Efficacy, Tolerability, and Pharmacokinetics of Multiple Doses of Oral TAK-831 in Adults With Friedreich Ataxia

• Sponsor: Neurocrine Biosciences (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03214588
• Collaborator: Takeda (Industry)
• Enrollment: 67
• Locations: 6
• Arms: 3
• Actual Duration (Months): 13.6
• Patients Per Site: 11.2
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Friedreich Ataxia	Drug: TAK-831; Drug: TAK-831 Placebo	Phase 2

Detailed Description

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):

• TAK-831 High dose

• TAK-831 Low dose

• Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 67 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Arm Study to Evaluate Efficacy, Tolerability, and Pharmacokinetics of Multiple Doses of Oral TAK-831 in Adult Subjects With Friedreich Ataxia
• Actual Study Start Date: Nov 8, 2017
• Actual Primary Completion Date: Dec 27, 2018
• Actual Study Completion Date: Dec 27, 2018

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks.	Drug: TAK-831 Placebo; TAK-831 placebo matching tablets
Experimental: TAK-831 75 mg TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.	Drug: TAK-831; TAK-831 tablets
Experimental: TAK-831 300 mg TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.	Drug: TAK-831; TAK-831 tablets

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the Inverse Time to Complete the 9-Hole Peg Test (9-HPT-1) [Baseline and Week 12]

   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.

Secondary Outcome Measures

1. Change From Baseline in the Activities of Daily Living (ADL) Component Score of the Friedreich Ataxia Rating Scale (FARS) [Baseline and Weeks 2, 7 and 12]

   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.

2. Change From Baseline in the Inverse Time to Complete the 9-HPT-1 [Baseline and Weeks 2 and 7]

   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.

3. Change From Baseline in the ADL Component Individual Item Scores [Baseline and Weeks 2, 7 and 12]

   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.

4. Change From Baseline in the Modified Friedreich Ataxia Rating Scale Neurological Examination (mFARS-neuro) Total Score [Baseline and Weeks 2, 7 and 12]

   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.

5. Change From Baseline in the mFARS-neuro Subscales Scores [Baseline and Weeks 2, 7, and 12]

   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.

6. Change From Baseline in the mFARS-neuro Individual Item Scores [Baseline and Weeks 2, 7, and 12]

   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.

7. Change From Baseline in the Timed 25-Foot Walk (T25FW) [Baseline and Weeks 2, 7 and 12]

   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.

8. Change From Baseline in the 9-HPT and T25FW Composite Score [Baseline and Weeks 2, 7, and 12]

   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.

9. Change From Baseline in Low-Contrast Letter Acuity (LCLA) Test Score [Baseline and Weeks 2, 7, and, 12]

   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.

10. Number of Participants by Clinical Global Impression-Improvement (CGI-I) (Global Change) Score Categories [Weeks 2, 7, and 12]

    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.

11. Number of Participants by Patient Global Impression-Improvement (PGI-I) (Global Change) Score Categories [Weeks 2, 7 and 12]

    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.

12. Number of Participants by CGI-I (Upper Extremity Functional Change) Score Categories [Weeks 2, 7, and 12]

    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.

13. Number of Participants by PGI-I (Upper Extremity Functional Change) Score Categories [Weeks 2, 7, and 12]

    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.

14. Number of Participants by Clinical Global Impression-Severity (CGI-S) (Global Severity) Score Categories Relative to Baseline [Baseline and Weeks 2, 7, and 12]

    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.

15. Number of Participants by Patient Global Impression-Severity (PGI-S) (Global Severity) Score Categories Relative to Baseline [Baseline and Weeks 2, 7, and 12]

    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.

16. Number of Participants by CGI-S (Upper Extremity Functional Severity) Score Categories Relative to Baseline [Baseline and Week 2, 7, and 12]

    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.

17. Number of Participants by PGI-S (Upper Extremity Functional Severity) Score Categories [Baseline and Weeks 2, 7, and 12]

    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.

18. Change From Baseline in the ADL Component Score for Upper Limb Function Items of the FARS [Baseline and Weeks 2, 7 and 12]

    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.

19. Number of Participants With at Least a 15 Percent (%) or at Least a 20% Reduction in 9-HPT Completion Time From Baseline [Baseline up to Week 12]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

1. Received a diagnosis of ataxic syndromes other than FRDA.

2. Has a history of cancer, except basal cell carcinoma or in situ cervical cancer that has been in remission for greater than or equal to (>=5) years prior to first dose of study drug.

3. Known to be currently infected or has been infected with human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus.

4. Has a known hypersensitivity to any component of the formulation of TAK-831.

5. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse.

6. Has taken any excluded medication, or has had insufficient washout of medications or is unable or unwilling to discontinue medications as required by the protocol.

7. If male, the participant intends to donate sperm during the course of this study or for 95 days after the last dose of study drug.

8. If female, the participant is of childbearing potential and lactating, pregnant (positive prerandomization serum pregnancy test), or plans to become pregnant before participating in the study, during the study, or within 35 days after last dose of the study drug, or intending to donate ova during such time period.

9. Has a history of neuroleptic malignant syndrome, water intoxication, or paralytic ileus or other conditions that may interfere with absorption of study medication.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCLA Ataxia Center	Los Angeles	California	United States	90095
2	University of Florida Center for Movement Disorders	Gainesville	Florida	United States	32607
3	USF College of Medicine	Tampa	Florida	United States	33612
4	University of Iowa Children's Hospital	Iowa City	Iowa	United States	52242
5	Ohio State University Wexner Medical Center	Columbus	Ohio	United States	43220
6	The Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• Neurocrine Biosciences
• Takeda

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Oct 6, 2017
• Statistical Analysis Plan - Feb 1, 2019

More Information

Publications

None provided.

• Responsible Party: Neurocrine Biosciences
• ClinicalTrials.gov Identifier: NCT03214588
• Other Study ID Numbers: TAK-831-1501; U1111-1189-7951
• First Posted: Jul 11, 2017
• Last Update Posted: Jun 14, 2021
• Last Verified: Jun 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Neurocrine Biosciences: Drug Therapy
• Additional relevant MeSH terms: Ataxia; Cerebellar Ataxia; Friedreich Ataxia

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 6 investigative sites in the United States from 08 November 2017 to 27 December 2018.
Pre-assignment Detail	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.

Arm/Group Title	Placebo	TAK-831 75 mg	TAK-831 300 mg
Arm/Group Description	TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks.	TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.	TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
Period Title: Overall Study
STARTED	27	14	26
COMPLETED	26	13	24
NOT COMPLETED	1	1	2

Baseline Characteristics

Arm/Group Title	Placebo	TAK-831 75 mg	TAK-831 300 mg	Total
Arm/Group Description	TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks.	TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.	TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.	Total of all reporting groups
Overall Participants	27	14	26	67
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.5 (11.01)	31.1 (11.28)	29.6 (8.92)	31.1 (10.23)
Sex: Female, Male (Count of Participants)
Female	17 63%	5 35.7%	15 57.7%	37 55.2%
Male	10 37%	9 64.3%	11 42.3%	30 44.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	27 100%	13 92.9%	26 100%	66 98.5%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 7.1%	0 0%	1 1.5%
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	24.89 (4.920)	24.94 (4.400)	23.02 (3.862)	24.18 (4.456)
Average Inverse Time to Complete 9-hole peg test (9-HPT-1) (1/seconds) [Median (Full Range) ]
First Assessment	0.01740	0.01660	0.01575	0.01680
Second Assessment	0.01710	0.01605	0.01595	0.01660

