Multiple System Atrophy
Conditions
Keywords
Multiple System Atrophy (MSA)
Brief summary
The purpose of this study is to compare the efficacy of verdiperstat (BHV-3241) versus placebo in participants with Multiple System Atrophy
Interventions
DRUGVerdiperstat
300mg 2 oral tablets, twice daily
DRUGPlacebo
Matching placebo
Sponsors
Biohaven Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Double-blind to Sponsor, Investigator and Subject
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of probable or possible MSA according to consensus clinical criteria (Gilman et al 2008), including participants with MSA of either subtype (MSA-P or MSA-C). 2. Able to ambulate without the assistance of another person, defined as the ability to take at least 10 steps. Use of assistive devices (e.g., walker or cane) is allowed. 3. Anticipated survival of at least 3 years at the time of Screening, as judged by the Investigator.
Exclusion criteria
1. Any condition that would interfere with the participant's ability to comply with study instructions, place the participant at unacceptable risk, and/or confound the interpretation of safety or efficacy data from the study, as judged by the Investigator. 2. Diagnosis of neurological disorders, other than MSA.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Modified UMSARS Score at Week 48 | Baseline and Week 48 | UMSARS - clinician-rated scale comprised of 4 parts: Part I (Historical Review), Part II (Motor Examination), Part III (Autonomic Examination), Part IV (Global Disability Scale). Modified UMSARS is composed of subset of 9 items from original UMSARS Part I and Part II. Responses are measured on 4-point scale ranged from 0-3, where 0= no/mild impairment, 1= moderate impairment, 2= severe impairment, 3=complete impairment. Total modified UMSARS score is sum of these 9 items, score range from 0 to 27. Higher scores indicate greater impairment. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Up to 100 weeks | An adverse event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in participants or clinical investigation participants administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. A serious AE (SAE) is defined as any event that met any of the following criteria at any dose: death; life-threatening; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect in the offspring of a participant who received study drug; other important medical events that may not have resulted in death, be life-threatening, or required hospitalization, or, based upon appropriate medical judgment, they may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the other serious outcomes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Multiple System Atrophy Quality of Life (MSA-QoL) Non-motor Subscale at Week 48 | Baseline and Week 48 | The MSA-QoL is a participant-rated scale that was designed to measure health-related quality of life specifically in MSA. It assesses activities of daily living and has subscales for motor, nonmotor, and emotional/social domains. The MSA-QoL nonmotor subscale includes 12 items. The response to each question ranges from 0= no problem, to 4= extreme problem, with a total scale ranging from 0-48. Higher scores indicates higher impact of the disease on the aspect measured by each subscale. |
| Change From Baseline in UMSARS Part I and Part II Total Score at Week 48 | Baseline and Week 48 | The UMSARS is a clinician-rated scale comprised of 4 parts: Part I (Historical Review with 12 questions), Part II (Motor Examination with 14 questions), Part III (Autonomic Examination), and Part IV (Global Disability Scale). UMSARS Part I and Part II responses are measured on a 5-point scale ranging from 0 to 4, where 0= no impairment, 1= mild impairment, 2= moderate impairment, 3= severe impairment, 4=complete impairment. Each subscale score is a sum of its items and total score is sum of all 26 items, score range from 0 to 104. Higher scores indicates greater impairment. |
| Change From Baseline in Patient Global Impression of Severity (PGI-S) at Week 48 | Baseline and Week 48 | The PGI-S is a participant-rated scale that measures how participants perceive the severity of their illness. The PGI-S is a 1-item questionnaire on a 4-point scale ranging from 1 to 4, where, 1 = normal, 2 = mild, 3 = moderate, 4 = severe. Higher scores indicate greater impairment. |
