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| ID | Type | Description | Link |
|---|---|---|---|
| U1111-1189-7951 | Registry Identifier | WHO |
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| Name | Class |
|---|---|
| Takeda | INDUSTRY |
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The purpose of this study is to evaluate the efficacy of TAK-831 versus placebo on upper extremity (arm and hands) motor function and manual dexterity. This study will also evaluate the efficacy of TAK-831 versus placebo on activities of daily living (ADL) and other secondary assessments.
The drug being tested in this study is called TAK-831. TAK-831 is being tested to treat people who have Friedreich ataxia. This study will look at upper extremity (arms and hands) motor function and manual dexterity of people who take TAK-831. Efficacy evaluations also include other neurological, functional, and patient performance assessments.
The study will enroll approximately 65 participants. Participants will be randomly assigned in a 2:1:2 ratio to one of the three treatment groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):
All participants will be asked to take three tablets of high dose, low dose, or placebo twice a day for 12 weeks.
This multi-center trial will be conducted in the United States. The overall time to participate in this study is approximately 13 weeks. Participants will make 5 visits to the clinic, and will be contacted by telephone for an exit interview no later than 7 days after their final visit or termination. Participants will also receive a safety follow-up phone call 7 to 17 days after receiving their last dose of TAK-831.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | Placebo Comparator | TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks. |
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| TAK-831 75 mg | Experimental | TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks. |
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| TAK-831 300 mg | Experimental | TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| TAK-831 | Drug | TAK-831 tablets |
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| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in the Inverse Time to Complete the 9-Hole Peg Test (9-HPT-1) | The 9-HPT-1 is a measure of timed upper extremity (arm and hand) function and manual dexterity. The participant picks up pegs 1 at a time (9 in total), using 1 hand only, and places them into holes on the board as quickly as possible, in any order until all holes are filled. Then, without pausing, the participant removes the pegs 1 at a time and returns them as quickly as possible. Each participant performs this task twice with each hand separately. Results on both tests are then averaged for an overall task completion time and the inverse transform is performed. A positive change from Baseline indicates improvement. Change from Baseline in 9-HPT-1 was analyzed using mixed model for repeated measures (MMRM) analysis of covariance (ANCOVA) with Baseline 9-HPT-1 as a covariate; pooled site, visit, treatment, and ambulation status (randomization factor) as fixed factors; and treatment-by-visit and Baseline 9-HPT-1-by-visit interactions. | Baseline and Week 12 |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in the Activities of Daily Living (ADL) Component Score of the Friedreich Ataxia Rating Scale (FARS) | The ADL component of the FARS includes 9 subscales: speech, swallowing, cutting food and handling utensils, dressing, personal hygiene, falling, walking, quality of sitting position, and bladder function. Each of these subscales is rated on a 5-point scale where 0=normal to 4=severe disability/inability to carry out activity independently for a total possible score of 0 to 36, with higher scores representing greater disability/dependency. A negative change from Baseline indicates improvement. Change from Baseline in FARS ADL upper limb function items were analyzed using MMRM ANCOVA with Baseline FARS ADL as a covariate; pooled site, visit, treatment, and ambulation status (randomization factor) as fixed factors; and treatment-by-visit and Baseline FARS ADL-by-visit interactions. |
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Key Inclusion Criteria:
1. Has a genetically-confirmed diagnosis (homozygous for guanine-adenine-adenine [GAA] repeat expansions in the frataxin gene [FXN] in the affected range of Friedreich ataxia [FRDA] or a compound heterozygous expansion with a point mutation or deletion), with an established disease stage of 2 to 5, inclusive, as determined by the Functional Staging for Ataxia, at Screening.
Key Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| UCLA Ataxia Center | Los Angeles | California | 90095 | United States | ||
| University of Florida Center for Movement Disorders |
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Participants with a diagnosis of Friedreich Ataxia were randomized in a 2:1:2 ratio to receive TAK-831 75 mg TAK-831 300 mg or TAK-831 placebo-matching tablets twice daily.
Participants took part in the study at 6 investigative sites in the United States from 08 November 2017 to 27 December 2018.
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo | TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks. |
| FG001 | TAK-831 75 mg | TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Oct 6, 2017 | Dec 2, 2019 |
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| TAK-831 Placebo |
| Drug |
TAK-831 placebo matching tablets |
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| Baseline and Weeks 2, 7 and 12 |
| Change From Baseline in the Inverse Time to Complete the 9-HPT-1 | The 9-HPT-1 is a measure of timed upper extremity (arm and hand) function and manual dexterity. The participant picks up pegs 1 at a time (9 in total), using 1 hand only, and places them into holes on the board as quickly as possible, in any order until all holes are filled. Then, without pausing, the participant removes the pegs 1 at a time and returns them as quickly as possible. Each participant performs this task twice with each hand separately. Results on both tests are then averaged for an overall task completion time, and the inverse transform is performed. A positive change from Baseline indicates improvement. Change from Baseline in 9-HPT-1 was analyzed using MMRM ANCOVA with Baseline 9-HPT-1 as a covariate; pooled site, visit, treatment, and ambulation status (randomization factor) as fixed factors; and treatment-by-visit and Baseline 9-HPT-1-by-visit interactions. | Baseline and Weeks 2 and 7 |