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the Inverse Time to Complete the 9-Hole Peg Test (9-HPT-1)
Description	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.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	TAK-831 75 mg	TAK-831 300 mg
Arm/Group Description	TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks.	TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.	TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
Measure Participants	24	12	24
Least Squares Mean (Standard Error) [1/seconds]	0.00038 (0.000448)	-0.00017 (0.000622)	-0.00032 (0.000445)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change from Baseline at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.00054
	Confidence Interval	(2-Sided) 90%; -0.00179 to 0.00070
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.000746
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change from Baseline at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.00069
	Confidence Interval	(2-Sided) 90%; -0.00172 to 0.00033
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.000616
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in the Activities of Daily Living (ADL) Component Score of the Friedreich Ataxia Rating Scale (FARS)
Description	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.
Time Frame	Baseline and Weeks 2, 7 and 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	TAK-831 75 mg	TAK-831 300 mg
Arm/Group Description	TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks.	TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.	TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
Measure Participants	27	14	26
Change from Baseline at Week 2	-0.25 (0.468)	-1.12 (0.665)	0.34 (0.463)
Change from Baseline at Week 7	-0.33 (0.465)	-0.15 (0.655)	0.03 (0.467)
Change from Baseline at Week 12	-0.61 (0.493)	-0.37 (0.696)	-0.24 (0.488)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change from Baseline at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.135
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.87
	Confidence Interval	(2-Sided) 90%; -2.18 to 0.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.782
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change from Baseline at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.818
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.59
	Confidence Interval	(2-Sided) 90%; -0.48 to 1.66
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.640
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change from Baseline at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.591
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.18
	Confidence Interval	(2-Sided) 90%; -1.11 to 1.47
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.770
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change from Baseline at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.713
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.36
	Confidence Interval	(2-Sided) 90%; -0.71 to 1.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.643
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change from Baseline at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.616
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.24
	Confidence Interval	(2-Sided) 90%; -1.13 to 1.62
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.822
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change from Baseline at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.708
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.37
	Confidence Interval	(2-Sided) 90%; -0.76 to 1.51
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.679
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in the Inverse Time to Complete the 9-HPT-1
Description	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.
Time Frame	Baseline and Weeks 2 and 7

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	TAK-831 75 mg	TAK-831 300 mg
Arm/Group Description	TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks.	TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.	TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
Measure Participants	27	14	26
Change from Baseline at Week 2	0.00087 (0.000371)	0.00048 (0.000508)	-0.00006 (0.000370)
Change from Baseline at Week 7	0.00040 (0.000462)	0.00026 (0.000643)	-0.00004 (0.000471)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change from Baseline at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.741
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.00039
	Confidence Interval	(2-Sided) 90%; -0.00140 to 0.00062
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.000604
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change from Baseline at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.964
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.00093
	Confidence Interval	(2-Sided) 90%; -0.00177 to -0.00008
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.000505
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change from Baseline at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.573
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.00014
	Confidence Interval	(2-Sided) 90%; -0.00143 to 0.00115
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.000772
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change from Baseline at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.749
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.00044
	Confidence Interval	(2-Sided) 90%; -0.00152 to 0.00064
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.000646
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in the ADL Component Individual Item Scores
Description	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.
Time Frame	Baseline and Weeks 2, 7 and 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	TAK-831 75 mg	TAK-831 300 mg
Arm/Group Description	TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks.	TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.	TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
Measure Participants	27	14	26
Change at Week 2, Speech	0.07 (0.494)	-0.15 (0.427)	-0.06 (0.432)
Change at Week 7, Speech	0.06 (0.516)	-0.08 (0.400)	-0.15 (0.429)
Change at Week 12, Speech	0.06 (0.425)	-0.17 (0.492)	-0.02 (0.403)
Change at Week 2, Swallowing	0.00 (0.555)	0.04 (0.320)	-0.19 (0.618)
Change at Week 7, Swallowing	0.04 (0.422)	0.08 (0.534)	-0.06 (0.756)
Change at Week 12, Swallowing	-0.15 (0.403)	0.13 (0.311)	-0.27 (0.589)
Change at Week 2, Cutting-Handling Utensils	-0.13 (0.451)	-0.04 (0.380)	0.12 (0.535)
Change at Week 7, Cutting-Handling Utensils	-0.21 (0.619)	-0.15 (0.240)	0.08 (0.525)
Change at Week 12, Cutting-Handling Utensils	-0.19 (0.548)	-0.08 (0.417)	0.08 (0.482)
Change at Week 2, Dressing	0.00 (0.392)	-0.12 (0.506)	0.12 (0.516)
Change at Week 7, Dressing	0.04 (0.372)	0.04 (0.380)	-0.04 (0.292)
Change at Week 12, Dressing	0.02 (0.561)	-0.04 (0.498)	-0.10 (0.361)
Change at Week 2, Personal Hygiene	-0.02 (0.427)	0.00 (0.456)	0.15 (0.485)
Change at Week 7, Personal Hygiene	0.08 (0.659)	0.19 (0.560)	0.04 (0.530)
Change at Week 12, Personal Hygiene	0.08 (0.602)	0.21 (0.656)	0.06 (0.517)
Change at Week 2, Falling	0.06 (0.560)	0.04 (0.660)	0.02 (0.435)
Change at Week 7, Falling	-0.13 (0.481)	0.54 (1.266)	-0.04 (0.706)
Change at Week 12, Falling	-0.29 (0.932)	0.50 (0.739)	-0.33 (0.856)
Change at Week 2, Walking	-0.02 (0.470)	-0.08 (0.494)	0.08 (0.272)
Change at Week 7, Walking	0.00 (0.245)	-0.08 (0.344)	-0.06 (0.450)
Change at Week 12, Walking	0.13 (0.516)	-0.08 (0.557)	0.02 (0.179)
Change at Week 2, Quality of Sitting Position	0.09 (0.605)	-0.31 (0.663)	0.10 (0.375)
Change at Week 7, Quality of Sitting Position	0.06 (0.497)	-0.27 (0.753)	0.00 (0.511)
Change at Week 12,Quality of Sitting Position	0.10 (0.589)	-0.33 (0.778)	0.08 (0.458)
Change at Week 2, Bladder Function	-0.09 (0.555)	-0.27 (0.439)	0.13 (0.460)
Change at Week 7, Bladder Function	-0.08 (0.643)	-0.15 (0.555)	0.08 (0.381)
Change at Week 12, Bladder Function	-0.17 (0.504)	-0.42 (0.557)	-0.04 (0.550)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Cutting-Handling Utensils
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.571
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 90%; -0.23 to 0.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.154
	Estimation Comments	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.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Cutting-Handling Utensils
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.963
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.23
	Confidence Interval	(2-Sided) 90%; 0.02 to 0.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.126
	Estimation Comments	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.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, Cutting-Handling Utensils
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.515
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 90%; -0.27 to 0.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.165
	Estimation Comments	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.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Cutting-Handling Utensils
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.986
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.31
	Confidence Interval	(2-Sided) 90%; 0.08 to 0.54
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.138
	Estimation Comments	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.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, Cutting-Handling Utensils
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.718
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.09
	Confidence Interval	(2-Sided) 90%; -0.18 to 0.37
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.162
	Estimation Comments	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.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, Cutting-Handling Utensils
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.986
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.30
	Confidence Interval	(2-Sided) 90%; 0.08 to 0.52
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.133
	Estimation Comments	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.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Dressing
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.153
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 90%; -0.40 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.148
	Estimation Comments	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.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Dressing
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.861
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.13
	Confidence Interval	(2-Sided) 90%; -0.07 to 0.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.119
	Estimation Comments	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.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, Dressing
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.443
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 90%; -0.22 to 0.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.120
	Estimation Comments	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.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Dressing
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.359
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 90%; -0.20 to 0.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.100
	Estimation Comments	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.

