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)

• ClinicalTrials.gov Identifier: NCT00977665
• Recruitment Status: Completed
• First Posted: September 16, 2009
• Results First Posted: February 26, 2015
• Last Update Posted: February 26, 2015
• Sponsor: Teva Pharmaceutical Industries
• Collaborator: H. Lundbeck A/S
• Information provided by (Responsible Party): Teva Pharmaceutical Industries

Tracking Information

• First Submitted Date: September 15, 2009
• First Posted Date: September 16, 2009
• Results First Submitted Date: February 10, 2015
• Results First Posted Date: February 26, 2015
• Last Update Posted Date: February 26, 2015
• Study Start Date: December 2009
• Actual Primary Completion Date: October 2011 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 10, 2015)

Change From Baseline to Week 48/Termination Visit in the Total Unified Multiple System Atrophy Rating Scale (UMSARS Part I and II) [ Time Frame: Day 0 (baseline), Week 48 ]

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.

• Original Primary Outcome Measures (submitted: September 15, 2009): Change from baseline to Week 48/Termination visit in the total UMSARS score [ Time Frame: 48 weeks ]

Current Secondary Outcome Measures (submitted: February 10, 2015)

• Clinical Global Impression Improvement (CGI-I) at Week 48/Termination Visit [ Time Frame: Week 48 ]
  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.
• Change From Baseline to Week 24 in Total Unified Multiple System Atrophy Rating Scale (UMSARS) Score [ Time Frame: Day 0 (baseline), Week 24 ]
  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.
• Percentage of Participants Who Achieved a Score of >=3 on the Unified Multiple System Atrophy Rating Scale (UMSARS) Question #7 Regarding Ambulation [ Time Frame: up to week 48 ]
  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.
• Mean Score of the Composite Autonomic Symptom Scale Select (COMPASS_Select Change) at Week 48/Termination Visit [ Time Frame: 48 weeks ]
  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.
• Change From Baseline to Week 48/Termination Visit in the Multiple System Atrophy (MSA) Health-related Quality of Life (QoL) Scale [ Time Frame: Day 0 (baseline), Week 48 ]
  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".
• Rate of Progression in Total Unified Multiple System Atrophy Rating Scale (UMSARS) Score From Baseline to Weeks 12-48 [ Time Frame: Day 0 (baseline), 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.
• Change From Baseline to Week 48 or Termination in UMSARS Subscores for Parts I, II and IV [ Time Frame: Day 0 (baseline), Week 48 or termination visit ]
  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).
• Change From Baseline to Week 12 in Total UMSARS Score for Symptomatic Effect [ Time Frame: Day 0 (baseline), Week 12 ]
  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.
• Estimates for Time to Change in Anti-Parkinsonian or Anti-Orthostatis Hypotension Medications [ Time Frame: Day 0 (baseline) to Week 48 or termination visit ]
  Change in anti-parkinsonian or anti-orthostatic hypotension medication is defined by at least one of the following events:

  1. An addition of a new anti-parkinsonian or anti-orthostatic hypotension medication during study.
  2. 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.
• Change From Baseline to Week 48 or Termination in the Montreal Cognitive Assessment Scale (MoCA) Scale [ Time Frame: Day 0 (baseline), Week 48 or termination visit ]
  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.
• 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) [ Time Frame: up to week 48 ]
  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).
• Change From Baseline to Week 48 or Termination in the Beck Depression Inventory Scale (BDI-II) [ Time Frame: Day 0 (baseline), Week 48 or termination visit ]
  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.
• Total Number of Falls During the Study [ Time Frame: Day 1 up to week 48 ]
  Participants recorded each time they fell during the study in a diary.

Original Secondary Outcome Measures (submitted: September 15, 2009)

• Change from baseline to week 24 in total UMSARS score. [ Time Frame: 24 weeks ]
• Change from baseline to Week 48/Termination visit in putaminal fractional anisotropy (FA) values of other brain regions on a ROI-basis [ Time Frame: 48 weeks ]
• Change from baseline to Week 48/Termination visit in DWI abnormalities [Trace(D) and FA] of other brain regions on a ROI-basis (pons, cerebellum, middle cerebellar peduncle, caudate nucleus, globus pallidum) [ Time Frame: 48 weeks ]
• Change from baseline in frequency and severity of putaminal atrophy, putaminal hyperintense rim, putaminal signal hypointensity, pontine atrophy, the hot cross bun sign of the pons, atrophy of the cerebellum, atrophy of the MCP and hyperintensity in MCP [ Time Frame: 48 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• Official Title: 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)
• Brief Summary: To test the clinical effect of rasagiline on subjects with MSA of the parkinsonian subtype.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Multiple System Atrophy

Intervention

• Drug: rasagiline mesylate
  rasagiline 1 mg tablet/day for 48 weeks
  Other Names:

  • Azilect
  • TVP-1012
• Drug: placebo
  placebo tablet for 48 weeks

Study Arms

• Experimental: rasagiline mesylate
  rasagiline tablet, 1 mg/day for up to 48 weeks.
  Intervention: Drug: rasagiline mesylate
• Placebo Comparator: placebo
  placebo tablet for up to 48 weeks.
  Intervention: Drug: placebo

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 19, 2012): 174
• Original Estimated Enrollment (submitted: September 15, 2009): 140
• Actual Study Completion Date: October 2011
• Actual Primary Completion Date: October 2011 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 30 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Canada, France, Germany, Hungary, Israel, Italy, Netherlands, Portugal, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT00977665
• Other Study ID Numbers: MSA-RAS-202; 2009-014644-11 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Teva Pharmaceutical Industries
• Study Sponsor: Teva Pharmaceutical Industries
• Collaborators: H. Lundbeck A/S

Investigators

• Principal Investigator: Werner Poewe, Prof; Innsbruck Medical University, Innsbruck, Austria

• PRS Account: Teva Pharmaceutical Industries
• Verification Date: February 2015