Study of Rifampicin in Multiple System Atrophy

Condition(s) targeted: Multiple System Atrophy

Intervention: Rifampicin (Drug); placebo (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Mayo Clinic

Official(s) and/or principal investigator(s):
Phillip A Low, MD, Principal Investigator, Affiliation: Mayo Clinic
David Robertson, MD, Principal Investigator, Affiliation: Vanderbilt University
Sid Gilman, MD, Principal Investigator, Affiliation: University of Michigan

The purpose of this study is to determine whether Rifampicin is 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 will be done on participants with early MSA. The study will consist of taking the drug 2 times a day for 12 months. Participants will undergo an evaluation of symptoms and function and will undergo neurologic examination at the beginning of the study, at 6 months and at 12 months. They will also be contacted at 3 and 9 months by telephone. Studies will be done at 10 participating sites.

Official title: Double-Blind, Placebo-Controlled Study of Rifampicin in Multiple System Atrophy

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Primary outcome: Rate of Change from baseline to 12 months in the total UMSARS I score

Secondary outcome:

Change from baseline to completion in total UMSARS score

Slope analysis: rate of progression in total UMSARS score from baseline to 12 months

Change from baseline to 12 months in UMSARS subscores

Whether or not a participant achieves a score of ≥3 on each of the following UMSARS questions: #1 (Speech impairment), #2 (Swallowing impairment), #8 (Falling)

Change from baseline to 12 months in the COMPASS_Select scale

Improvement in COMPASS_Select_change scale

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 is 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, Rifampicin will improve behavioral abnormalities of MSA and halt or reverse the pathological changes. The primary objective is to undertake a double-blind placebo-controlled clinical trial on the effect of Rifampicin on progression of neurological and autonomic failure in MSA.

Minimum age: 30 Years. Maximum age: 80 Years. Gender(s): Both.

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 MMSE. We will require a value >24.

- Patients should be able to swallow capsules whole.

Exclusion Criteria:

- Pregnant or lactating females.

- 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 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 according to Table 3 of Operations Manual.

- 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 MAO-A inhibitor within one month prior to the baseline visit are also exclusionary. For details, see Table 1 of Operations Manual.

- Diseases with features of PD; e. g., progressive supranuclear palsy, essential tremor,

inherited cerebellar degeneration, or postencephalitic parkinsonism.

- Dementia (DSM-IV criteria - Amer. Psych. Assoc., 1994). The score on the Mini-Mental

State Examination must be >24.

UCLA Medical Center, Los Angeles, California 90095, United States; Not yet recruiting
Susan Perlman, MD, Phone: 310-794-1195, Email: SPerlman@mednet.ucla.edu
Susan Perlman, MD, Principal Investigator

University of California, San Diego, San Diego, California 92103, United States; Not yet recruiting
Stephanie Lessig, MD, Phone: 858-552-8585, Ext: 5409, Email: slessig@ucsd.edu
Stephanie Lessig, MD, Principal Investigator

Mayo Clinic, Jacksonville, Florida 32224, United States; Not yet recruiting
William Cheshire, MD, Phone: 904-953-7229, Email: cheshire@mayo.edu
William Cheshire, MD, Principal Investigator

University of South Florida, Tampa, Florida 33606, United States; Not yet recruiting
Robert A Hauser, MD, Phone: 813-844-4077, Email: rhauser@health.usf.edu
Robert A Hauser, MD, Principal Investigator

Harvard Medical School, Boston, Massachusetts 02215, United States; Recruiting
Roy Freeman, MD, Phone: 617-632-8454, Email: rfreeman@bidmc.harvard.edu
Roy Freeman, MD, Principal Investigator

University of Michigan, Ann Arbor, Michigan 48109, United States; Not yet recruiting
Sid Gilman, MD, Phone: 734-936-1808, Email: sgilman@umich.edu
Sid Gilman, MD, Principal Investigator

Mayo Clinic, Rochester, Minnesota 55905, United States; Recruiting
Tonette Gehrking, Phone: 507-284-0336, Email: adc.research@mayo.edu
Phillip A Low, MD, Principal Investigator

New York University, New York, New York 10016, United States; Recruiting
Horacio Kaufmann, MD, Phone: 212-263-7225, Email: horacio.kaufmann@nyumc.org
Horacio Kaufmann, MD, Principal Investigator

Vanderbilt University, Nashville, Tennessee 37232, United States; Recruiting
David Robertson, MD, Phone: 615-343-6499, Email: david.robertson@vanderbilt.edu
David Robertson, MD, Principal Investigator

University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States; Recruiting
Steven Vernino, MD, Phone: 214-648-8816, Email: steven.vernino@utsouthwestern.edu
Steven Vernino, MD, Principal Investigator

Starting date: March 2011
Last updated: June 15, 2011