Multiple System Atrophy
Conditions
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.
Interventions
DRUGRifampicin
300 mg, 2 times daily
DRUGplacebo
placebo
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Vanderbilt University
Rare Disease Research Network Autonomic Consortium
Phillip Low
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Change From Baseline to 12 Months in the Total Unified Multiple System Atrophy Rating Scale (UMSARS) Part I Score (Minus Question 11) | baseline, 12 months | 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
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 12 Months in UMSARS Part II | baseline, 12 months | 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) | baseline, 12 months | 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). |
| Change From Baseline to 12 Months in UMSARS Part I Score (Minus Question 11) | baseline, 12 months | 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 the COMPASS-Select Scale | baseline, 12 months | 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 | baseline, 12 months | 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). |
| 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 | 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. |
Countries
United States
Participant flow
Recruitment details
Subjects were enrolled from 10 specialized tertiary centers in the United States from April 2011 through April 2012.
Participants by arm
| Arm | Count |
|---|---|
| Rifampicin Subjects randomized to this arm will receive 300 mg Rifampicin two times a day for 12 months. | 50 |
| Placebo Subjects randomized to this arm will receive placebo capsules twice daily for 12 months. The capsules will contain riboflavin (vitamin B2). | 50 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 3 |
| Overall Study | Lack of Perceived Benefit | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Rifampicin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 60.9 years STANDARD_DEVIATION 7.8 | 61.1 years STANDARD_DEVIATION 9.2 | 61.0 years STANDARD_DEVIATION 8.5 |
| Certainty of Multiple System Atrophy (MSA) Diagnosis Possible | 19 participants | 16 participants | 35 participants |
| Certainty of Multiple System Atrophy (MSA) Diagnosis Probable | 31 participants | 34 participants | 65 participants |
| Multiple System Atrophy (MSA) Type Cerebellar (MSA-C) | 31 participants | 28 participants | 59 participants |
| Multiple System Atrophy (MSA) Type Parkinsonian (MSA-P) | 19 participants | 22 participants | 41 participants |
| Region of Enrollment United States | 50 participants | 50 participants | 100 participants |
| Sex: Female, Male Female | 23 Participants | 16 Participants | 39 Participants |
| Sex: Female, Male Male | 27 Participants | 34 Participants | 61 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 31 / 50 | 26 / 50 |
| serious Total, serious adverse events | 3 / 50 | 12 / 50 |
Outcome results
Primary
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.
Time frame: baseline, 12 months
Population: Analysis was done using intention to treat principles and no imputations were done for any missing values or slope estimates. All randomized participants who took at least two doses of the study drug were included in the principal efficacy analysis. One subject on the Rifampicin arm did not return after the baseline visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rifampicin | Rate of Change From Baseline to 12 Months in the Total Unified Multiple System Atrophy Rating Scale (UMSARS) Part I Score (Minus Question 11) | 0.5 units on a scale per month | Standard Deviation 0.7 |
| Placebo | Rate of Change From Baseline to 12 Months in the Total Unified Multiple System Atrophy Rating Scale (UMSARS) Part I Score (Minus Question 11) | 0.5 units on a scale per month | Standard Deviation 0.5 |
Comparison: Given that there were no imbalances identified between the two groups at baseline and the slope estimates for the two treatment arms did not support assumption of normality, the analysis was performed using Wilcoxon rank-sum test.p-value: 0.82Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline to 12 Months in the COMPASS-Select Scale
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).
Time frame: baseline, 12 months
Population: Analysis was done using intention to treat principles. Not all patients reached the 12 month time point due to missed visits or the early termination of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rifampicin | Change From Baseline to 12 Months in the COMPASS-Select Scale | 6.9 units on a scale | Standard Deviation 16.5 |
| Placebo | Change From Baseline to 12 Months in the COMPASS-Select Scale | 4.6 units on a scale | Standard Deviation 13.4 |
Comparison: Given that there were no imbalances identified between the two groups at baseline and the slope estimates for the two treatment arms did not support assumption of normality, the analysis was performed using Wilcoxon rank-sum test.p-value: 0.61Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline to 12 Months in Total UMSARS (i.e., UMSARS Part I Minus Question 11 + UMSARS Part II)
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).