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, Dressing
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.268
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 90%; -0.36 to 0.17
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.157
	Estimation Comments	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.

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, Dressing
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.411
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.03
	Confidence Interval	(2-Sided) 90%; -0.24 to 0.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.129
	Estimation Comments	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.

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Personal Hygiene
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.358
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.06
	Confidence Interval	(2-Sided) 90%; -0.31 to 0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.151
	Estimation Comments	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.

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Personal Hygiene
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.946
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.20
	Confidence Interval	(2-Sided) 90%; 0.00 to 0.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.123
	Estimation Comments	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.

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, Personal Hygiene
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.505
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 90%; -0.32 to 0.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.193
	Estimation Comments	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.

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Personal Hygiene
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.658
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 90%; -0.20 to 0.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.158
	Estimation Comments	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.

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, Personal Hygiene
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.649
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.07
	Confidence Interval	(2-Sided) 90%; -0.24 to 0.38
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.184
	Estimation Comments	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.

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, Personal Hygiene
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.661
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 90%; -0.19 to 0.32
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.151
	Estimation Comments	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.

5. Secondary Outcome

Title	Change From Baseline in the Modified Friedreich Ataxia Rating Scale Neurological Examination (mFARS-neuro) Total Score
Description	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.
Time Frame	Baseline and Weeks 2, 7 and 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	TAK-831 75 mg	TAK-831 300 mg
Arm/Group Description	TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks.	TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.	TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
Measure Participants	27	14	26
Change from Baseline at Week 2	-3.36 (0.650)	-0.70 (0.919)	-0.58 (0.647)
Change from Baseline at Week 7	-2.41 (0.799)	-2.01 (1.114)	-1.35 (0.828)
Change from Baseline at Week 12	-3.30 (0.762)	-1.28 (1.057)	-1.19 (0.752)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change from Baseline at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.992
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	2.67
	Confidence Interval	(2-Sided) 90%; 0.86 to 4.47
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.078
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change from Baseline at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.999
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	2.78
	Confidence Interval	(2-Sided) 90%; 1.29 to 4.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.892
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change from Baseline at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.616
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.40
	Confidence Interval	(2-Sided) 90%; -1.84 to 2.64
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.338
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change from Baseline at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.823
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 90%; -0.83 to 2.95
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.131
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change from Baseline at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.942
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	2.02
	Confidence Interval	(2-Sided) 90%; -0.10 to 4.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.266
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change from Baseline at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.975
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	2.11
	Confidence Interval	(2-Sided) 90%; 0.35 to 3.87
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.053
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in the mFARS-neuro Subscales Scores
Description	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.
Time Frame	Baseline and Weeks 2, 7, and 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	TAK-831 75 mg	TAK-831 300 mg
Arm/Group Description	TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks.	TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.	TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
Measure Participants	27	14	26
Change at Week 2, Bulbar	0.08 (0.080)	0.15 (0.112)	0.14 (0.082)
Change at Week 7, Bulbar	0.01 (0.074)	-0.08 (0.102)	0.17 (0.079)
Change at Week 12, Bulbar	0.01 (0.085)	0.06 (0.118)	0.21 (0.087)
Change at Week 2, Upper Limb Coordination	-1.55 (0.425)	0.44 (0.601)	-0.53 (0.419)
Change at Week 7, Upper Limb Coordination	-0.90 (0.533)	0.17 (0.741)	-0.72 (0.547)
Change at Week 12, Upper Limb Coordination	-1.19 (0.608)	0.02 (0.848)	-0.65 (0.602)
Change at Week 2, Lower Limb Coordination	-0.92 (0.292)	-0.52 (0.415)	-0.14 (0.289)
Change at Week 7, Lower Limb Coordination	-0.84 (0.494)	-0.88 (0.691)	-0.67 (0.516)
Change at Week 12, Lower Limb Coordination	-1.62 (0.449)	-0.63 (0.625)	-0.67 (0.445)
Change at Week 2, Upright Stability	-0.5 (0.37)	-0.3 (0.53)	0.5 (0.38)
Change at Week 7, Upright Stability	-0.2 (0.27)	-0.8 (0.38)	0.4 (0.28)
Change at Week 12, Upright Stability	-0.1 (0.35)	-0.3 (0.48)	0.4 (0.34)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Bulbar
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.07
	Confidence Interval	(2-Sided) 90%; -0.15 to 0.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.133
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Bulbar
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 90%; -0.12 to 0.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.110
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, Bulbar
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 90%; -0.30 to 0.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.122
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Bulbar
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 90%; -0.02 to 0.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.104
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, Bulbar
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 90%; -0.19 to 0.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.141
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, Bulbar
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.20
	Confidence Interval	(2-Sided) 90%; 0.00 to 0.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.118
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Upper Limb Coordination
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	1.99
	Confidence Interval	(2-Sided) 90%; 0.83 to 3.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.689
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Upper Limb Coordination
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	1.02
	Confidence Interval	(2-Sided) 90%; 0.06 to 1.97
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.571
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, Upper Limb Coordination
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	1.08
	Confidence Interval	(2-Sided) 90%; -0.40 to 2.55
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.882
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Upper Limb Coordination
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.18
	Confidence Interval	(2-Sided) 90%; -1.06 to 1.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.743
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, Upper Limb Coordination
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	1.21
	Confidence Interval	(2-Sided) 90%; -0.48 to 2.91
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.016
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, Upper Limb Coordination
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.53
	Confidence Interval	(2-Sided) 90%; -0.87 to 1.94
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.840
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Lower Limb Coordination
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.40
	Confidence Interval	(2-Sided) 90%; -0.41 to 1.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.482
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Lower Limb Coordination
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 90%; 0.12 to 1.45
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.397
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, Lower Limb Coordination
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 90%; -1.44 to 1.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.837
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Lower Limb Coordination
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.17
	Confidence Interval	(2-Sided) 90%; -1.01 to 1.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.707
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, Lower Limb Coordination
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 90%; -0.27 to 2.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.755
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, Lower Limb Coordination
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 90%; -0.09 to 2.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.626
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Upright Stability
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 90%; -0.8 to 1.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.63
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Upright Stability
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	1.0
	Confidence Interval	(2-Sided) 90%; 0.1 to 1.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.52
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, Upright Stability
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 90%; -1.3 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.45
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Upright Stability
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.6
	Confidence Interval	(2-Sided) 90%; 0.0 to 1.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.38
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, Upright Stability
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 90%; -1.2 to 0.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.57
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, Upright Stability