| Change From Baseline in the ADL Component Individual Item Scores | The ADL component of the FARS includes 9 subscales: speech, swallowing, cutting food and handling utensils, dressing, personal hygiene, falling, walking, quality of sitting position, and bladder function. Each of these subscales is rated on a 5-point scale where 0=normal to 4=severe disability/inability to carry out activity independently. A negative change from Baseline indicates improvement. Statistical analyses were available for the following subscales: cutting food-handling utensils, dressing and personal hygiene. | Baseline and Weeks 2, 7 and 12 |
| Change From Baseline in the Modified Friedreich Ataxia Rating Scale Neurological Examination (mFARS-neuro) Total Score | The mFARS-neuro neurological examination is a clinician-rated measure based on neural substrates affected in Friedreich ataxia including: bulbar on a scale of 0-11, upper limb coordination on a scale of 0-36, lower limb coordination on a scale of 0-16, and upright stability/gait functions on a scale of 0-36 for a total possible score of 0 to 99 with higher scores representing greater disability. A negative change from Baseline indicates improvement. Change from Baseline in mFARS-neuro was analyzed using MMRM ANCOVA with Baseline mFARS-neuro as a covariate; pooled site, visit, treatment, and ambulation status (randomization factor) as fixed factors; and treatment-by-visit and Baseline mFARS-neuro-by-visit interactions. | Baseline and Weeks 2, 7 and 12 |
| Change From Baseline in the mFARS-neuro Subscales Scores | The mFARS-neuro neurological examination is a clinician-rated measure based on neural substrates affected in Friedreich ataxia including: bulbar on a scale of 0-11, upper limb coordination on a scale of 0-36, lower limb coordination on a scale of 0-16, and upright stability/gait functions on a scale of 0-36, with the higher scores representing greater disability. A negative change from Baseline indicates improvement. Change from Baseline in mFARS-neuro was analyzed using MMRM ANCOVA with Baseline mFARS-neuro as a covariate; pooled site, visit, treatment, and ambulation status (randomization factor) as fixed factors; and treatment-by-visit and Baseline mFARS-neuro-by visit interactions. | Baseline and Weeks 2, 7, and 12 |
| Change From Baseline in the mFARS-neuro Individual Item Scores | mFARS-neuro examination is a clinician-rated measure based on neural substrates affected in Friedreich ataxia individual items:Cough,Speech,Right(R)Finger to Finger Test,Left(L)Finger to Finger Test,R-Nose to Finger Test,L-Nose to Finger Test,R-Dysmetria Test,L-Dysmetria Test,Rapid Alternating Movement(RAM)of R-Hands,RAM of L-Hands,R-Finger Taps(FT),L-FT,R-Heel Along Shin Slide,L-Heel Along Shin Slide,R-Heel Along Shin Tap,L-Heel Along Shin Tap,Siting Posture,Stance Feet Apart(SFA)-3 Trial Average(TTA),SFA(Eyes Closed)-TTA,Stance Feet Together(SFT)-TTA,SFT(Eyes Closed)-TTA,Tandem Stance-TTA,Stance on Dominant Foot-TTA,Tandem Walk and Gait.Items were scored on scale of 0 to 2,3,4 or 5,with higher scores indicating greater disability.Negative change from Baseline(BL)indicates improvement.Change from BL in mFARS-neuro was analyzed using MMRM ANCOVA with BL as covariate;pooled site,visit,treatment,ambulation status as fixed factors;treatment-by-visit,BL mFARS-neuro-by visit interactions. | Baseline and Weeks 2, 7, and 12 |
| Change From Baseline in the Timed 25-Foot Walk (T25FW) | The participant was instructed to walk 25 feet as quickly as possible, but safely. The time was calculated from the initiation of the instruction to start and ends when the participant has reached the 25-foot mark. The task was immediately administered again by having the participant walk back the same distance. The two trials were averaged. A negative change from Baseline indicates improvement. Change from Baseline in T25FW was analyzed using MMRM ANCOVA with Baseline T25FW as a covariate; pooled site, visit, treatment, and ambulation status (randomization factor) as fixed factors; and treatment-by-visit and Baseline T25FW-by-visit interactions. | Baseline and Weeks 2, 7 and 12 |
| Change From Baseline in the 9-HPT and T25FW Composite Score | 9-HPT and T25FW were evaluated together as a performance-based composite measure. The inverse transform of each score was computed. The inverse scores from each test were tabulated and converted to test-specific Z scores by subtracting the cohort mean from the raw score, and then dividing by the cohort standard deviation (SD) to create a Z score for the test. The composite Z scores were created by subtracting Z-score for T25FW from the Z-score for 9-HPT-1. A larger Z-score represents a better outcome. A positive change from Baseline indicates improvement. Change from Baseline in composite score was analyzed using MMRM ANCOVA with Baseline composite score as a covariate; pooled site, visit, treatment, and ambulation status (randomization factor) as fixed factors; and treatment-by-visit and Baseline composite score-by-visit interactions. | Baseline and Weeks 2, 7, and 12 |
| Change From Baseline in Low-Contrast Letter Acuity (LCLA) Test Score | The LCLA test assessed visual function in both eyes using the Low-Contrast Sloan Letter Charts at different contrast levels. The score ranged from 0 to 70, where 0=worst visual functioning and 70=best visual functioning. A positive change from Baseline indicates improvement. The change from Baseline in LCLA was analyzed using MMRM ANCOVA with Baseline LCLA as a covariate; pooled site, visit, treatment, and ambulation status (randomization factor) as fixed factors; and treatment-by-visit and Baseline LCLA-by-visit interactions. | Baseline and Weeks 2, 7, and, 12 |
| Number of Participants by Clinical Global Impression-Improvement (CGI-I) (Global Change) Score Categories | The clinician used the CGI-I scale to assess the participant's improvement (or worsening) overall relative to Baseline on a 7-point scale where: 1=Much improved, 2=Moderately improved, 3=A little improved, 4=No change, 5=A little worse, 6=Moderately worse and 7=Much worse. Only those score categories reported for at least one participant at the given time-point are presented. | Weeks 2, 7, and 12 |
