the total score for total UMSARS Parts I minus Question 11 + Part II could range from 0 (normal) to 104 (extreme dysfunction).

    Participant-specific rate of change in points per month was estimated using slope estimate from least square regression where for each participant, their total UMSARS scores were plotted over time measured in months.


  • Change From Baseline to 12 Months in the COMPASS-Select Scale [ Time Frame: baseline, 12 months ] [ Designated as safety issue: No ]
    The composite autonomic symptoms score (COMPASS) provides a score of autonomic symptom severity with appropriate weighting. In the COMPASS_select, symptoms are confined to 6 select domains of symptoms. The version of the COMPASS-Select used (06-09-2009 v1) has 46 questions, with multiple parts, scores ranging from "much worse" to "no such symptoms." Scores could range from 0 (no such symptoms) to 85 (much worse).

  • Change in the COMPASS-Select-Change Scale From Baseline to 12 Months [ Time Frame: baseline, 12 months ] [ Designated as safety issue: No ]
    The change in COMPASS is a derivative of COMPASS and evaluates the change in symptoms over time on selected domains of symptoms as a function of natural history or intervention therapy. The focus is on 7 selected domains. The version of the COMPASS-Change -Select Scale used (06-09-2009 Ver. 1) has 16 questions, with multiple parts, scores ranging from "much worse" to "no such symptoms." The score could range from 0 (no such symptoms) to 94 (much worse).


Enrollment: 100
Study Start Date: March 2011
Study Completion Date: January 2013
Primary Completion Date: November 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Rifampicin
Subjects randomized to this arm will receive 300 mg Rifampicin two times a day for 12 months.
Drug: Rifampicin
300 mg, 2 times daily
Other Names:
  • Rifampin
  • Rifadin
  • Rimactane
  • Rifater
  • Rimactazid
  • Rimycin
  • Rofact
Placebo Comparator: Placebo
Subjects randomized to this arm will receive placebo capsules twice daily for 12 months. The capsules will contain riboflavin (vitamin B2).
Drug: placebo
placebo
Other Names:
  • vitamin B2
  • riboflavin

Detailed Description:

MSA is a progressive, fatal disorder characterized by autonomic failure and parkinsonism and/or cerebellar involvement. Neuropathologically, MSA is characterized by glial cytoplasmic inclusions (GCI) of abnormally aggregated α-synuclein (α-syn). This was a study to test the hypothesis that Rifampicin, because of its ability to inhibit the formation of α-synuclein fibrils and disaggregate fibrils already formed, will delay progression or reverse neurologic and autonomic functions and symptoms in MSA. This approach has been proposed as a potential approach to treat parkinsonism and specifically, MSA. In an experimental model of MSA, it was hypothesized that Rifampicin would improve behavioral abnormalities of MSA and halt or reverse the pathological changes. The primary objective was to undertake a double-blind placebo-controlled clinical trial on the effect of Rifampicin on progression of neurological and autonomic failure in MSA.

The Data Safety Monitoring Board (DSMB) recommended stopping the study after an interim analysis of the primary endpoint revealed that futility criteria were met.

  Eligibility

Ages Eligible for Study:   30 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participants aged 30-80 years old with a diagnosis of Possible or Probable MSA of the parkinsonian subtype (MSA-P) or cerebellar subtype (MSA-C) according to The Gilman Criteria (2008).
  • Participants who are less than 4 years from the time of documented MSA diagnosis.
  • 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.
  • "Normal" cognition as assessed by Mini-Mental State Examination (MMSE). We will require a value >24.
  • Patients should be able to swallow capsules whole.

