Clinical Trial to Assess Efficacy, Safety, and Tolerability of Rasagiline Mesylate 1 mg in Patients With Multiple System Atrophy of the Parkinsonian Subtype (MSA-P)

Study Overview
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Brief Summary
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To test the clinical effect of rasagiline on subjects with MSA of the parkinsonian subtype.

Official Title
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A Multi-centered, Randomized, Double-blind, Placebo-controlled Clinical Trial to Assess the Efficacy, Safety, and Tolerability of Rasagiline Mesylate 1 mg in Patients With Multiple System Atrophy of the Parkinsonian Subtype (MSA-P)

Conditions
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Multiple System Atrophy

Intervention / Treatment
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* Drug: rasagiline mesylate
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects over 30 years old with a diagnosis of Possible or Probable MSA of the parkinsonian subtype (MSA-P) according to The Gilman Criteria (2008). Subjects who are less than 3 years from the time of documented MSA diagnosis. Subjects with an anticipated survival of at least 3 years in the opinion of the investigator. Subjects who are willing and able to give informed consent. Subjects who are not able to write may give verbal consent in the presence of at least one witness, and the witness should sign the informed consent form. Exclusion Criteria: Subjects receiving treatment with midodrine or other sympathomimetics within 4 weeks prior to baseline visit. Subjects with severe orthostatic symptoms as assessed by a score of ≥ 3 on Unified Multiple System Atrophy Rating Scale (UMSARS) question 9. Subjects who meet any of the following criteria which tend to suggest advanced disease: Speech impairment as assessed by a score of ≥ 3 on UMSARS question 1 Swallowing impairment as assessed by a score of ≥ 3 on UMSARS question 2 Impairment in ambulation as assessed by a score of ≥ 3 on UMSARS question 7 Falling more frequently than once per week as assessed by a score of ≥ 3 on UMSARS question 8 Subjects taking disallowed medications according to the locally approved Azilect® label. Subjects taking monoamine oxidase (MAO) inhibitors within 3 months prior to baseline visit. Subjects with hypertension whose blood pressure, in the investigator's opinion, is not well controlled. Subjects who, based on the investigator's judgment, have a clinically significant or unstable medical or surgical condition that may preclude safe and complete study participation. Subjects with moderate or severe hepatic impairment. Subjects 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, oral contraceptive, contraceptive patch, long-acting injectable contraceptive, partner's vasectomy, a double-protection method (condom or diaphragm with spermicide)]. Pregnant or nursing women.