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 90%; -0.3 to 1.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.48
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in the mFARS-neuro Individual Item Scores
Description	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.
Time Frame	Baseline and Weeks 2, 7, and 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	TAK-831 75 mg	TAK-831 300 mg
Arm/Group Description	TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks.	TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.	TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
Measure Participants	27	14	26
Change at Week 2, Cough (0-2)	0.06 (0.051)	0.07 (0.072)	0.06 (0.051)
Change at Week 7, Cough (0-2)	0.01 (0.063)	-0.05 (0.087)	0.11 (0.065)
Change at Week 12, Cough (0-2)	0.01 (0.063)	0.08 (0.088)	0.13 (0.063)
Change at Week 2, Speech (0-3)	0.00 (0.058)	0.08 (0.083)	0.10 (0.060)
Change at Week 7, Speech (0-3)	0.00 (0.043)	-0.04 (0.060)	0.07 (0.045)
Change at Week 12, Speech (0-3)	0.00 (0.056)	0.00 (0.079)	0.09 (0.057)
Change at Week 2,Right Finger to Finger Test(0-3)	0.10 (0.079)	0.17 (0.109)	0.06 (0.078)
Change at Week 7,Right Finger to Finger Test(0-3)	0.04 (0.075)	0.12 (0.102)	-0.02 (0.075)
Change at Week 12,Right Finger to Finger Test(0-3)	0.21 (0.077)	0.12 (0.105)	0.06 (0.074)
Change at Week 2, Left Finger to Finger Test (0-3)	0.04 (0.085)	0.13 (0.120)	0.07 (0.084)
Change at Week 7, Left Finger to Finger Test (0-3)	0.05 (0.075)	0.07 (0.104)	0.07 (0.077)
Change at Week 12,Left Finger to Finger Test(0-3)	0.13 (0.095)	0.22 (0.132)	0.04 (0.093)
Change at Week 2, Right Nose to Finger Test (0-4)	-0.08 (0.085)	0.21 (0.126)	0.06 (0.085)
Change at Week 7, Right Nose to Finger Test (0-4)	0.01 (0.103)	0.09 (0.147)	-0.07 (0.107)
Change at Week 12, Right Nose to Finger Test (0-4)	0.00 (0.098)	-0.15 (0.140)	0.00 (0.097)
Change at Week 2, Left Nose to Finger Test (0-4)	-0.05 (0.096)	0.08 (0.137)	0.05 (0.095)
Change at Week 7, Left Nose to Finger Test (0-4)	0.15 (0.095)	0.32 (0.133)	0.01 (0.098)
Change at Week 12, Left Nose to Finger Test (0-4)	0.11 (0.103)	0.10 (0.141)	0.14 (0.099)
Change at Week 2, Right Dysmetria Test (0-4)	-0.11 (0.106)	-0.15 (0.151)	0.01 (0.105)
Change at Week 7, Right Dysmetria Test (0-4)	-0.23 (0.129)	-0.11 (0.181)	-0.06 (0.134)
Change at Week 12, Right Dysmetria Test (0-4)	-0.11 (0.132)	0.01 (0.185)	-0.16 (0.130)
Change at Week 2, Left Dysmetria Test (0-4)	-0.27 (0.111)	0.02 (0.160)	-0.12 (0.110)
Change at Week 7, Left Dysmetria Test (0-4)	-0.02 (0.136)	-0.26 (0.191)	-0.16 (0.141)
Change at Week 12, Left Dysmetria Test (0-4)	-0.17 (0.151)	-0.11 (0.211)	0.06 (0.149)
Change at Week 2, RAM of Right Hands (0-3)	-0.18 (0.103)	0.05 (0.145)	-0.06 (0.102)
Change at Week 7, RAM of Right Hands (0-3)	0.03 (0.122)	-0.03 (0.170)	0.03 (0.126)
Change at Week 12, RAM of Right Hands (0-3)	-0.07 (0.113)	0.12 (0.156)	-0.12 (0.112)
Change at Week 2, RAM of Left Hands (0-3)	-0.11 (0.085)	-0.03 (0.120)	-0.03 (0.085)
Change at Week 7, RAM of Left Hands (0-3)	-0.08 (0.123)	0.01 (0.173)	0.05 (0.129)
Change at Week 12, RAM of Left Hands (0-3)	-0.20 (0.096)	0.11 (0.133)	0.02 (0.095)
Change at Week 2, Right Finger Taps (0-4)	-0.39 (0.121)	0.05 (0.172)	-0.23 (0.124)
Change at Week 7, Right Finger Taps (0-4)	-0.18 (0.136)	0.04 (0.190)	-0.19 (0.143)
Change at Week 12, Right Finger Taps (0-4)	-0.31 (0.140)	-0.13 (0.195)	-0.37 (0.140)
Change at Week 2, Left Finger Taps (0-4)	-0.22 (0.132)	0.28 (0.189)	-0.17 (0.132)
Change at Week 7, Left Finger Taps (0-4)	-0.37 (0.131)	0.22 (0.182)	-0.21 (0.136)
Change at Week 12, Left Finger Taps (0-4)	-0.50 (0.161)	0.07 (0.225)	-0.17 (0.160)
Change at Week 2,Right Heel Along Shin Slide(0-4)	-0.24 (0.118)	-0.04 (0.166)	-0.24 (0.117)
Change at Week 7,Right Heel Along Shin Slide(0-4)	-0.18 (0.152)	-0.32 (0.209)	-0.35 (0.155)
Change at Week 12,Right Heel Along Shin Slide(0-4)	-0.43 (0.164)	-0.09 (0.223)	-0.30 (0.160)
Change at Week 2, Left Heel Along Shin Slide (0-4)	0.01 (0.121)	-0.15 (0.174)	0.05 (0.121)
Change at Week 7, Left Heel Along Shin Slide (0-4)	0.08 (0.133)	-0.23 (0.187)	-0.09 (0.138)
Change at Week 12,Left Heel Along Shin Slide(0-4)	-0.16 (0.151)	-0.18 (0.210)	-0.15 (0.149)
Change at Week 2, Right Heel Along Shin Tap (0-4)	-0.39 (0.114)	-0.17 (0.159)	0.04 (0.113)
Change at Week 7, Right Heel Along Shin Tap (0-4)	-0.14 (0.163)	-0.41 (0.224)	-0.14 (0.168)
Change at Week 12, Right Heel Along Shin Tap (0-4)	-0.32 (0.137)	-0.18 (0.184)	0.01 (0.131)
Change at Week 2, Left Heel Along Shin Tap (0-4)	-0.38 (0.121)	-0.22 (0.171)	-0.05 (0.120)
Change at Week 7, Left Heel Along Shin Tap (0-4)	-0.36 (0.165)	0.01 (0.230)	-0.15 (0.171)
Change at Week 12, Left Heel Along Shin Tap (0-4)	-0.52 (0.180)	-0.21 (0.251)	-0.27 (0.178)
Change at Week 2, Siting Posture (0-4)	-0.3 (0.11)	-0.1 (0.15)	-0.1 (0.11)
Change at Week 7, Siting Posture (0-4)	-0.4 (0.11)	-0.5 (0.15)	-0.2 (0.11)
Change at Week 12, Siting Posture (0-4)	-0.1 (0.12)	-0.3 (0.16)	-0.1 (0.11)
Change at Week 2, SFA -TTA (0-4)	-0.1 (0.15)	0.0 (0.21)	-0.1 (0.15)
Change at Week 7, SFA - TTA (0-4)	0.1 (0.12)	0.0 (0.17)	-0.1 (0.12)
Change at Week 12, SFA - TTA (0-4)	-0.1 (0.13)	0.0 (0.19)	0.0 (0.13)
Change at Week 2, SFA (Eyes Closed) - TTA (0-4)	0.0 (0.07)	0.1 (0.10)	-0.1 (0.07)
Change at Week 7, SFA (Eyes Closed) - TTA (0-4)	0.2 (0.11)	0.1 (0.16)	0.0 (0.12)
Change at Week 12, SFA (Eyes Closed) - TTA (0-4)	0.2 (0.14)	0.2 (0.19)	0.0 (0.14)
Change at Week 2, SFT - TTA (0-4)	0.0 (0.18)	-0.3 (0.26)	0.4 (0.19)
Change at Week 7, SFT - TTA (0-4)	-0.1 (0.11)	-0.1 (0.15)	0.3 (0.11)
Change at Week 12, SFT - TTA (0-4)	0.0 (0.14)	-0.2 (0.19)	0.3 (0.14)
Change at Week 2, SFT (Eyes Closed) - TTA (0-4)	0.1 (0.06)	0.1 (0.09)	0.0 (0.06)
Change at Week 7, SFT (Eyes Closed) - TTA (0-4)	0.1 (0.06)	0.1 (0.09)	0.1 (0.07)
Change at Week 12, SFT (Eyes Closed) - TTA (0-4)	0.0 (0.07)	0.0 (0.09)	-0.1 (0.06)
Change at Week 2, Tandem Stance - TTA (0-4)	0.0 (0.05)	0.0 (0.07)	0.0 (0.05)
Change at Week 7, Tandem Stance - TTA (0-4)	0.0 (0.05)	-0.1 (0.07)	0.1 (0.05)
Change at Week 12, Tandem Stance - TTA (0-4)	0.1 (0.05)	0.0 (0.07)	0.1 (0.05)
Change at Week 2,Stance on Dominant Foot-TTA(0-4)	NA (NA)	NA (NA)	NA (NA)
Change at Week 7,Stance on Dominant Foot-TTA(0-4)	NA (NA)	NA (NA)	NA (NA)
Change at Week 12,Stance on Dominant Foot-TTA(0-4)	NA (NA)	NA (NA)	NA (NA)
Change at Week 2, Tandem Walk (0-3)	0.0 (0.05)	0.0 (0.07)	0.0 (0.05)
Change at Week 7, Tandem Walk (0-3)	0.0 (0.05)	-0.1 (0.07)	0.0 (0.05)
Change at Week 12, Tandem Walk (0-3)	0.0 (0.06)	-0.1 (0.08)	0.0 (0.06)
Change at Week 2, Gait (0-5)	-0.3 (0.12)	-0.2 (0.17)	0.2 (0.12)
Change at Week 7, Gait (0-5)	-0.1 (0.11)	-0.3 (0.15)	0.2 (0.11)
Change at Week 12, Gait (0-5)	-0.1 (0.11)	-0.2 (0.15)	0.1 (0.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Cough
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 90%; -0.13 to 0.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.084
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Cough
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 90%; -0.11 to 0.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.069
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, Cough
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.06
	Confidence Interval	(2-Sided) 90%; -0.24 to 0.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.105
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Cough
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.10
	Confidence Interval	(2-Sided) 90%; -0.05 to 0.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.088
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, Cough
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.07
	Confidence Interval	(2-Sided) 90%; -0.11 to 0.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.106
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, Cough
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.12
	Confidence Interval	(2-Sided) 90%; -0.03 to 0.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.087
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Speech
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 90%; -0.09 to 0.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.100
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Speech
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.10
	Confidence Interval	(2-Sided) 90%; -0.04 to 0.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.083
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, Speech
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 90%; -0.16 to 0.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.071
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Speech
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.07
	Confidence Interval	(2-Sided) 90%; -0.03 to 0.17
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.060
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, Speech
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 90%; -0.16 to 0.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.095
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, Speech
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.09
	Confidence Interval	(2-Sided) 90%; -0.04 to 0.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.079
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Right Finger to Finger Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.07
	Confidence Interval	(2-Sided) 90%; -0.14 to 0.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.131
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Right Finger to Finger Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 90%; -0.22 to 0.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.108
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, Right Finger to Finger Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.07
	Confidence Interval	(2-Sided) 90%; -0.13 to 0.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.122
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Right Finger to Finger Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 90%; -0.24 to 0.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.103
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, Right Finger to Finger Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 90%; -0.30 to 0.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.126
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, Right Finger to Finger Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 90%; -0.32 to 0.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.104
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Left Finger to Finger Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.09
	Confidence Interval	(2-Sided) 90%; -0.15 to 0.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.142
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Left Finger to Finger Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 90%; -0.16 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.117
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, Left Finger to Finger Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 90%; -0.18 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.123
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Left Finger to Finger Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 90%; -0.15 to 0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.104
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, Left Finger to Finger Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.09
	Confidence Interval	(2-Sided) 90%; -0.17 to 0.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.158
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, Left Finger to Finger Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 90%; -0.30 to 0.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.130
	Estimation Comments