| Number of Participants by Patient Global Impression-Improvement (PGI-I) (Global Change) Score Categories | The participant used the PGI-I scale to assess their improvement (or worsening) overall relative to Baseline on a 7-point scale where: 1=Much improved, 2=Moderately improved, 3=A little improved, 4=No change, 5=A little worse, 6=Moderately worse and 7=Much worse. Only those score categories reported for at least one participant at the given time-point are presented. | Weeks 2, 7 and 12 |
| Number of Participants by CGI-I (Upper Extremity Functional Change) Score Categories | The clinician used the CGI-I scale to assess the participant's improvement (or worsening) in upper extremity function relative to Baseline on a 7-point scale where: 1=Much improved, 2=Moderately improved, 3=A little improved, 4=No change, 5=A little worse, 6=Moderately worse and 7=Much worse. Only those score categories reported for at least one participant at the given time-point are presented. | Weeks 2, 7, and 12 |
| Number of Participants by PGI-I (Upper Extremity Functional Change) Score Categories | The participant used the PGI-I scale to assess their improvement (or worsening) in upper extremity function relative to Baseline on a 7-point scale where: 1=Much improved, 2=Moderately improved, 3=A little improved, 4=No change, 5=A little worse, 6=Moderately worse and 7=Much worse. Only those score categories reported for at least one participant at the given time-point are presented. | Weeks 2, 7, and 12 |
| Number of Participants by Clinical Global Impression-Severity (CGI-S) (Global Severity) Score Categories Relative to Baseline | The clinician used the CGI-S scale to assess the severity of the participant's disease overall on a 5-point scale where: 0=No symptoms, 1=Mild, 2=Moderate, 3=Severe and 4=Very severe. The number of participants by CGI-S score category is reported relative to their CGI-S score at Baseline. Only those score categories reported for at least one participant at the given time-point are presented. | Baseline and Weeks 2, 7, and 12 |
| Number of Participants by Patient Global Impression-Severity (PGI-S) (Global Severity) Score Categories Relative to Baseline | The participant assessed the severity of their disease overall using the PGI-S 5-point scale where: 0=No symptoms, 1=Mild, 2=Moderate, 3=Severe and 4=Very severe. The number of participants by PGI-S score category is reported relative to their PGI-S score at Baseline. Only those score categories reported for at least one participant at the given time-point are presented. | Baseline and Weeks 2, 7, and 12 |
| Number of Participants by CGI-S (Upper Extremity Functional Severity) Score Categories Relative to Baseline | The clinician used the CGI-S scale to assess the severity of the participant's upper extremity function on a 5-point scale where: 0=Not impaired, 1=Mildly impaired, 2=Moderately impaired, 3=Severely impaired and 4=Very severely impaired. The number of participants by CGI-S score category is reported relative to their CGI-S score at Baseline. Only those score categories reported for at least one participant at the given time-point are presented. | Baseline and Week 2, 7, and 12 |
| Number of Participants by PGI-S (Upper Extremity Functional Severity) Score Categories | The participant assessed the severity of their upper extremity function using the PGI-S 5-point scale where: 0=Not impaired, 1=Mildly impaired, 2=Moderately impaired, 3=Severely impaired and 4=Very severely impaired. The number of participants by PGI-S score category is reported relative to their PGI-S score at Baseline. Only those score categories reported for at least one participant at the given time-point are presented. | Baseline and Weeks 2, 7, and 12 |
| Change From Baseline in the ADL Component Score for Upper Limb Function Items of the FARS | The ADL component of the FARS includes 9 subscales: speech, swallowing, cutting food and handling utensils, dressing, personal hygiene, falling, walking, quality of sitting position, and bladder function. Items 3 to 5 are directly related to upper limb function. Each of these subscales is rated on a 5-point scale where 0=normal to 4=severe disability/inability to carry out activity independently for a total possible score of 0 to 12, with higher scores representing greater disability/dependency. A negative change from Baseline indicates improvement. Change from Baseline in Friedreich ataxia rating scale activities of daily living (FARS ADL) upper limb function items was analyzed using MMRM ANCOVA with Baseline FARS ADL as a covariate; pooled site, visit, treatment, and ambulation status (randomization factor) as fixed factors; and treatment-by-visit and Baseline FARS ADL-by-visit interactions. | Baseline and Weeks 2, 7 and 12 |
| Number of Participants With at Least a 15 Percent (%) or at Least a 20% Reduction in 9-HPT Completion Time From Baseline | The 9-HPT-1 is a measure of timed upper extremity (arm and hand) function and manual dexterity. The participant picks up pegs 1 at a time (9 in total), using 1 hand only, and places them into holes on the board as quickly as possible, in any order until all holes are filled. Then, without pausing, the participant removes the pegs 1 at a time and returns them as quickly as possible. Each participant performs this task twice with each hand separately. Results on both tests are then averaged for an overall task completion time. | Baseline up to Week 12 |
| Gainesville |
| Florida |
| 32607 |
| United States |
| USF College of Medicine | Tampa | Florida | 33612 | United States |
| University of Iowa Children's Hospital | Iowa City | Iowa | 52242 | United States |
| Ohio State University Wexner Medical Center | Columbus | Ohio | 43220 | United States |
| The Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | 19104 | United States |
| FG002 | TAK-831 300 mg | TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks. |
| COMPLETED |
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| NOT COMPLETED |
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Full analysis set (FAS) included all randomized participants who received at least 1 dose of the study drug for the treatment period.