| Clinical Global Impression of Improvement (CGI-I) Score at Week 48 | Week 48 | The CGI-I is a clinician-rated scale measuring the change in the participant's clinical status from a specific point in time. It is scored on a 7- point scale, ranging from 1 (very much improved) to 7 (very much worse), with a score of 4 indicating no change. Higher scores indicate greater impairment. |
| Change From Baseline in UMSARS Part III at Week 48 (Blood Pressure (BP) Only) | Baseline and Week 48 | The UMSARS is a clinician-rated scale comprised of 4 parts: Part I (Historical Review), Part II (Motor Examination), Part III (Autonomic Examination) and Part IV (Global Disability Scale). Only Part III of UMSARS was analyzed. Part III of the UMSARS is an Autonomic Exam, consisting of Supine and Standing Systolic and Diastolic Blood Pressure, Heart rate and presence Orthostatic Symptoms. Only change in Orthostatic Blood Pressure reported. |
| Change From Baseline in UMSARS Part III at Week 48 (Heart Rate (HR) Only) | Baseline and Week 48 | The UMSARS is a clinician-rated scale comprised of 4 parts: Part I (Historical Review), Part II (Motor Examination), Part III (Autonomic Examination) and Part IV (Global Disability Scale). Only Part III of UMSARS was analyzed. Part III of the UMSARS is an Autonomic Exam, consisting of Supine and Standing Systolic and Diastolic Blood Pressure, Heart rate and presence Orthostatic Symptoms. Only change in Orthostatic Heart Rate reported. |
| Change From Baseline in UMSARS Part IV at Week 48 | Baseline and Week 48 | The UMSARS is a clinician-rated scale comprised of 4 parts: Part I (Historical Review), Part II (Motor Examination), Part III (Autonomic Examination) and Part IV (Global Disability Scale). Only Part IV of UMSARS was analyzed. Part IV was measured on a 5-point scale ranging from 1= Completely independent. Able to do all chores with minimal difficulty or impairment. Essentially normal. Unaware of any difficulty, to 5= Totally dependent and helpless. Bedridden. Higher scores indicate greater impairment. |
| Change From Baseline in Clinical Global Impression of Severity (CGI-S) at Week 48 | Baseline and Week 48 | The CGI-S is a clinician-rated scale measuring the severity of the participant's illness. It is scored on a 7- point scale ranging from 1 (normal, not ill at all) to 7 (among the most extremely ill patients). Higher scores indicate greater impairment. |
| Change From Baseline in Multiple System Atrophy Quality of Life (MSA-QoL) Motor Subscale at Week 48 | Baseline and Week 48 | The MSA-QoL is a participant-rated scale that was designed to measure health-related quality of life specifically in MSA. It assesses activities of daily living and has subscales for motor, nonmotor, and emotional/social domains. The MSA-QoL motor subscale includes 14 items. The response to each question ranges from 0= no problem, to 4= extreme problem, with a total scale ranging from 0-56. Higher scores indicates higher impact of the disease on the aspect measured by each subscale. |
Countries
Austria, France, Germany, Italy, United Kingdom, United States
Participant flow
Recruitment details
This Phase 3, randomized, double-blind, placebo-controlled study was conducted in participants with multiple system atrophy (MSA) at 48 centers in the US and EU between 29-Jul-2019 and 29-Jul-2021.
Pre-assignment details
A total of 421 participants were enrolled, of which 336 participants were randomized in a 1:1: ratio to receive verdiperstat or placebo. 85 participants were not randomized due to withdrawal of consent, adverse events, failed inclusion/exclusion criteria, or other reasons.
Participants by arm
| Arm | Count |
|---|---|
| Verdiperstat Randomization phase (Randomization through Week 48): Participants received verdiperstat 300 mg tablet orally once daily for 1 week, followed by 300 mg twice daily for 1 week, and then 600 mg twice daily for the remaining 46 weeks of the double-blind phase.
OLE phase (48 weeks): Participants who completed the double-blind phase were offered the opportunity to enroll in an OLE phase to continue verdiperstat 600 mg orally twice daily for 48 weeks. | 168 |
| Placebo Randomization phase (Randomization through Week 48): Participants received placebo matching with verdiperstat for 48 weeks.