Time frame: baseline, 12 months
Population: Analysis was done using intention to treat principles. Not all patients reached the 12 month time point due to missed visits or the early termination of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rifampicin | Change From Baseline to 12 Months in Total UMSARS (i.e., UMSARS Part I Minus Question 11 + UMSARS Part II) | 12.9 units on a scale | Standard Deviation 10.6 |
| Placebo | Change From Baseline to 12 Months in Total UMSARS (i.e., UMSARS Part I Minus Question 11 + UMSARS Part II) | 10.8 units on a scale | Standard Deviation 10.7 |
Comparison: Given that there were no imbalances identified between the two groups at baseline and the slope estimates for the two treatment arms did not support assumption of normality, the analysis was performed using Wilcoxon rank-sum test.p-value: 0.31Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline to 12 Months in UMSARS Part II
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).
Time frame: baseline, 12 months
Population: Analysis was done using intention to treat principles. Not all patients reached the 12 month time point due to missed visits or the early termination of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rifampicin | Change From Baseline to 12 Months in UMSARS Part II | 7.0 units on a scale | Standard Deviation 6.3 |
| Placebo | Change From Baseline to 12 Months in UMSARS Part II | 5.4 units on a scale | Standard Deviation 6.6 |
Comparison: Given that there were no imbalances identified between the two groups at baseline and the slope estimates for the two treatment arms did not support assumption of normality, the analysis was performed using Wilcoxon rank-sum test.p-value: 0.23Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline to 12 Months in 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).
Time frame: baseline, 12 months
Population: Analysis was done using intention to treat principles. Not all patients reached the 12 month time point due to missed visits or the early termination of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rifampicin | Change From Baseline to 12 Months in UMSARS Part I Score (Minus Question 11) | 6.2 units on a scale | Standard Deviation 5.6 |
| Placebo | Change From Baseline to 12 Months in UMSARS Part I Score (Minus Question 11) | 5.6 units on a scale | Standard Deviation 5 |
Comparison: Given that there were no imbalances identified between the two groups at baseline and the slope estimates for the two treatment arms did not support assumption of normality, the analysis was performed using Wilcoxon rank-sum test.p-value: 0.62Wilcoxon (Mann-Whitney)
Secondary
Change in the COMPASS-Select-Change Scale From Baseline to 12 Months
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).
Time frame: baseline, 12 months
Population: Analysis was done using intention to treat principles. Not all patients reached the 12 month time point due to missed visits or the early termination of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rifampicin | Change in the COMPASS-Select-Change Scale From Baseline to 12 Months | 41.4 units on a scale | Standard Deviation 33.8 |
| Placebo | Change in the COMPASS-Select-Change Scale From Baseline to 12 Months | 32.1 units on a scale | Standard Deviation 35.7 |
Comparison: Given that there were no imbalances identified between the two groups at baseline and the slope estimates for the two treatment arms did not support assumption of normality, the analysis was performed using Wilcoxon rank-sum test.p-value: 0.22Wilcoxon (Mann-Whitney)
Secondary
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
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.
Time frame: baseline, 12 months
Population: Analysis was done using intention to treat principles. Not all patients reached the 12 month time point due to missed visits or the early termination of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rifampicin | 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 | 1.1 units on a scale per month | Standard Deviation 1 |
| Placebo | 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 | 1.2 units on a scale per month | Standard Deviation 1.2 |
Comparison: Given that there were no imbalances identified between the two groups at baseline and the slope estimates for the two treatment arms did not support assumption of normality, the analysis was performed using Wilcoxon rank-sum test.p-value: 0.65Wilcoxon (Mann-Whitney)