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Right Nose to Finger Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.29
	Confidence Interval	(2-Sided) 90%; 0.04 to 0.53
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.145
	Estimation Comments

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Right Nose to Finger Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.14
	Confidence Interval	(2-Sided) 90%; -0.06 to 0.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.118
	Estimation Comments

Statistical Analysis 27

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, Right Nose to Finger Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.07
	Confidence Interval	(2-Sided) 90%; -0.22 to 0.37
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.174
	Estimation Comments

Statistical Analysis 28

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Right Nose to Finger Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 90%; -0.32 to 0.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.146
	Estimation Comments

Statistical Analysis 29

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, Right Nose to Finger Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 90%; -0.43 to 0.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.166
	Estimation Comments

Statistical Analysis 30

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, Right Nose to Finger Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 90%; -0.23 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.136
	Estimation Comments

Statistical Analysis 31

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Left Nose to Finger Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.13
	Confidence Interval	(2-Sided) 90%; -0.14 to 0.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.161
	Estimation Comments

Statistical Analysis 32

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Left Nose to Finger Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.10
	Confidence Interval	(2-Sided) 90%; -0.12 to 0.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.133
	Estimation Comments

Statistical Analysis 33

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, Left Nose to Finger Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.17
	Confidence Interval	(2-Sided) 90%; -0.09 to 0.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.157
	Estimation Comments

Statistical Analysis 34

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Left Nose to Finger Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 90%; -0.36 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.134
	Estimation Comments

Statistical Analysis 35

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, Left Nose to Finger Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 90%; -0.29 to 0.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.169
	Estimation Comments

Statistical Analysis 36

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, Left Nose to Finger Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 90%; -0.21 to 0.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.141
	Estimation Comments

Statistical Analysis 37

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Right Dysmetria Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 90%; -0.33 to 0.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.176
	Estimation Comments

Statistical Analysis 38

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Right Dysmetria Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.12
	Confidence Interval	(2-Sided) 90%; -0.12 to 0.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.145
	Estimation Comments

Statistical Analysis 39

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, Right Dysmetria Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.12
	Confidence Interval	(2-Sided) 90%; -0.25 to 0.48
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.217
	Estimation Comments

Statistical Analysis 40

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Right Dysmetria Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.17
	Confidence Interval	(2-Sided) 90%; -0.14 to 0.47
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.183
	Estimation Comments

Statistical Analysis 41

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, Right Dysmetria Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 90%; -0.26 to 0.48
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.221
	Estimation Comments

Statistical Analysis 42

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, Right Dysmetria Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.06
	Confidence Interval	(2-Sided) 90%; -0.36 to 0.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.183
	Estimation Comments

Statistical Analysis 43

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Left Dysmetria Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.29
	Confidence Interval	(2-Sided) 90%; -0.02 to 0.60
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.185
	Estimation Comments

Statistical Analysis 44

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Left Dysmetria Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.15
	Confidence Interval	(2-Sided) 90%; -0.10 to 0.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.153
	Estimation Comments