OLE phase (48 weeks): Participants who completed the double-blind phase were offered the opportunity to enroll in an OLE phase to receive verdiperstat 600 mg tablet orally twice daily for 48 weeks. | 168 |
| Total | 336 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| OLE Phase (48 Weeks) | Adverse Event | 18 | 29 |
| OLE Phase (48 Weeks) | Disease Progression | 6 | 9 |
| OLE Phase (48 Weeks) | Other | 16 | 13 |
| OLE Phase (48 Weeks) | Participant Request to Discontinue | 35 | 38 |
| OLE Phase (48 Weeks) | Withdrawal by Subject | 4 | 5 |
| Randomization Phase (Weeks 1 Through 48) | Adverse Event | 26 | 15 |
| Randomization Phase (Weeks 1 Through 48) | Disease progression | 5 | 0 |
| Randomization Phase (Weeks 1 Through 48) | Other | 1 | 0 |
| Randomization Phase (Weeks 1 Through 48) | Participant request | 5 | 5 |
| Randomization Phase (Weeks 1 Through 48) | Withdrawal by Subject | 4 | 2 |
Baseline characteristics
| Characteristic | Verdiperstat | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 62.4 years STANDARD_DEVIATION 7.12 | 61.3 years STANDARD_DEVIATION 6.99 | 60.1 years STANDARD_DEVIATION 6.68 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 10 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 163 Participants | 326 Participants | 163 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 12 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) White | 155 Participants | 311 Participants | 156 Participants |
| Sex: Female, Male Female | 83 Participants | 166 Participants | 83 Participants |
| Sex: Female, Male Male | 85 Participants | 170 Participants | 85 Participants |
| Unified Multiple System Atrophy Rating Scale (UMSARS) Modified Score | 6.1 units on a scale STANDARD_DEVIATION 4.24 | 6.0 units on a scale STANDARD_DEVIATION 3.99 | 5.8 units on a scale STANDARD_DEVIATION 3.74 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 11 / 168 | 5 / 168 | 12 / 123 | 10 / 140 |
| other Total, other adverse events | 125 / 168 | 130 / 168 | 55 / 123 | 71 / 140 |
| serious Total, serious adverse events | 44 / 168 | 29 / 168 | 30 / 123 | 27 / 140 |
Outcome results
Primary
Change From Baseline in the Modified UMSARS Score at Week 48
UMSARS - clinician-rated scale comprised of 4 parts: Part I (Historical Review), Part II (Motor Examination), Part III (Autonomic Examination), Part IV (Global Disability Scale). Modified UMSARS is composed of subset of 9 items from original UMSARS Part I and Part II. Responses are measured on 4-point scale ranged from 0-3, where 0= no/mild impairment, 1= moderate impairment, 2= severe impairment, 3=complete impairment. Total modified UMSARS score is sum of these 9 items, score range from 0 to 27. Higher scores indicate greater impairment.
Time frame: Baseline and Week 48
Population: Modified Intent to Treat (mITT) population included randomized participants who received at least 1 dose of blinded study therapy and provided a baseline and at least 1 post-baseline efficacy assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Verdiperstat - Randomization Phase | Change From Baseline in the Modified UMSARS Score at Week 48 | 5.20 units on a scale |
| Placebo - Randomization Phase | Change From Baseline in the Modified UMSARS Score at Week 48 | 4.85 units on a scale |
p-value: 0.465695% CI: [-0.6, 1.3]Mixed Models Analysis
Primary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs
An adverse event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in participants or clinical investigation participants administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. A serious AE (SAE) is defined as any event that met any of the following criteria at any dose: death; life-threatening; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect in the offspring of a participant who received study drug; other important medical events that may not have resulted in death, be life-threatening, or required hospitalization, or, based upon appropriate medical judgment, they may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the other serious outcomes.
Time frame: Up to 100 weeks
Population: Treated population included enrolled participants who received at least 1 dose of blinded study therapy (verdiperstat or placebo).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Verdiperstat - Randomization Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | TEAE | 160 participants |
| Verdiperstat - Randomization Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAE | 44 participants |
| Placebo - Randomization Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAE | 29 participants |
| Placebo - Randomization Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | TEAE | 156 participants |
| Verdiperstat - Randomization Phase/ Verdiperstat - OLE Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | TEAE | 95 participants |
| Verdiperstat - Randomization Phase/ Verdiperstat - OLE Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAE | 30 participants |
| Placebo - Randomization Phase/ Verdiperstat - OLE Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | TEAE | 112 participants |
| Placebo - Randomization Phase/ Verdiperstat - OLE Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAE | 27 participants |
Secondary
Change From Baseline in Clinical Global Impression of Severity (CGI-S) at Week 48
The CGI-S is a clinician-rated scale measuring the severity of the participant's illness. It is scored on a 7- point scale ranging from 1 (normal, not ill at all) to 7 (among the most extremely ill patients). Higher scores indicate greater impairment.
