Clinical trial NCT01287221: Study of Rifampicin in Multiple System Atrophy
Official title: Double-Blind, Placebo-Controlled Study of Rifampicin in Multiple System Atrophy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Multiple System Atrophy
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
name: Vanderbilt University
name: Rare Disease Research Network Autonomic Consortium
First posted: 2011-02-01
Enrollment: 100
Sex: ALL
Minimum age (years): 30
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Rate of Change From Baseline to 12 Months in the Total Unified Multiple System Atrophy Rating Scale (UMSARS) Part I Score (Minus Question 11)
timeFrame: baseline, 12 months
Secondary outcomes:
measure: Change From Baseline to 12 Months in UMSARS Part I Score (Minus Question 11)
timeFrame: baseline, 12 months
measure: Change From Baseline to 12 Months in UMSARS Part II
timeFrame: baseline, 12 months
measure: Change From Baseline to 12 Months in Total UMSARS (i.e., UMSARS Part I Minus Question 11 + UMSARS Part II)
timeFrame: baseline, 12 months
measure: 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
timeFrame: baseline, 12 months
measure: Change From Baseline to 12 Months in the COMPASS-Select Scale
timeFrame: baseline, 12 months
measure: Change in the COMPASS-Select-Change Scale From Baseline to 12 Months
timeFrame: baseline, 12 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: San Diego
country: United States
facility: University of California, San Diego
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Boston
country: United States
facility: Harvard Medical School
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: New York University
state: New York
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
Study officials:
affiliation: Mayo Clinic
name: Phillip A Low, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Vanderbilt University
name: David Robertson, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Michigan
name: Sid Gilman, retired, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.