Statistical Analysis 45

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, Left Dysmetria Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.25
	Confidence Interval	(2-Sided) 90%; -0.63 to 0.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.228
	Estimation Comments

Statistical Analysis 46

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Left Dysmetria Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 90%; -0.47 to 0.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.192
	Estimation Comments

Statistical Analysis 47

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, Left Dysmetria Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 90%; -0.37 to 0.48
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.254
	Estimation Comments

Statistical Analysis 48

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, Left Dysmetria Test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.23
	Confidence Interval	(2-Sided) 90%; -0.11 to 0.58
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.209
	Estimation Comments

Statistical Analysis 49

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, RAM of Right Hands
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.22
	Confidence Interval	(2-Sided) 90%; -0.06 to 0.51
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.170
	Estimation Comments

Statistical Analysis 50

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, RAM of Right Hands
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 90%; -0.12 to 0.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.141
	Estimation Comments

Statistical Analysis 51

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, RAM of Right Hands
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.06
	Confidence Interval	(2-Sided) 90%; -0.41 to 0.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.204
	Estimation Comments

Statistical Analysis 52

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, RAM of Right Hands
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 90%; -0.29 to 0.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.172
	Estimation Comments

Statistical Analysis 53

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, RAM of Right Hands
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.19
	Confidence Interval	(2-Sided) 90%; -0.12 to 0.51
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.187
	Estimation Comments

Statistical Analysis 54

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, RAM of Right Hands
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 90%; -0.31 to 0.21
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.156
	Estimation Comments

Statistical Analysis 55

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, RAM of Left Hands
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 90%; -0.15 to 0.32
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.141
	Estimation Comments

Statistical Analysis 56

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, RAM of Left Hands
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 90%; -0.12 to 0.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.116
	Estimation Comments

Statistical Analysis 57

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, RAM of Left Hands
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 90%; -0.27 to 0.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.209
	Estimation Comments

Statistical Analysis 58

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, RAM of Left Hands
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.12
	Confidence Interval	(2-Sided) 90%; -0.17 to 0.42
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.176
	Estimation Comments

Statistical Analysis 59

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, RAM of Left Hand
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.31
	Confidence Interval	(2-Sided) 90%; 0.04 to 0.58
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.159
	Estimation Comments

Statistical Analysis 60

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, RAM of Left Hand
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.21
	Confidence Interval	(2-Sided) 90%; -0.01 to 0.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.132
	Estimation Comments

Statistical Analysis 61

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Right Finger Taps
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.44
	Confidence Interval	(2-Sided) 90%; 0.10 to 0.77
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.201
	Estimation Comments

Statistical Analysis 62

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Right Finger Taps
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 90%; -0.12 to 0.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.168
	Estimation Comments

Statistical Analysis 63

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Right Finger Taps
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.22
	Confidence Interval	(2-Sided) 90%; -0.16 to 0.60
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.227
	Estimation Comments

Statistical Analysis 64

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Right Finger Taps
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 90%; -0.33 to 0.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.193
	Estimation Comments

Statistical Analysis 65

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, Right Finger Taps
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.17
	Confidence Interval	(2-Sided) 90%; -0.22 to 0.56
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.233
	Estimation Comments

Statistical Analysis 66

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, Right Finger Taps
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 90%; -0.39 to 0.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.194
	Estimation Comments

Statistical Analysis 67

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Left Finger Taps
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.50
	Confidence Interval	(2-Sided) 90%; 0.12 to 0.87
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.223
	Estimation Comments

Statistical Analysis 68

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Left Finger Taps
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 90%; -0.25 to 0.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.183
	Estimation Comments

Statistical Analysis 69

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, Left Finger Taps
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.59
	Confidence Interval	(2-Sided) 90%; 0.22 to 0.95
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.218
	Estimation Comments

Statistical Analysis 70

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Left Finger Taps
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 90%; -0.15 to 0.47
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.184
	Estimation Comments

Statistical Analysis 71

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, Left Finger Taps
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.57
	Confidence Interval	(2-Sided) 90%; 0.11 to 1.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.272
	Estimation Comments

Statistical Analysis 72

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, Left Finger Taps
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.33
	Confidence Interval	(2-Sided) 90%; -0.04 to 0.71
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.224
	Estimation Comments

Statistical Analysis 73

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Right Heel Along Shin Slide
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.20
	Confidence Interval	(2-Sided) 90%; -0.12 to 0.53
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.193
	Estimation Comments

Statistical Analysis 74

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Right Heel Along Shin Slide
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 90%; -0.26 to 0.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.161
	Estimation Comments

Statistical Analysis 75

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, Right Heel Along Shin Slide
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 90%; -0.56 to 0.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.251
	Estimation Comments

Statistical Analysis 76

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Right Heel Along Shin Slide
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 90%; -0.53 to 0.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.214
	Estimation Comments

Statistical Analysis 77

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12,Right Heel Along Shin Slide
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.33
	Confidence Interval	(2-Sided) 90%; -0.12 to 0.78
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.270
	Estimation Comments

Statistical Analysis 78

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12,Right Heel Along Shin Slide
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.13
	Confidence Interval	(2-Sided) 90%; -0.25 to 0.51
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.226
	Estimation Comments

Statistical Analysis 79

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Left Heel Along Shin Slide
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 90%; -0.51 to 0.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.205
	Estimation Comments

Statistical Analysis 80

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Left Heel Along Shin Slide
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 90%; -0.25 to 0.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.166
	Estimation Comments

Statistical Analysis 81

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, Left Heel Along Shin Slide
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.31
	Confidence Interval	(2-Sided) 90%; -0.68 to 0.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.224
	Estimation Comments

Statistical Analysis 82

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Left Heel Along Shin Slide
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 90%; -0.48 to 0.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.188
	Estimation Comments

Statistical Analysis 83

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, Left Heel Along Shin Slide
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 90%; -0.45 to 0.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.254
	Estimation Comments

Statistical Analysis 84

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, Left Heel Along Shin Slide
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 90%; -0.34 to 0.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.209
	Estimation Comments

Statistical Analysis 85

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Right Heel Along Shin Tap
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.22
	Confidence Interval	(2-Sided) 90%; -0.10 to 0.53
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.187
	Estimation Comments

Statistical Analysis 86

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Right Heel Along Shin Tap
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.43
	Confidence Interval	(2-Sided) 90%; 0.17 to 0.69
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.155
	Estimation Comments

Statistical Analysis 87

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, Right Heel Along Shin Tap
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.27
	Confidence Interval	(2-Sided) 90%; -0.72 to 0.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.272
	Estimation Comments

Statistical Analysis 88

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Right Heel Along Shin Tap
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 90%; -0.38 to 0.39
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.231
	Estimation Comments

Statistical Analysis 89

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, Right Heel Along Shin Tap
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.14
	Confidence Interval	(2-Sided) 90%; -0.23 to 0.51
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.222
	Estimation Comments

Statistical Analysis 90

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, Right Heel Along Shin Tap
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.33
	Confidence Interval	(2-Sided) 90%; 0.02 to 0.64
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.186
	Estimation Comments

Statistical Analysis 91

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Left Heel Along Shin Tap
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 90%; -0.17 to 0.50
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.199
	Estimation Comments

Statistical Analysis 92

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Left Heel Along Shin Tap
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.34
	Confidence Interval	(2-Sided) 90%; 0.06 to 0.61
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.164
	Estimation Comments

Statistical Analysis 93

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, Left Heel Along Shin Tap
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.37
	Confidence Interval	(2-Sided) 90%; -0.09 to 0.84
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.277
	Estimation Comments