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo | TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks. |
| BG001 | TAK-831 75 mg | TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks. |
| BG002 | TAK-831 300 mg | TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks. |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Body Mass Index (BMI) | Body Mass Index = weight(kg)/[height(m)^2] | Mean | Standard Deviation | kg/m^2 |
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| Average Inverse Time to Complete 9-hole peg test (9-HPT-1) | The inverse of the time to complete the 9-hole peg test (9-HPT-1), defined as 1/(time to complete the 9-hole peg test), is summarized. | Median | Full Range | 1/seconds |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Primary | Change From Baseline in the Inverse Time to Complete the 9-Hole Peg Test (9-HPT-1) | The 9-HPT-1 is a measure of timed upper extremity (arm and hand) function and manual dexterity. The participant picks up pegs 1 at a time (9 in total), using 1 hand only, and places them into holes on the board as quickly as possible, in any order until all holes are filled. Then, without pausing, the participant removes the pegs 1 at a time and returns them as quickly as possible. Each participant performs this task twice with each hand separately. Results on both tests are then averaged for an overall task completion time and the inverse transform is performed. A positive change from Baseline indicates improvement. Change from Baseline in 9-HPT-1 was analyzed using mixed model for repeated measures (MMRM) analysis of covariance (ANCOVA) with Baseline 9-HPT-1 as a covariate; pooled site, visit, treatment, and ambulation status (randomization factor) as fixed factors; and treatment-by-visit and Baseline 9-HPT-1-by-visit interactions. | Full analysis set (FAS) included all randomized participant who received at least 1 dose of the study drug for the treatment period. Number analyzed is the number of participants with data available for analysis at the given time-point. | Posted | Least Squares Mean | Standard Error | 1/seconds | Baseline and Week 12 |
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| Secondary | Change From Baseline in the Activities of Daily Living (ADL) Component Score of the Friedreich Ataxia Rating Scale (FARS) | The ADL component of the FARS includes 9 subscales: speech, swallowing, cutting food and handling utensils, dressing, personal hygiene, falling, walking, quality of sitting position, and bladder function. Each of these subscales is rated on a 5-point scale where 0=normal to 4=severe disability/inability to carry out activity independently for a total possible score of 0 to 36, with higher scores representing greater disability/dependency. A negative change from Baseline indicates improvement. Change from Baseline in FARS ADL upper limb function items were analyzed using MMRM ANCOVA with Baseline FARS ADL as a covariate; pooled site, visit, treatment, and ambulation status (randomization factor) as fixed factors; and treatment-by-visit and Baseline FARS ADL-by-visit interactions. | FAS included all randomized participant who received at least 1 dose of the study drug for the treatment period. Number analyzed is the number of participants with data available for analysis at the given time-point. | Posted | Least Squares Mean | Standard Error | score on a scale | Baseline and Weeks 2, 7 and 12 |
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| Secondary | Change From Baseline in the Inverse Time to Complete the 9-HPT-1 | The 9-HPT-1 is a measure of timed upper extremity (arm and hand) function and manual dexterity. The participant picks up pegs 1 at a time (9 in total), using 1 hand only, and places them into holes on the board as quickly as possible, in any order until all holes are filled. Then, without pausing, the participant removes the pegs 1 at a time and returns them as quickly as possible. Each participant performs this task twice with each hand separately. Results on both tests are then averaged for an overall task completion time, and the inverse transform is performed. A positive change from Baseline indicates improvement. Change from Baseline in 9-HPT-1 was analyzed using MMRM ANCOVA with Baseline 9-HPT-1 as a covariate; pooled site, visit, treatment, and ambulation status (randomization factor) as fixed factors; and treatment-by-visit and Baseline 9-HPT-1-by-visit interactions. | FAS included all randomized participant who received at least 1 dose of the study drug for the treatment period. Number analyzed is the number of participants with data available for analysis at the given time-point. | Posted | Least Squares Mean | Standard Error | 1/seconds | Baseline and Weeks 2 and 7 |
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| Secondary | Change From Baseline in the ADL Component Individual Item Scores | The ADL component of the FARS includes 9 subscales: speech, swallowing, cutting food and handling utensils, dressing, personal hygiene, falling, walking, quality of sitting position, and bladder function. Each of these subscales is rated on a 5-point scale where 0=normal to 4=severe disability/inability to carry out activity independently. A negative change from Baseline indicates improvement. Statistical analyses were available for the following subscales: cutting food-handling utensils, dressing and personal hygiene. | FAS included all randomized participant who received at least 1 dose of the study drug for the treatment period. Number analyzed is the number of participants with data available for analysis at the given time-point. | Posted | Mean | Standard Deviation | score on a scale | Baseline and Weeks 2, 7 and 12 |
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| Secondary | Change From Baseline in the Modified Friedreich Ataxia Rating Scale Neurological Examination (mFARS-neuro) Total Score | The mFARS-neuro neurological examination is a clinician-rated measure based on neural substrates affected in Friedreich ataxia including: bulbar on a scale of 0-11, upper limb coordination on a scale of 0-36, lower limb coordination on a scale of 0-16, and upright stability/gait functions on a scale of 0-36 for a total possible score of 0 to 99 with higher scores representing greater disability. A negative change from Baseline indicates improvement. Change from Baseline in mFARS-neuro was analyzed using MMRM ANCOVA with Baseline mFARS-neuro as a covariate; pooled site, visit, treatment, and ambulation status (randomization factor) as fixed factors; and treatment-by-visit and Baseline mFARS-neuro-by-visit interactions. | FAS included all randomized participant who received at least 1 dose of the study drug for the treatment period. Number analyzed is the number of participants with data available for analysis at the given time-point. | Posted | Least Squares Mean | Standard Error | score on a scale | Baseline and Weeks 2, 7 and 12 |