Time frame: Baseline and Week 48
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Verdiperstat - Randomization Phase | Change From Baseline in Clinical Global Impression of Severity (CGI-S) at Week 48 | 0.79 units on a scale |
| Placebo - Randomization Phase | Change From Baseline in Clinical Global Impression of Severity (CGI-S) at Week 48 | 0.78 units on a scale |
Secondary
Change From Baseline in Multiple System Atrophy Quality of Life (MSA-QoL) Motor Subscale at Week 48
The MSA-QoL is a participant-rated scale that was designed to measure health-related quality of life specifically in MSA. It assesses activities of daily living and has subscales for motor, nonmotor, and emotional/social domains. The MSA-QoL motor subscale includes 14 items. The response to each question ranges from 0= no problem, to 4= extreme problem, with a total scale ranging from 0-56. Higher scores indicates higher impact of the disease on the aspect measured by each subscale.
Time frame: Baseline and Week 48
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Verdiperstat - Randomization Phase | Change From Baseline in Multiple System Atrophy Quality of Life (MSA-QoL) Motor Subscale at Week 48 | 13.83 units on a scale |
| Placebo - Randomization Phase | Change From Baseline in Multiple System Atrophy Quality of Life (MSA-QoL) Motor Subscale at Week 48 | 13.45 units on a scale |
Secondary
Change From Baseline in Multiple System Atrophy Quality of Life (MSA-QoL) Non-motor Subscale at Week 48
The MSA-QoL is a participant-rated scale that was designed to measure health-related quality of life specifically in MSA. It assesses activities of daily living and has subscales for motor, nonmotor, and emotional/social domains. The MSA-QoL nonmotor subscale includes 12 items. The response to each question ranges from 0= no problem, to 4= extreme problem, with a total scale ranging from 0-48. Higher scores indicates higher impact of the disease on the aspect measured by each subscale.
Time frame: Baseline and Week 48
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Verdiperstat - Randomization Phase | Change From Baseline in Multiple System Atrophy Quality of Life (MSA-QoL) Non-motor Subscale at Week 48 | 7.52 units on a scale |
| Placebo - Randomization Phase | Change From Baseline in Multiple System Atrophy Quality of Life (MSA-QoL) Non-motor Subscale at Week 48 | 5.56 units on a scale |
Secondary
Change From Baseline in Patient Global Impression of Severity (PGI-S) at Week 48
The PGI-S is a participant-rated scale that measures how participants perceive the severity of their illness. The PGI-S is a 1-item questionnaire on a 4-point scale ranging from 1 to 4, where, 1 = normal, 2 = mild, 3 = moderate, 4 = severe. Higher scores indicate greater impairment.
Time frame: Baseline and Week 48
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Verdiperstat - Randomization Phase | Change From Baseline in Patient Global Impression of Severity (PGI-S) at Week 48 | 0.33 units on a scale |
| Placebo - Randomization Phase | Change From Baseline in Patient Global Impression of Severity (PGI-S) at Week 48 | 0.27 units on a scale |
Secondary
Change From Baseline in UMSARS Part I and Part II Total Score at Week 48
The UMSARS is a clinician-rated scale comprised of 4 parts: Part I (Historical Review with 12 questions), Part II (Motor Examination with 14 questions), Part III (Autonomic Examination), and Part IV (Global Disability Scale). UMSARS Part I and Part II responses are measured on a 5-point scale ranging from 0 to 4, where 0= no impairment, 1= mild impairment, 2= moderate impairment, 3= severe impairment, 4=complete impairment. Each subscale score is a sum of its items and total score is sum of all 26 items, score range from 0 to 104. Higher scores indicates greater impairment.