Statistical Analysis 94

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Left Heel Along Shin Tap
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.21
	Confidence Interval	(2-Sided) 90%; -0.19 to 0.60
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.234
	Estimation Comments

Statistical Analysis 95

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, Left Heel Along Shin Tap
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.31
	Confidence Interval	(2-Sided) 90%; -0.20 to 0.82
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.303
	Estimation Comments

Statistical Analysis 96

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, Left Heel Along Shin Tap
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.25
	Confidence Interval	(2-Sided) 90%; -0.17 to 0.67
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.250
	Estimation Comments

Statistical Analysis 97

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Siting Posture
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 90%; -0.1 to 0.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.18
	Estimation Comments

Statistical Analysis 98

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Siting Posture
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 90%; -0.1 to 0.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.15
	Estimation Comments

Statistical Analysis 99

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, Siting Posture
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 90%; -0.4 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.18
	Estimation Comments

Statistical Analysis 100

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Siting Posture
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 90%; 0.0 to 0.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.15
	Estimation Comments

Statistical Analysis 101

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, Siting Posture
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 90%; -0.5 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.19
	Estimation Comments

Statistical Analysis 102

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, Siting Posture
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 90%; -0.2 to 0.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.16
	Estimation Comments

Statistical Analysis 103

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, SFA - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 90%; -0.4 to 0.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.25
	Estimation Comments

Statistical Analysis 104

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, SFA - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 90%; -0.3 to 0.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.20
	Estimation Comments

Statistical Analysis 105

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, SFA - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 90%; -0.4 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.20
	Estimation Comments

Statistical Analysis 106

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, SFA - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 90%; -0.5 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.17
	Estimation Comments

Statistical Analysis 107

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, SFA - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 90%; -0.3 to 0.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.22
	Estimation Comments

Statistical Analysis 108

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, SFA - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 90%; -0.2 to 0.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.19
	Estimation Comments

Statistical Analysis 109

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, SFA (Eyes Closed) - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 90%; -0.1 to 0.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.11
	Estimation Comments

Statistical Analysis 110

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, SFA (Eyes Closed) - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 90%; -0.2 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.09
	Estimation Comments

Statistical Analysis 111

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, SFA (Eyes Closed) - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 90%; -0.4 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.19
	Estimation Comments

Statistical Analysis 112

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, SFA (Eyes Closed) - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 90%; -0.4 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.16
	Estimation Comments

Statistical Analysis 113

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, SFA (Eyes Closed) - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 90%; -0.3 to 0.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.23
	Estimation Comments

Statistical Analysis 114

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, SFA (Eyes Closed) - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 90%; -0.5 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.19
	Estimation Comments

Statistical Analysis 115

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, SFT - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 90%; -0.8 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.32
	Estimation Comments

Statistical Analysis 116

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, SFT - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 90%; 0.0 to 0.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.26
	Estimation Comments

Statistical Analysis 117

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, SFT - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 90%; -0.3 to 0.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.18
	Estimation Comments

Statistical Analysis 118

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, SFT - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 90%; 0.2 to 0.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.15
	Estimation Comments

Statistical Analysis 119

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, SFT - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 90%; -0.5 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.23
	Estimation Comments

Statistical Analysis 120

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, SFT - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 90%; 0.0 to 0.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.19
	Estimation Comments

Statistical Analysis 121

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, SFT (Eyes Closed) - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 90%; -0.2 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.11
	Estimation Comments

Statistical Analysis 122

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, SFT (Eyes Closed) - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 90%; -0.2 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.09
	Estimation Comments

Statistical Analysis 123

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, SFT (Eyes Closed) - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 90%; -0.2 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.11
	Estimation Comments

Statistical Analysis 124

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, SFT (Eyes Closed) - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 90%; -0.1 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.09
	Estimation Comments

Statistical Analysis 125

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, SFT (Eyes Closed) - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 90%; -0.2 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.11
	Estimation Comments

Statistical Analysis 126

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, SFT (Eyes Closed) - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 90%; -0.3 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.09
	Estimation Comments

Statistical Analysis 127

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Tandem Stance - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 90%; -0.2 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.09
	Estimation Comments

Statistical Analysis 128

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Tandem Stance - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 90%; -0.1 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.07
	Estimation Comments

Statistical Analysis 129

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, Tandem Stance - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 90%; -0.2 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.09
	Estimation Comments

Statistical Analysis 130

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Tandem Stance - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 90%; -0.1 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.07
	Estimation Comments

Statistical Analysis 131

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, Tandem Stance - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 90%; -0.2 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.09
	Estimation Comments

Statistical Analysis 132

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, Tandem Stance - TTA
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 90%; -0.1 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.07
	Estimation Comments

Statistical Analysis 133

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Tandem Walk
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 90%; -0.1 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.08
	Estimation Comments

Statistical Analysis 134

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Tandem Walk
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 90%; -0.1 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.07
	Estimation Comments

Statistical Analysis 135

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, Tandem Walk
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 90%; -0.2 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.09
	Estimation Comments

Statistical Analysis 136

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Tandem Walk
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 90%; -0.1 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.07
	Estimation Comments

Statistical Analysis 137

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, Tandem Walk
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 90%; -0.3 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.10
	Estimation Comments

Statistical Analysis 138

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, Tandem Walk
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 90%; -0.2 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.08
	Estimation Comments

Statistical Analysis 139

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 2, Gait
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 90%; -0.2 to 0.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.20
	Estimation Comments

Statistical Analysis 140

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 2, Gait
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 90%; 0.1 to 0.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.17
	Estimation Comments

Statistical Analysis 141

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 7, Gait
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 90%; -0.4 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.17
	Estimation Comments

Statistical Analysis 142

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 7, Gait
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 90%; 0.1 to 0.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.15
	Estimation Comments

Statistical Analysis 143

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change at Week 12, Gait
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 90%; -0.4 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.17
	Estimation Comments

Statistical Analysis 144

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change at Week 12, Gait
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 90%; 0.0 to 0.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.14
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline in the Timed 25-Foot Walk (T25FW)
Description	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.
Time Frame	Baseline and Weeks 2, 7 and 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	TAK-831 75 mg	TAK-831 300 mg
Arm/Group Description	TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks.	TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.	TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
Measure Participants	27	14	26
Change from Baseline at Week 2	0.61 (0.901)	0.84 (1.124)	1.95 (0.990)
Change from Baseline at Week 7	1.67 (0.948)	1.77 (1.255)	1.37 (1.080)
Change from Baseline at Week 12	0.52 (0.903)	2.70 (1.226)	1.30 (1.057)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change from Baseline at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.599
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.23
	Confidence Interval	(2-Sided) 90%; -1.31 to 1.76
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.889
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change from Baseline at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.978
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	1.34
	Confidence Interval	(2-Sided) 90%; 0.26 to 2.42
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.625
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change from Baseline at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.533
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.09
	Confidence Interval	(2-Sided) 90%; -1.87 to 2.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.140
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change from Baseline at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.370
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.30
	Confidence Interval	(2-Sided) 90%; -1.83 to 1.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.886
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change from Baseline at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.972
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	2.18
	Confidence Interval	(2-Sided) 90%; 0.32 to 4.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.078
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change from Baseline at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.825
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 90%; -0.63 to 2.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.819
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline in the 9-HPT and T25FW Composite Score
Description	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.
Time Frame	Baseline and Weeks 2, 7, and 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	TAK-831 75 mg	TAK-831 300 mg
Arm/Group Description	TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks.	TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.	TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
Measure Participants	27	14	26
Change from Baseline at Week 2	0.1369 (0.21905)	0.1819 (0.28555)	-0.1911 (0.24051)
Change from Baseline at Week 7	-0.1112 (0.24167)	0.0336 (0.32731)	-0.0998 (0.26792)
Change from Baseline at Week 12	0.0060 (0.22484)	-0.2007 (0.31057)	0.1233 (0.25501)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change from Baseline at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.426
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.0450
	Confidence Interval	(2-Sided) 90%; -0.3665 to 0.4565
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.23858
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change from Baseline at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.975
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.3281
	Confidence Interval	(2-Sided) 90%; -0.6005 to -0.0557
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.15794
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change from Baseline at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.324
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.1448
	Confidence Interval	(2-Sided) 90%; -0.3931 to 0.6826
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.31186
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change from Baseline at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.481
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.0113
	Confidence Interval	(2-Sided) 90%; -0.3891 to 0.4117
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.23213
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change from Baseline at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.765
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.2067
	Confidence Interval	(2-Sided) 90%; -0.6911 to 0.2778
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.28088
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change from Baseline at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.280
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.1173
	Confidence Interval	(2-Sided) 90%; -0.2238 to 0.4585
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.19778
	Estimation Comments