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| Secondary | Change From Baseline in the mFARS-neuro Subscales Scores | The mFARS-neuro neurological examination is a clinician-rated measure based on neural substrates affected in Friedreich ataxia including: bulbar on a scale of 0-11, upper limb coordination on a scale of 0-36, lower limb coordination on a scale of 0-16, and upright stability/gait functions on a scale of 0-36, with the higher scores representing greater disability. A negative change from Baseline indicates improvement. Change from Baseline in mFARS-neuro was analyzed using MMRM ANCOVA with Baseline mFARS-neuro as a covariate; pooled site, visit, treatment, and ambulation status (randomization factor) as fixed factors; and treatment-by-visit and Baseline mFARS-neuro-by visit interactions. | FAS included all randomized participant who received at least 1 dose of the study drug for the treatment period. Number analyzed is the number of participants with data available for analysis at the given time-point. | Posted | Least Squares Mean | Standard Error | unit on a scale | Baseline and Weeks 2, 7, and 12 |
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| Secondary | Change From Baseline in the mFARS-neuro Individual Item Scores | mFARS-neuro examination is a clinician-rated measure based on neural substrates affected in Friedreich ataxia individual items:Cough,Speech,Right(R)Finger to Finger Test,Left(L)Finger to Finger Test,R-Nose to Finger Test,L-Nose to Finger Test,R-Dysmetria Test,L-Dysmetria Test,Rapid Alternating Movement(RAM)of R-Hands,RAM of L-Hands,R-Finger Taps(FT),L-FT,R-Heel Along Shin Slide,L-Heel Along Shin Slide,R-Heel Along Shin Tap,L-Heel Along Shin Tap,Siting Posture,Stance Feet Apart(SFA)-3 Trial Average(TTA),SFA(Eyes Closed)-TTA,Stance Feet Together(SFT)-TTA,SFT(Eyes Closed)-TTA,Tandem Stance-TTA,Stance on Dominant Foot-TTA,Tandem Walk and Gait.Items were scored on scale of 0 to 2,3,4 or 5,with higher scores indicating greater disability.Negative change from Baseline(BL)indicates improvement.Change from BL in mFARS-neuro was analyzed using MMRM ANCOVA with BL as covariate;pooled site,visit,treatment,ambulation status as fixed factors;treatment-by-visit,BL mFARS-neuro-by visit interactions. | FAS included all randomized participant who received at least 1 dose of the study drug for the treatment period. Number analyzed is the number of participants with data available for analysis at the given time-point. | Posted | Least Squares Mean | Standard Error | score on a scale | Baseline and Weeks 2, 7, and 12 |
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| Secondary | Change From Baseline in the Timed 25-Foot Walk (T25FW) | The participant was instructed to walk 25 feet as quickly as possible, but safely. The time was calculated from the initiation of the instruction to start and ends when the participant has reached the 25-foot mark. The task was immediately administered again by having the participant walk back the same distance. The two trials were averaged. A negative change from Baseline indicates improvement. Change from Baseline in T25FW was analyzed using MMRM ANCOVA with Baseline T25FW as a covariate; pooled site, visit, treatment, and ambulation status (randomization factor) as fixed factors; and treatment-by-visit and Baseline T25FW-by-visit interactions. | FAS included all randomized participant who received at least 1 dose of the study drug for the treatment period. Number analyzed is the number of participants with data available for analysis at the given time-point. | Posted | Least Squares Mean | Standard Error | seconds | Baseline and Weeks 2, 7 and 12 |
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| Secondary | Change From Baseline in the 9-HPT and T25FW Composite Score | 9-HPT and T25FW were evaluated together as a performance-based composite measure. The inverse transform of each score was computed. The inverse scores from each test were tabulated and converted to test-specific Z scores by subtracting the cohort mean from the raw score, and then dividing by the cohort standard deviation (SD) to create a Z score for the test. The composite Z scores were created by subtracting Z-score for T25FW from the Z-score for 9-HPT-1. A larger Z-score represents a better outcome. A positive change from Baseline indicates improvement. Change from Baseline in composite score was analyzed using MMRM ANCOVA with Baseline composite score as a covariate; pooled site, visit, treatment, and ambulation status (randomization factor) as fixed factors; and treatment-by-visit and Baseline composite score-by-visit interactions. | FAS included all randomized participant who received at least 1 dose of the study drug for the treatment period. Number analyzed is the number of participants with data available for analysis at the given time-point. | Posted | Least Squares Mean | Standard Error | z-score | Baseline and Weeks 2, 7, and 12 |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Change From Baseline in Low-Contrast Letter Acuity (LCLA) Test Score | The LCLA test assessed visual function in both eyes using the Low-Contrast Sloan Letter Charts at different contrast levels. The score ranged from 0 to 70, where 0=worst visual functioning and 70=best visual functioning. A positive change from Baseline indicates improvement. The change from Baseline in LCLA was analyzed using MMRM ANCOVA with Baseline LCLA as a covariate; pooled site, visit, treatment, and ambulation status (randomization factor) as fixed factors; and treatment-by-visit and Baseline LCLA-by-visit interactions. | FAS included all randomized participant who received at least 1 dose of the study drug for the treatment period. Number analyzed is the number of participants with data available for analysis at the given time-point. | Posted | Least Squares Mean | Standard Error | score on a scale | Baseline and Weeks 2, 7, and, 12 |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Number of Participants by Clinical Global Impression-Improvement (CGI-I) (Global Change) Score Categories | The clinician used the CGI-I scale to assess the participant's improvement (or worsening) overall relative to Baseline on a 7-point scale where: 1=Much improved, 2=Moderately improved, 3=A little improved, 4=No change, 5=A little worse, 6=Moderately worse and 7=Much worse. Only those score categories reported for at least one participant at the given time-point are presented. | FAS included all randomized participant who received at least 1 dose of the study drug for the treatment period. Number analyzed is the number of participants with data available for analysis at the given time-point. | Posted | Count of Participants | Participants | Weeks 2, 7, and 12 |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Number of Participants by Patient Global Impression-Improvement (PGI-I) (Global Change) Score Categories | The participant used the PGI-I scale to assess their