Study of Rifampicin in Multiple System Atrophy

NCT01287221 | Terminated Phase 3 Results DMC

• 3 other identifiers: 10-003108P01NS044233U54NS065736
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 10

Brief Summary

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.

Conditions

Multiple System Atrophy

Outcome Measures

Primary Outcomes (1)

• Rate of Change From Baseline to 12 Months in the Total Unified Multiple System Atrophy Rating Scale (UMSARS) Part I Score (Minus Question 11)

  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.

  baseline, 12 months

Secondary Outcomes (6)

• Change From Baseline to 12 Months in UMSARS Part I Score (Minus Question 11)

  baseline, 12 months

• Change From Baseline to 12 Months in UMSARS Part II

  baseline, 12 months

• Change From Baseline to 12 Months in Total UMSARS (i.e., UMSARS Part I Minus Question 11 + UMSARS Part II)

  baseline, 12 months

• 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

  baseline, 12 months

• Change From Baseline to 12 Months in the COMPASS-Select Scale

  baseline, 12 months

Study Arms (2)

Rifampicin

ACTIVE COMPARATOR

Subjects randomized to this arm will receive 300 mg Rifampicin two times a day for 12 months.

Drug: Rifampicin

Placebo

PLACEBO COMPARATOR

Subjects randomized to this arm will receive placebo capsules twice daily for 12 months. The capsules will contain riboflavin (vitamin B2).

Drug: placebo

Interventions

Rifampicin DRUG

300 mg, 2 times daily

Also known as: Rifampin, Rifadin, Rimactane, Rifater, Rimactazid, Rimycin, Rofact

Rifampicin

placebo DRUG

placebo

Also known as: vitamin B2, riboflavin

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 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Phillip Low: lead
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator
• Vanderbilt University: collaborator
• Rare Disease Research Network Autonomic Consortium: collaborator

Study Sites (10)

UCLA Medical Center

Los Angeles, California, 90095, United States

Location

University of California, San Diego

San Diego, California, 92103, United States

Location

Mayo Clinic

Jacksonville, Florida, 32224, United States

Location

University of South Florida

Tampa, Florida, 33606, United States

Location

Harvard Medical School

Boston, Massachusetts, 02215, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

New York University

New York, New York, 10016, United States

Location

Vanderbilt University

Nashville, Tennessee, 37232, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Related Publications (1)

• Low PA, Robertson D, Gilman S, Kaufmann H, Singer W, Biaggioni I, Freeman R, Perlman S, Hauser RA, Cheshire W, Lessig S, Vernino S, Mandrekar J, Dupont WD, Chelimsky T, Galpern WR. Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2014 Mar;13(3):268-75. doi: 10.1016/S1474-4422(13)70301-6. Epub 2014 Feb 5.

  PMID: 24507091 RESULT

MeSH Terms

Conditions

Multiple System Atrophy

Interventions

Rifampin; isoniazid, pyrazinamide, rifampin drug combination; Riboflavin

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)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Flavins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, 3-Ring; Coenzymes; Enzymes and Coenzymes; Pigments, Biological; Biological Factors

Limitations and Caveats

The study was terminated early; the Data Safety and Monitoring Board recommended stopping the study after an interim analysis of the primary endpoint revealed that futility criteria were met.

Results Point of Contact

• Title: Dr. Phillip A. Low
• Organization: Mayo Clinic

low@mayo.edu

507-284-3375

Study Officials

• Phillip A Low, MD

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

• David Robertson, MD

  Vanderbilt University

  PRINCIPAL INVESTIGATOR

• Sid Gilman, retired, MD

  University of Michigan

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: January 28, 2011
• First Posted: February 1, 2011
• Study Start: March 1, 2011
• Primary Completion: November 1, 2012
• Study Completion: January 1, 2013
• Last Updated: March 28, 2014
• Results First Posted: March 28, 2014

Record last verified: 2014-02

Locations

US (10)