Time frame: Baseline and Week 48
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Verdiperstat - Randomization Phase | Change From Baseline in UMSARS Part I and Part II Total Score at Week 48 | 12.00 units on a scale |
| Placebo - Randomization Phase | Change From Baseline in UMSARS Part I and Part II Total Score at Week 48 | 11.34 units on a scale |
Secondary
Change From Baseline in UMSARS Part III at Week 48 (Blood Pressure (BP) Only)
The UMSARS is a clinician-rated scale comprised of 4 parts: Part I (Historical Review), Part II (Motor Examination), Part III (Autonomic Examination) and Part IV (Global Disability Scale). Only Part III of UMSARS was analyzed. Part III of the UMSARS is an Autonomic Exam, consisting of Supine and Standing Systolic and Diastolic Blood Pressure, Heart rate and presence Orthostatic Symptoms. Only change in Orthostatic Blood Pressure reported.
Time frame: Baseline and Week 48
Population: mITT population.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Verdiperstat - Randomization Phase | Change From Baseline in UMSARS Part III at Week 48 (Blood Pressure (BP) Only) | Change in Orthostatic Systolic BP | -2.18 millimeter of mercury |
| Verdiperstat - Randomization Phase | Change From Baseline in UMSARS Part III at Week 48 (Blood Pressure (BP) Only) | Change in Orthostatic Diastolic BP | -2.87 millimeter of mercury |
| Placebo - Randomization Phase | Change From Baseline in UMSARS Part III at Week 48 (Blood Pressure (BP) Only) | Change in Orthostatic Systolic BP | -3.09 millimeter of mercury |
| Placebo - Randomization Phase | Change From Baseline in UMSARS Part III at Week 48 (Blood Pressure (BP) Only) | Change in Orthostatic Diastolic BP | -2.54 millimeter of mercury |
Secondary
Change From Baseline in UMSARS Part III at Week 48 (Heart Rate (HR) Only)
The UMSARS is a clinician-rated scale comprised of 4 parts: Part I (Historical Review), Part II (Motor Examination), Part III (Autonomic Examination) and Part IV (Global Disability Scale). Only Part III of UMSARS was analyzed. Part III of the UMSARS is an Autonomic Exam, consisting of Supine and Standing Systolic and Diastolic Blood Pressure, Heart rate and presence Orthostatic Symptoms. Only change in Orthostatic Heart Rate reported.
Time frame: Baseline and Week 48
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Verdiperstat - Randomization Phase | Change From Baseline in UMSARS Part III at Week 48 (Heart Rate (HR) Only) | 0.20 beats per minute |
| Placebo - Randomization Phase | Change From Baseline in UMSARS Part III at Week 48 (Heart Rate (HR) Only) | -0.68 beats per minute |
Secondary
Change From Baseline in UMSARS Part IV at Week 48
The UMSARS is a clinician-rated scale comprised of 4 parts: Part I (Historical Review), Part II (Motor Examination), Part III (Autonomic Examination) and Part IV (Global Disability Scale). Only Part IV of UMSARS was analyzed. Part IV was measured on a 5-point scale ranging from 1= Completely independent. Able to do all chores with minimal difficulty or impairment. Essentially normal. Unaware of any difficulty, to 5= Totally dependent and helpless. Bedridden. Higher scores indicate greater impairment.
Time frame: Baseline and Week 48
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Verdiperstat - Randomization Phase | Change From Baseline in UMSARS Part IV at Week 48 | 0.82 units on a scale |
| Placebo - Randomization Phase | Change From Baseline in UMSARS Part IV at Week 48 | 0.85 units on a scale |
Secondary
Clinical Global Impression of Improvement (CGI-I) Score at Week 48
The CGI-I is a clinician-rated scale measuring the change in the participant's clinical status from a specific point in time. It is scored on a 7- point scale, ranging from 1 (very much improved) to 7 (very much worse), with a score of 4 indicating no change. Higher scores indicate greater impairment.
Time frame: Week 48
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Verdiperstat - Randomization Phase | Clinical Global Impression of Improvement (CGI-I) Score at Week 48 | 5.07 units on a scale |
| Placebo - Randomization Phase | Clinical Global Impression of Improvement (CGI-I) Score at Week 48 | 5.14 units on a scale |