improvement (or worsening) overall relative to Baseline on a 7-point scale where: 1=Much improved, 2=Moderately improved, 3=A little improved, 4=No change, 5=A little worse, 6=Moderately worse and 7=Much worse. Only those score categories reported for at least one participant at the given time-point are presented. | FAS included all randomized participant who received at least 1 dose of the study drug for the treatment period. Number analyzed is the number of participants with data available for analysis at the given time-point. | Posted | Count of Participants | Participants | Weeks 2, 7 and 12 |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Number of Participants by CGI-I (Upper Extremity Functional Change) Score Categories | The clinician used the CGI-I scale to assess the participant's improvement (or worsening) in upper extremity function relative to Baseline on a 7-point scale where: 1=Much improved, 2=Moderately improved, 3=A little improved, 4=No change, 5=A little worse, 6=Moderately worse and 7=Much worse. Only those score categories reported for at least one participant at the given time-point are presented. | FAS included all randomized participant who received at least 1 dose of the study drug for the treatment period. Number analyzed is the number of participants with data available for analysis at the given time-point. | Posted | Count of Participants | Participants | Weeks 2, 7, and 12 |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Number of Participants by PGI-I (Upper Extremity Functional Change) Score Categories | The participant used the PGI-I scale to assess their improvement (or worsening) in upper extremity function relative to Baseline on a 7-point scale where: 1=Much improved, 2=Moderately improved, 3=A little improved, 4=No change, 5=A little worse, 6=Moderately worse and 7=Much worse. Only those score categories reported for at least one participant at the given time-point are presented. | FAS included all randomized participant who received at least 1 dose of the study drug for the treatment period. Number analyzed is the number of participants with data available for analysis at the given time-point. | Posted | Count of Participants | Participants | Weeks 2, 7, and 12 |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Number of Participants by Clinical Global Impression-Severity (CGI-S) (Global Severity) Score Categories Relative to Baseline | The clinician used the CGI-S scale to assess the severity of the participant's disease overall on a 5-point scale where: 0=No symptoms, 1=Mild, 2=Moderate, 3=Severe and 4=Very severe. The number of participants by CGI-S score category is reported relative to their CGI-S score at Baseline. Only those score categories reported for at least one participant at the given time-point are presented. | FAS included all randomized participant who received at least 1 dose of the study drug for the treatment period. Number analyzed is the number of participants with data available for analysis at the given time-point. | Posted | Count of Participants | Participants | Baseline and Weeks 2, 7, and 12 |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Number of Participants by Patient Global Impression-Severity (PGI-S) (Global Severity) Score Categories Relative to Baseline | The participant assessed the severity of their disease overall using the PGI-S 5-point scale where: 0=No symptoms, 1=Mild, 2=Moderate, 3=Severe and 4=Very severe. The number of participants by PGI-S score category is reported relative to their PGI-S score at Baseline. Only those score categories reported for at least one participant at the given time-point are presented. | FAS included all randomized participant who received at least 1 dose of the study drug for the treatment period. Number analyzed is the number of participants with data available for analysis at the given time-point. | Posted | Count of Participants | Participants | Baseline and Weeks 2, 7, and 12 |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Number of Participants by CGI-S (Upper Extremity Functional Severity) Score Categories Relative to Baseline | The clinician used the CGI-S scale to assess the severity of the participant's upper extremity function on a 5-point scale where: 0=Not impaired, 1=Mildly impaired, 2=Moderately impaired, 3=Severely impaired and 4=Very severely impaired. The number of participants by CGI-S score category is reported relative to their CGI-S score at Baseline. Only those score categories reported for at least one participant at the given time-point are presented. | FAS included all randomized participant who received at least 1 dose of the study drug for the treatment period. Number analyzed is the number of participants with data available for analysis at the given time-point. | Posted | Count of Participants | Participants | Baseline and Week 2, 7, and 12 |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Number of Participants by PGI-S (Upper Extremity Functional Severity) Score Categories | The participant assessed the severity of their upper extremity function using the PGI-S 5-point scale where: 0=Not impaired, 1=Mildly impaired, 2=Moderately impaired, 3=Severely impaired and 4=Very severely impaired. The number of participants by PGI-S score category is reported relative to their PGI-S score at Baseline. Only those score categories reported for at least one participant at the given time-point are presented. | FAS included all randomized participant who received at least 1 dose of the study drug for the treatment period. Number analyzed is the number of participants with data available for analysis at the given time-point. | Posted | Count of Participants | Participants | Baseline and Weeks 2, 7, and 12 |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Change From Baseline in the ADL Component Score for Upper Limb Function Items of the FARS | The ADL component of the FARS includes 9 subscales: speech, swallowing, cutting food and handling utensils, dressing, personal hygiene, falling, walking, quality of sitting position, and bladder function. Items 3 to 5 are directly related to upper limb function. Each of these subscales is rated on a 5-point scale where 0=normal to 4=severe disability/inability to carry out activity independently for a total possible score of 0 to 12, with higher scores representing greater disability/dependency. A negative change from Baseline indicates improvement. Change from Baseline in Friedreich ataxia rating scale activities of daily living (FARS ADL) upper limb function items was analyzed using MMRM ANCOVA with Baseline FARS ADL as a covariate; pooled site, visit, treatment, and ambulation status (randomization factor) as fixed factors; and treatment-by-visit and Baseline FARS ADL-by-visit interactions. | FAS included all randomized participant who received at least 1 dose of the study drug for the treatment period. Number analyzed is the number of participants with data