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rasagiline mesylate<br>rasagiline tablet, 1 mg/day for up to 48 weeks. | Drug: rasagiline mesylate<br>* rasagiline 1 mg tablet/day for 48 weeks<br>* Other names: TVP-1012;|
| Placebo Comparator: placebo<br>placebo tablet for up to 48 weeks. | Drug: placebo<br>* placebo tablet for 48 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 48/Termination Visit in the Total Unified Multiple System Atrophy Rating Scale (UMSARS Part I and II) | This outcome represents the sum of 2 UMSARS sub-scales: Part I: Historical Review that includes 12 items and Part II: Motor Examination that includes 14 items. All items range from 0 to 4. Each subscale score is the sum of its items and the total UMSARS score is the sum of all 26 items. Hence the total UMSARS score can range from 0 to 104, with 0 meaning no impairment and 104 indicating severe impairment. Negative change from baseline scores indicate improvement. In the case that 6 items or more (out of 26) were missing at a certain visit, the UMSARS score for that visit was assigned a missing value. | Day 0 (baseline), Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Global Impression Improvement (CGI-I) at Week 48/Termination Visit | Outcome measures the investigator's clinical impression of the participants' improvement at Week 48 as compared to Week 12. CGI scale range from 1-7, with 1=very much improved, 4= no change, and 7=very much worse. In order to maintain the overall (hypotheses about primary and key secondary endpoints) type I error at the 0.05 level an hierarchy will be employed as follows: If the primary endpoint will be found to be significant at a significance level of 0.05 then the first key secondary endpoint will be tested, if this endpoint will be found to be significant in a significance level of 0.05 then the second key secondary endpoint will be tested and so on. The 'key' secondary endpoints are outcomes 2-6. | Week 48 | 
| Change From Baseline to Week 24 in Total Unified Multiple System Atrophy Rating Scale (UMSARS) Score | The UMSARS is composed of 2 sub-scales: Part I: Historical Review that includes 12 items and Part II: Motor Examination that includes 14 items. All items range from 0 to 4. Each subscale score is the sum of its items and the total UMSARS score is the sum of all 26 items. Hence the total UMSARS score can range from 0 to 104, with 0 meaning no impairment and 104 indicating severe impairment. Negative change from baseline scores indicate improvement. In the case that 6 items or more (out of 26) were missing at a certain visit, the UMSARS score for that visit was assigned a missing value. | Day 0 (baseline), Week 24 | 
| Percentage of Participants Who Achieved a Score of >=3 on the Unified Multiple System Atrophy Rating Scale (UMSARS) Question #7 Regarding Ambulation | UMSARS' Question #7 concerns the participant's ability to walk, rated on a scale of 0=normal to 4=cannot walk at all even with assistance. This endpoint counts participants rated a 3 or worse. Rating 3 = Severely impaired; assistance and/or walking aid needed occasionally. | up to week 48 | 
| Mean Score of the Composite Autonomic Symptom Scale Select (COMPASS_Select Change) at Week 48/Termination Visit | COMPASS_Select change is comprised of 5 of the 11 domains in the COMPASS scale: Orthostatic Intolerance, Bladder Disorder, Sweating, Vasomotor, and Sleep Disorder COMPASS_Select change has a range of -150 to 150, with -150 indicating symptoms are much better and 150 indicating symptoms are much worse. | 48 weeks | 
| Change From Baseline to Week 48/Termination Visit in the Multiple System Atrophy (MSA) Health-related Quality of Life (QoL) Scale | The Multiple System Atrophy Quality of Life questionnaire (MSA-QoL) is a self-reported questionnaire focusing on MSA-specific symptoms and has a scale ranging from 0 - 160, with 0= 'no problem' and 160= extreme problem. | Day 0 (baseline), Week 48 | 
| Rate of Progression in Total Unified Multiple System Atrophy Rating Scale (UMSARS) Score From Baseline to Weeks 12-48 | The UMSARS is composed of 2 sub-scales: Part I: Historical Review that includes 12 items and Part II: Motor Examination that includes 14 items. All items range from 0 to 4. Each subscale score is the sum of its items and the total UMSARS score is the sum of all 26 items. Hence the total UMSARS score can range from 0 to 104, with 0 meaning no impairment and 104 indicating severe impairment. The rate of progression of atrophy is represented by the slope of change from baseline scores for visits between Weeks 12 and 48. | Day 0 (baseline), Weeks 12-48 | 
| Change From Baseline to Week 48 or Termination in UMSARS Subscores for Parts I, II and IV | UMSARS Part I is an historical review and scores symptoms of neurological and autonomic dysfunction with 12 items rated on a scale of 0 (normal) to 4 (extreme dysfunction). The full scale for Part 1 is therefore 0 (normal) to 48 (extreme dysfunction). Part II is a motor examination and has 14 items also rated on a scale of 0 to 4 for a full scale of 0 (normal) to 56 (extreme dysfunction). Part IV is a global disability scale with rates the extent of disease from 1 (normal) to 5 (severe disease). | Day 0 (baseline), Week 48 or termination visit | 
| Change From Baseline to Week 12 in Total UMSARS Score for Symptomatic Effect | This outcome represents the sum of 2 UMSARS sub-scales: Part I: Historical Review that includes 12 items and Part II: Motor Examination that includes 14 items. All items range from 0 to 4. Each subscale score is the sum of its items and the total UMSARS score is the sum of all 26 items. Hence the total UMSARS score can range from 0 to 104, with 0 meaning no impairment and 104 indicating severe impairment. Negative change from baseline scores indicate improvement. | Day 0 (baseline), Week 12 | 
| Estimates for Time to Change in Anti-Parkinsonian or Anti-Orthostatis Hypotension Medications | Change in anti-parkinsonian or anti-orthostatic hypotension medication is defined by at least one of the following events: An addition of a new anti-parkinsonian or anti-orthostatic hypotension medication during study. Dose modification of anti-parkinsonian or anti-orthostatic hypotension concomitant medications reflecting disease progression. The event of interest, determined on a by patient basis, therefore, is the earliest event of the two events defined above. Otherwise, patient is right censored according to his/her study termination date. Since less than 25% of participants had an event, median estimatation for time to change in medications is not possible. | Day 0 (baseline) to Week 48 or termination visit | 
| Change From Baseline to Week 48 or Termination in the Montreal Cognitive Assessment Scale (MoCA) Scale | MoCA is a cognitive screening test which helps health professionals identify mild cognitive impairment. The total scale is 0 (significant cognitive impairment) to 30 (no impairment detected). Scores >=26 are considered normal. Positive change from baseline scores indicate improvement in cognition. | Day 0 (baseline), Week 48 or termination visit | 
| Percentage of Participants Who Achieved a Score of >=3 on the Unified Multiple System Atrophy Rating Scale (UMSARS) Question #1 (Speech Impairment), Question #2 (Swallowing Impairment) and Question #8 (Falling) | UMSARS' questions are rated on a scale of 0=normal to 4=extreme impairment. This endpoint reports the percentage of participants rated a 3 or worse. Rating 3 = Severely impaired speech (Question #1), swallowing (Question #2) or falling more frequently than once per week (Question #8). | up to week 48 | 
| Change From Baseline to Week 48 or Termination in the Beck Depression Inventory Scale (BDI-II) | The Beck Depression Inventory (BDI-II), is a 21-question multiple-choice self-report inventory, one of the most widely used instruments for measuring the severity of depression. Participants are asked to pick the answer for each question that best describes the way they have been feeling in the past two weeks, including the day participants complete the questionnaire. Each question is rated on a scale of 0-3, with 0 meaning the participant does not feel the emotion described in the question, and 3 meaning the participant has extremely strong feelings. Total scale is 0 (no evidence of depression) to 63 (extreme depression). Negative change from baseline scores indicate improvement in level of depression. | Day 0 (baseline), Week 48 or termination visit | 
| Total Number of Falls During the Study | Participants recorded each time they fell during the study in a diary. | Day 1 up to week 48 |