Study of Rifampicin in Multiple System Atrophy

NCT ID: NCT01287221

Last Updated: 2014-03-28

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 100 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-03-31
• Study Completion Date: 2013-01-31

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.

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.

Conditions

Multiple System Atrophy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Rifampicin

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

Group Type: ACTIVE_COMPARATOR

Rifampicin

Intervention Type: DRUG

300 mg, 2 times daily

Placebo

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

Group Type: PLACEBO_COMPARATOR

placebo

Intervention Type: DRUG

placebo

Interventions

Rifampicin

300 mg, 2 times daily

Intervention Type: DRUG

placebo

placebo

Intervention Type: DRUG

Other Intervention Names

Rifampin; Rifadin; Rimactane; Rifater; Rimactazid; Rimycin; Rofact; vitamin B2; riboflavin

Eligibility 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.

• Minimum Eligible Age: 30 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Neurological Disorders and Stroke (NINDS)

NIH

Sponsor Role: collaborator

Vanderbilt University

OTHER

Sponsor Role: collaborator

Rare Disease Research Network Autonomic Consortium

UNKNOWN

Sponsor Role: collaborator

Phillip Low

OTHER

Sponsor Role: lead

Responsible Party

Phillip Low

MD

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Phillip A Low, MD

Role: PRINCIPAL_INVESTIGATOR

Mayo Clinic

David Robertson, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University

Sid Gilman, retired, MD

Role: PRINCIPAL_INVESTIGATOR

University of Michigan

Locations

UCLA Medical Center

Los Angeles, California, United States

University of California, San Diego

San Diego, California, United States

Mayo Clinic

Jacksonville, Florida, United States

University of South Florida

Tampa, Florida, United States

Harvard Medical School

Boston, Massachusetts, United States

University of Michigan

Ann Arbor, Michigan, United States

Mayo Clinic

Rochester, Minnesota, United States

New York University

New York, New York, United States

Vanderbilt University

Nashville, Tennessee, United States

University of Texas Southwestern Medical Center

Dallas, Texas, United States

Countries

United States

References

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.

Reference Type: RESULT

PMID: 24507091 (View on PubMed)

Other Identifiers

P01NS044233

Identifier Type: NIH

Identifier Source: secondary_id

View Link

U54NS065736

Identifier Type: NIH

Identifier Source: secondary_id

View Link

10-003108

Identifier Type: -

Identifier Source: org_study_id