available for analysis at the given time-point. | Posted | Least Squares Mean | Standard Error | score on a scale | Baseline and Weeks 2, 7 and 12 |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Number of Participants With at Least a 15 Percent (%) or at Least a 20% Reduction in 9-HPT Completion Time From Baseline | The 9-HPT-1 is a measure of timed upper extremity (arm and hand) function and manual dexterity. The participant picks up pegs 1 at a time (9 in total), using 1 hand only, and places them into holes on the board as quickly as possible, in any order until all holes are filled. Then, without pausing, the participant removes the pegs 1 at a time and returns them as quickly as possible. Each participant performs this task twice with each hand separately. Results on both tests are then averaged for an overall task completion time. | FAS included all randomized participant who received at least 1 dose of the study drug for the treatment period. Number analyzed is the number of participants with data available for analysis at the given time-point. | Posted | Count of Participants | Participants | Baseline up to Week 12 |
|
First dose of study drug to up to 17 days past last dose (up to 14.4 weeks)
At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Safety analysis set included all randomized participants who received at least 1 dose of double-blind study medication.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo | TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks. | 0 | 27 | 0 | 27 | 21 | 27 |
| EG001 | TAK-831 75 mg | TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks. | 0 | 14 | 0 | 14 | 10 | 14 |
| EG002 | TAK-831 300 mg | TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks. | 0 | 26 | 0 | 26 | 24 | 26 |
Not provided
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Angina pectoris | Cardiac disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Vertigo | Ear and labyrinth disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Altered visual depth perception | Eye disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Nausea | Gastrointestinal disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Abdominal discomfort | Gastrointestinal disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Abdominal pain upper | Gastrointestinal disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Constipation | Gastrointestinal disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Fatigue | General disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Pain | General disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Urinary tract infection | Infections and infestations | MedDRA 21.0 | Systematic Assessment |
| |
| Gastroenteritis viral | Infections and infestations | MedDRA 21.0 | Systematic Assessment |
| |
| Nasopharyngitis | Infections and infestations | MedDRA 21.0 | Systematic Assessment |
| |
| Sinusitis | Infections and infestations | MedDRA 21.0 | Systematic Assessment |
| |
| Upper respiratory tract infection | Infections and infestations | MedDRA 21.0 | Systematic Assessment |
| |
| Fall | Injury, poisoning and procedural complications | MedDRA 21.0 | Systematic Assessment |
| |
| Laceration | Injury, poisoning and procedural complications | MedDRA 21.0 | Systematic Assessment |
| |
| Skin abrasion | Injury, poisoning and procedural complications | MedDRA 21.0 | Systematic Assessment |
| |
| Head injury | Injury, poisoning and procedural complications | MedDRA 21.0 | Systematic Assessment |
| |
| Decreased appetite | Metabolism and nutrition disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Flank pain | Musculoskeletal and connective tissue disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Melanocytic naevus | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 21.0 | Systematic Assessment |
| |
| Headache | Nervous system disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Dizziness | Nervous system disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Aphonia | Nervous system disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Balance disorder | Nervous system disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Coordination abnormal | Nervous system disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Migraine | Nervous system disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Aphasia | Nervous system disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Hypoaesthesia | Nervous system disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Paraesthesia | Nervous system disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Tremor | Nervous system disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Visual field defect | Nervous system disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Pollakiuria | Renal and urinary disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Urinary incontinence | Renal and urinary disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Micturition urgency | Renal and urinary disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Throat irritation | Respiratory, thoracic and mediastinal disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Dysphonia | Respiratory, thoracic and mediastinal disorders | MedDRA 21.0 | Systematic Assessment |
| |
| Eczema | Skin and subcutaneous tissue disorders | MedDRA 21.0 | Systematic Assessment |
|
Generally, the PI may publish results of the study following the publication of results by the Sponsor.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Neurocrine Medical Information | Neurocrine Biosciences | 877-641-3461 | medinfo@neurocrine.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Feb 1, 2019 | Dec 2, 2019 | SAP_001.pdf |
| ID | Term |
|---|---|
| D005621 | Friedreich Ataxia |
| ID | Term |
|---|---|
| D013132 | Spinocerebellar Degenerations |
| D002526 | Cerebellar Diseases |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D013118 | Spinal Cord Diseases |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D019636 | Neurodegenerative Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D028361 | Mitochondrial Diseases |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
Not provided
Not provided
| Male |
|
| Asian |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
| Second Assessment |
|
Change from Baseline at Week 12 |
| ANCOVA |
| >0.999 |
P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction. |
| Least Squares Mean Difference |
| -0.00069 |
| Standard Error of the Mean |
| 0.000616 |
| 2-Sided |
| 90 |
| -0.00172 |
| 0.00033 |
| Superiority |
| OG002 | TAK-831 300 mg | TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks. |
|
|
|
| OG002 | TAK-831 300 mg | TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks. |
|
|
|
|
|
|
| OG002 |
| TAK-831 300 mg |
TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks. |
|
|
|
TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks. |
|
|
|
TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.