Exclusion Criteria:

  • Pregnant or lactating females.
  • Unified Multiple System Atrophy Rating Scale (UMSARS) score >17 on modified UMSARS I (question 11 eliminated).
  • 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, thrombocytopenia (<50 x10(9)/L), immunosuppressed state, severe uncontrolled hypertension, severe cardiopulmonary disease, severe anemia (<8g/dl), severe liver or kidney disease (creatinine >2.3 mg/dl) uncontrolled diabetes mellitus (HbA1c >10g%), alcoholism, malignant neoplasms, amyloidosis, uncontrolled hypothyroidism, unstable peripheral neuropathies, concurrent infections, orthopedic problems that compromise mobility and activity of daily living, severe cerebrovascular accidents (such as hemiplegia, aphasia and non-dominant parietal lobe syndrome), and neurotoxins or neuroactive drug exposure, parkinsonism due to drugs (including neuroleptics, a-methyldopa, reserpine, metoclopramide).
  • Participants who have taken any investigational products within 60 days prior to baseline.
  • Women of child-bearing 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 taking Tetrabenazine, Rasagiline or Selegiline. The participant will qualify for the Rifampicin study after they have stopped these drugs for 3 months
  • Participants known to have porphyria.
  • Participants with abnormal liver function tests defined as 1.5 times the upper limit of normal.
  • Concomitant therapy with anticholinergic, alpha and beta adrenergic antagonists, or other medications that affect autonomic function will be stopped prior to autonomic evaluation.
  • The regular use of neuroleptics within the six months prior to the initial evaluation. Occasional use of a neuroleptic as an anti-emetic in the past is allowed, providing not more than three doses were taken within the previous 12 months.
  • Since Rifampicin has significant drug-drug interactions, particular attention has been devoted to the use of concomitant medications. Considering the target population, we will exclude participants taking antifungal medication (itraconazole), antiarrhythmics like amiodarone, digitalis and lorcainide, female hormones and quetiapine (Seroquel). Use of methylphenidate, cinnarizine, reserpine, amphetamine, atypical antipsychotics such as risperidone, olanzapine, and quetiapine or a Monoamine oxidase A (MAO-A) inhibitor within one month prior to the baseline visit are also exclusionary.
  • Diseases with features of Parkinson's Disease; e.g., progressive supranuclear palsy, essential tremor, inherited cerebellar degeneration, or postencephalitic parkinsonism.
  • Dementia (DSM-IV criteria - Amer. Psych. Association, 1994). The score on the MMSE must be >24.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01287221

Locations
United States, California
UCLA Medical Center
Los Angeles, California, United States, 90095
University of California, San Diego
San Diego, California, United States, 92103
United States, Florida
Mayo Clinic
Jacksonville, Florida, United States, 32224
University of South Florida
Tampa, Florida, United States, 33606
United States, Massachusetts
Harvard Medical School
Boston, Massachusetts, United States, 02215
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, New York
New York University
New York, New York, United States, 10016
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37232
United States, Texas
University of Texas Southwestern Medical Center
Dallas, Texas, United States, 75390
Sponsors and Collaborators
Phillip Low
Vanderbilt University
Rare Disease Research Network Autonomic Consortium
Investigators
Principal Investigator: Phillip A Low, MD Mayo Clinic
Principal Investigator: David Robertson, MD Vanderbilt University
Principal Investigator: Sid Gilman, retired, MD University of Michigan
  More Information

No publications provided

Responsible Party: Phillip Low, MD, Mayo Clinic
ClinicalTrials.gov Identifier: NCT01287221     History of Changes
Other Study ID Numbers: 10-003108, P01NS044233, U54NS065736
Study First Received: January 28, 2011
Results First Received: July 2, 2013
Last Updated: February 11, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Shy-Drager Syndrome
Multiple System Atrophy
Atrophy
Primary Dysautonomias
Autonomic Nervous System Diseases
Nervous System Diseases
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Hypotension
Vascular Diseases
Cardiovascular Diseases
Pathological Conditions, Anatomical
Riboflavin
Vitamins
Rifampin
Photosensitizing Agents
Radiation-Sensitizing Agents
Physiological Effects of Drugs
Pharmacologic Actions
Dermatologic Agents
Therapeutic Uses
Vitamin B Complex
Micronutrients
Growth Substances
Antibiotics, Antitubercular
Anti-Bacterial Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on April 17, 2014