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)

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)

To test the clinical effect of rasagiline on subjects with MSA of the parkinsonian subtype.

Study Overview

• Status: Completed
• Conditions: Multiple System Atrophy
• Intervention / Treatment: Drug: rasagiline mesylate; Drug: placebo

• Study Type: Interventional
• Enrollment (Actual): 174
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria
    • Teva Investigational Site 3305
  • Innsbruck, Austria
    • Teva Investigational Site 3304
• Canada
  • Ontario
    • Ottawa, Ontario, Canada
      • Teva Investigational Site 1109
  • Quebec
    • Greenfield Park, Quebec, Canada
      • Teva Investigational Site 1111
    • Montréal, Quebec, Canada
      • Teva Investigational Site 1108
    • Québec, Quebec, Canada
      • Teva Investigational Site 1110
• France
  • Lille Cedex, France
    • Teva Investigational Site 3503
  • Pessac, France
    • Teva Investigational Site 3502
• Germany
  • Dresden, Germany
    • Teva Investigational Site 3206
  • Kiel, Germany
    • Teva Investigational Site 3203
  • Marburg, Germany
    • Teva Investigational Site 3201
  • Muenchen, Germany
    • Teva Investigational Site 3205
  • Tuebingen, Germany
    • Teva Investigational Site 3204
  • Ulm, Germany
    • Teva Investigational Site 3202
• Hungary
  • Budapest, Hungary
    • Teva Investigational Site 5101
  • Debrecen, Hungary
    • Teva Investigational Site 5102
  • Miskolc, Hungary
    • Teva Investigational Site 5103
• Israel
  • Haifa, Israel
    • Teva Investigational Site 8004
  • Tel Aviv, Israel
    • Teva Investigational Site 8003
  • IL
    • Ramat -Gan, IL, Israel
      • Teva Investigational Site 8002
• Italy
  • Bologna, Italy
    • Teva Investigational Site 3006
  • Roma, Italy
    • Teva Investigational Site 3004
  • Venezia - Lido, Italy
    • Teva Investigational Site 3005
• Netherlands
  • Amersfoort, Netherlands
    • Teva Investigational Site 3801
  • Sittard-Geleen, Netherlands
    • Teva Investigational Site 3802
• Portugal
  • Lisbon, Portugal
    • Teva Investigational Site 3603
• Spain
  • Barcelona, Spain
    • Teva Investigational Site 3101
  • Barcelona, Spain
    • Teva Investigational Site 3102
  • Sevilla, Spain
    • Teva Investigational Site 3103
• United Kingdom
  • Cardiff, Wales, United Kingdom
    • Teva Investigational Site 3403
  • London, United Kingdom
    • Teva Investigational Site 3401
  • Newcastle-Upon-Tyne, United Kingdom
    • Teva Investigational Site 3402
• United States
  • California
    • Irvine, California, United States
      • Teva Investigational Site 1004
    • La Jolla, California, United States
      • Teva Investigational Site 1014
    • Sunnyvale, California, United States
      • Teva Investigational Site 1006
  • District of Columbia
    • Washington, District of Columbia, United States
      • Teva Investigational Site 1010
  • Florida
    • Boca Raton, Florida, United States
      • Teva Investigational Site 1061
    • Tampa, Florida, United States
      • Teva Investigational Site 1012
  • Massachusetts
    • Worcester, Massachusetts, United States
      • Teva Investigational Site 1009
  • Michigan
    • Ann Arbor, Michigan, United States
      • Teva Investigational Site 1003
  • Minnesota
    • Rochester, Minnesota, United States
      • Teva Investigational Site 1007
  • Missouri
    • St. Louis, Missouri, United States
      • Teva Investigational Site 1011
  • New York
    • Rochester, New York, United States
      • Teva Investigational Site 1008
  • Ohio
    • Cleveland, Ohio, United States
      • Teva Investigational Site 1001
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
      • Teva Investigational Site 1002
  • Tennessee
    • Nashville, Tennessee, United States
      • Teva Investigational Site 1013
  • Texas
    • Houston, Texas, United States
      • Teva Investigational Site 1005

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

  1. Speech impairment as assessed by a score of ≥ 3 on UMSARS question 1
  2. Swallowing impairment as assessed by a score of ≥ 3 on UMSARS question 2
  3. Impairment in ambulation as assessed by a score of ≥ 3 on UMSARS question 7
  4. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: rasagiline mesylate; rasagiline tablet, 1 mg/day for up to 48 weeks.	Drug: rasagiline mesylate; rasagiline 1 mg tablet/day for 48 weeks; Other Names: Azilect; TVP-1012
Placebo Comparator: placebo; placebo tablet for up to 48 weeks.	Drug: placebo; placebo tablet for 48 weeks

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
• Collaborators: H. Lundbeck A/S
• Investigators: Principal Investigator: Werner Poewe, Prof, Innsbruck Medical University, Innsbruck, Austria

Publications and helpful links

General Publications

• Poewe W, Seppi K, Fitzer-Attas CJ, Wenning GK, Gilman S, Low PA, Giladi N, Barone P, Sampaio C, Eyal E, Rascol O; Rasagiline-for-MSA investigators. Efficacy of rasagiline in patients with the parkinsonian variant of multiple system atrophy: a randomised, placebo-controlled trial. Lancet Neurol. 2015 Feb;14(2):145-52. doi: 10.1016/S1474-4422(14)70288-1. Epub 2014 Dec 8.

Study record dates

Study Major Dates

• Study Start: December 1, 2009
• Primary Completion (Actual): October 1, 2011
• Study Completion (Actual): October 1, 2011

Study Registration Dates

• First Submitted: September 15, 2009
• First Submitted That Met QC Criteria: September 15, 2009
• First Posted (Estimate): September 16, 2009

Study Record Updates

• Last Update Posted (Estimate): February 26, 2015
• Last Update Submitted That Met QC Criteria: February 10, 2015
• Last Verified: February 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Pathological Conditions, Anatomical; Autonomic Nervous System Diseases; Primary Dysautonomias; Hypotension; Atrophy; Multiple System Atrophy; Shy-Drager Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Neuroprotective Agents; Protective Agents; Monoamine Oxidase Inhibitors; Rasagiline
• Other Study ID Numbers: MSA-RAS-202; 2009-014644-11 (EudraCT Number)