| OG002 | TAK-831 300 mg | TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks. |
|
|
|
TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
|
|
|
| OG002 | TAK-831 300 mg | TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks. |
|
|
|
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| Units | Counts |
|---|---|
| Participants |
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| Units | Counts |
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| Participants |
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| Units | Counts |
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| Participants |
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| Units | Counts |
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| Participants |
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| Units | Counts |
|---|---|
| Participants |
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| Units | Counts |
|---|---|
| Participants |
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|
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| Units | Counts |
|---|---|
| Participants |
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|
|
| OG002 | TAK-831 300 mg | TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks. |
|
|
|
|
|
|
| Score at Baseline=1 (Mild) |
|
| Score at Baseline=2 (Moderate) |
|
| Score at Baseline=3 (Severe) |
|
| Score at Baseline=4 (Very Severe) |
|
| Score at Baseline=1 (Mild) |
|
| Score at Baseline=2 (Moderate) |
|
| Score at Baseline=3 (Severe) |
|
| Score at Baseline=4 (Very Severe) |
|
| Score at Baseline=1 (Mild) |
|
| Score at Baseline=2 (Moderate) |
|
| Score at Baseline=3 (Severe) |
|
| Score at Baseline=4 (Very Severe) |
|
| Score at Baseline=1 (Mild) |
|
| Score at Baseline=2 (Moderate) |
|
| Score at Baseline=3 (Severe) |
|
| Score at Baseline=4 (Very Severe) |
|
| Score at Baseline=1 (Mild) |
|
| Score at Baseline=2 (Moderate) |
|
| Score at Baseline=3 (Severe) |
|
| Score at Baseline=4 (Very Severe) |
|
| Score at Baseline=1 (Mild) |
|
| Score at Baseline=2 (Moderate) |
|
| Score at Baseline=3 (Severe) |
|
| Score at Baseline=4 (Very Severe) |
|
| Score at Baseline=1 (Mild) |
|
| Score at Baseline=2 (Moderate) |
|
| Score at Baseline=3 (Severe) |
|
| Score at Baseline=4 (Very Severe) |
|
| Score at Baseline=1 (Mild) |
|
| Score at Baseline=2 (Moderate) |
|
| Score at Baseline=3 (Severe) |
|
| Score at Baseline=4 (Very Severe) |
|
| Score at Baseline=1 (Mild) |
|
| Score at Baseline=2 (Moderate) |
|
| Score at Baseline=3 (Severe) |
|
| Score at Baseline=4 (Very Severe) |
|
| Score at Baseline=1 (Mild) |
|
| Score at Baseline=2 (Moderate) |
|
| Score at Baseline=3 (Severe) |
|
| Score at Baseline=4 (Very Severe) |
|
| Score at Baseline=1 (Mild) |
|
| Score at Baseline=2 (Moderate) |
|
| Score at Baseline=3 (Severe) |
|
| Score at Baseline=4 (Very Severe) |
|
| Score at Baseline=1 (Mild) |
|
| Score at Baseline=2 (Moderate) |
|
| Score at Baseline=3 (Severe) |
|
| Score at Baseline=4 (Very Severe) |
|
| Score at Baseline=1 (Mild) |
|
| Score at Baseline=2 (Moderate) |
|
| Score at Baseline=3 (Severe) |
|
| Score at Baseline=4 (Very Severe) |
|
| Score at Baseline=1 (Mild) |
|
| Score at Baseline=2 (Moderate) |
|
| Score at Baseline=3 (Severe) |
|
| Score at Baseline=4 (Very Severe) |
|
| Score at Baseline=1 (Mild) |
|
| Score at Baseline=2 (Moderate) |
|
| Score at Baseline=3 (Severe) |
|
| Score at Baseline=4 (Very Severe) |
|
| Score at Baseline=1 (Mild) |
|
| Score at Baseline=2 (Moderate) |
|
| Score at Baseline=3 (Severe) |
|
| Score at Baseline=4 (Very Severe) |
|
| Score at Baseline=1 (Mild) |
|
| Score at Baseline=2 (Moderate) |
|
| Score at Baseline=3 (Severe) |
|
| Score at Baseline=4 (Very Severe) |
|
| Score at Baseline=1 (Mild) |
|
| Score at Baseline=2 (Moderate) |
|
| Score at Baseline=3 (Severe) |
|
| Score at Baseline=4 (Very Severe) |
|
| Score at Baseline=1 (Mild) |
|
| Score at Baseline=2 (Moderate) |
|
| Score at Baseline=3 (Severe) |
|
| Score at Baseline=4 (Very Severe) |
|
| Score at Baseline=1 (Mild) |
|
| Score at Baseline=2 (Moderate) |
|
| Score at Baseline=3 (Severe) |
|
| Score at Baseline=4 (Very Severe) |
|
| Score at Baseline=1 (Mildly Impaired) |
|
| Score at Baseline=2 (Moderately Impaired) |
|
| Score at Baseline=3 (Severely Impaired) |
|
| Score at Baseline=4 (Very Severely Impaired) |
|
| Score at Baseline=1 (Mildly Impaired) |
|
| Score at Baseline=2 (Moderately Impaired) |
|
| Score at Baseline=3 (Severely Impaired) |
|
| Score at Baseline=4 (Very Severely Impaired) |
|
| Score at Baseline=1 (Mildly Impaired) |
|
| Score at Baseline=2 (Moderately Impaired) |
|
| Score at Baseline=3 (Severely Impaired) |
|
| Score at Baseline=4 (Very Severely Impaired) |
|
| Score at Baseline=1 (Mildly Impaired) |
|
| Score at Baseline=2 (Moderately Impaired) |
|
| Score at Baseline=3 (Severely Impaired) |
|
| Score at Baseline=4 (Very Severely Impaired) |
|
| Score at Baseline=1 (Mildly Impaired) |
|
| Score at Baseline=2 (Moderately Impaired) |
|
| Score at Baseline=3 (Severely Impaired) |
|
| Score at Baseline=4 (Very Severely Impaired) |
|
| Score at Baseline=1 (Mildly Impaired) |
|
| Score at Baseline=2 (Moderately Impaired) |
|
| Score at Baseline=3 (Severely Impaired) |
|
| Score at Baseline=4 (Very Severely Impaired) |
|
| Score at Baseline=1 (Mildly Impaired) |
|
| Score at Baseline=2 (Moderately Impaired) |
|
| Score at Baseline=3 (Severely Impaired) |
|
| Score at Baseline=4 (Very Severely Impaired) |
|
| Score at Baseline=1 (Mildly Impaired) |
|
| Score at Baseline=2 (Moderately Impaired) |
|
| Score at Baseline=3 (Severely Impaired) |
|
| Score at Baseline=4 (Very Severely Impaired) |
|
| Score at Baseline=1 (Mildly Impaired) |
|
| Score at Baseline=2 (Moderately Impaired) |
|
| Score at Baseline=3 (Severely Impaired) |
|
| Score at Baseline=4 (Very Severely Impaired) |
|
| Score at Baseline=1 (Mildly Impaired) |
|
| Score at Baseline=2 (Moderately Impaired) |
|
| Score at Baseline=3 (Severely Impaired) |
|
| Score at Baseline=4 (Very Severely Impaired) |
|
| Score at Baseline=1 (Mildly Impaired) |
|
| Score at Baseline=2 (Moderately Impaired) |
|
| Score at Baseline=3 (Severely Impaired) |
|
| Score at Baseline=4 (Very Severely Impaired) |
|
| Score at Baseline=1 (Mildly Impaired) |
|
| Score at Baseline=2 (Moderately Impaired) |
|
| Score at Baseline=3 (Severely Impaired) |
|
| Score at Baseline=4 (Very Severely Impaired) |
|
| Score at Baseline=1 (Mildly Impaired) |
|
| Score at Baseline=2 (Moderately Impaired) |
|
| Score at Baseline=3 (Severely Impaired) |
|
| Score at Baseline=4 (Very Severely Impaired) |
|
| Score at Baseline=1 (Mildly Impaired) |
|
| Score at Baseline=2 (Moderately Impaired) |
|
| Score at Baseline=3 (Severely Impaired) |
|
| Score at Baseline=4 (Very Severely Impaired) |
|
| Score at Baseline=1 (Mildly Impaired) |
|
| Score at Baseline=2 (Moderately Impaired) |
|
| Score at Baseline=3 (Severely Impaired) |
|
| Score at Baseline=4 (Very Severely Impaired) |
|