10. Secondary Outcome

Title	Change From Baseline in Low-Contrast Letter Acuity (LCLA) Test Score
Description	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.
Time Frame	Baseline and Weeks 2, 7, and, 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	TAK-831 75 mg	TAK-831 300 mg
Arm/Group Description	TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks.	TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.	TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
Measure Participants	27	14	26
Change from Baseline at Week 2	1.8 (2.56)	-0.9 (3.61)	5.1 (2.53)
Change from Baseline at Week 7	4.6 (2.20)	-2.3 (3.06)	6.0 (2.17)
Change from Baseline at Week 12	0.0 (2.61)	-5.7 (3.65)	3.1 (2.56)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change from Baseline at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.735
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-2.7
	Confidence Interval	(2-Sided) 90%; -9.9 to 4.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.28
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change from Baseline at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.182
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	3.2
	Confidence Interval	(2-Sided) 90%; -2.7 to 9.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.51
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change from Baseline at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.970
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-6.9
	Confidence Interval	(2-Sided) 90%; -12.9 to -0.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.59
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change from Baseline at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.321
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 90%; -3.6 to 6.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.00
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change from Baseline at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.905
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-5.8
	Confidence Interval	(2-Sided) 90%; -13.0 to 1.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.34
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change from Baseline at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.199
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	3.1
	Confidence Interval	(2-Sided) 90%; -2.9 to 9.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.57
	Estimation Comments

11. Secondary Outcome

Title	Number of Participants by Clinical Global Impression-Improvement (CGI-I) (Global Change) Score Categories
Description	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.
Time Frame	Weeks 2, 7, and 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	TAK-831 75 mg	TAK-831 300 mg
Arm/Group Description	TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks.	TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.	TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
Measure Participants	27	14	26
Week 2, Moderately Improved	1 3.7%	0 0%	2 7.7%
Week 2, A Little Improved	14 51.9%	3 21.4%	6 23.1%
Week 2, No Change	11 40.7%	10 71.4%	17 65.4%
Week 2, A little Worse	1 3.7%	0 0%	0 0%
Week 7, Moderately Improved	1 3.7%	0 0%	1 3.8%
Week 7, A Little Improved	13 48.1%	4 28.6%	8 30.8%
Week 7, No Change	11 40.7%	8 57.1%	11 42.3%
Week 7, A little Worse	1 3.7%	1 7.1%	1 3.8%
Week 12, Moderately Improved	1 3.7%	0 0%	0 0%
Week 12, A Little Improved	9 33.3%	3 21.4%	7 26.9%
Week 12, No Change	12 44.4%	7 50%	16 61.5%
Week 12, A little Worse	2 7.4%	1 7.1%	1 3.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.974
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.893
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.954
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.793
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.845
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.816
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

12. Secondary Outcome

Title	Number of Participants by Patient Global Impression-Improvement (PGI-I) (Global Change) Score Categories
Description	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.
Time Frame	Weeks 2, 7 and 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	TAK-831 75 mg	TAK-831 300 mg
Arm/Group Description	TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks.	TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.	TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
Measure Participants	27	14	26
Week 2, Moderately Improved	2 7.4%	0 0%	0 0%
Week 2, A Little Improved	6 22.2%	3 21.4%	8 30.8%
Week 2, No Change	19 70.4%	10 71.4%	16 61.5%
Week 2, A little Worse	0 0%	0 0%	2 7.7%
Week 7, Moderately Improved	3 11.1%	0 0%	3 11.5%
Week 7, A Little Improved	10 37%	4 28.6%	5 19.2%
Week 7, No Change	11 40.7%	8 57.1%	14 53.8%
Week 7, A little Worse	2 7.4%	1 7.1%	2 7.7%
Week 12, Much Improved	1 3.7%	0 0%	0 0%
Week 12, Moderately Improved	5 18.5%	1 7.1%	1 3.8%
Week 12, A Little Improved	8 29.6%	4 28.6%	3 11.5%
Week 12, No Change	7 25.9%	7 50%	15 57.7%
Week 12, A little Worse	3 11.1%	0 0%	4 15.4%
Week 12, Moderately Worse	0 0%	0 0%	1 3.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.840
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.854
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.922
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.794
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.830
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.998
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

13. Secondary Outcome

Title	Number of Participants by CGI-I (Upper Extremity Functional Change) Score Categories
Description	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.
Time Frame	Weeks 2, 7, and 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	TAK-831 75 mg	TAK-831 300 mg
Arm/Group Description	TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks.	TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.	TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
Measure Participants	27	14	26
Week 2, Moderately Improved	1 3.7%	0 0%	2 7.7%
Week 2, A Little Improved	13 48.1%	2 14.3%	7 26.9%
Week 2, No Change	12 44.4%	11 78.6%	16 61.5%
Week 2, A little Worse	1 3.7%	0 0%	0 0%
Week 7, Moderately Improved	1 3.7%	1 7.1%	0 0%
Week 7, A Little Improved	10 37%	5 35.7%	11 42.3%
Week 7, No Change	14 51.9%	6 42.9%	7 26.9%
Week 7, A little Worse	1 3.7%	1 7.1%	3 11.5%
Week 12, Moderately Improved	2 7.4%	2 14.3%	0 0%
Week 12, A Little Improved	11 40.7%	2 14.3%	9 34.6%
Week 12, No Change	9 33.3%	7 50%	15 57.7%
Week 12, A little Worse	2 7.4%	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.987
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.771
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.526
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.665
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.576
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.865
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

14. Secondary Outcome

Title	Number of Participants by PGI-I (Upper Extremity Functional Change) Score Categories
Description	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.
Time Frame	Weeks 2, 7, and 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	TAK-831 75 mg	TAK-831 300 mg
Arm/Group Description	TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks.	TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.	TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
Measure Participants	27	14	26
Week 2, Moderately Improved	5 18.5%	0 0%	0 0%
Week 2, A Little Improved	6 22.2%	3 21.4%	7 26.9%
Week 2, No Change	16 59.3%	10 71.4%	18 69.2%
Week 2, A little Worse	0 0%	0 0%	1 3.8%
Week 7, Much Improved	0 0%	0 0%	1 3.8%
Week 7, Moderately Improved	3 11.1%	0 0%	2 7.7%
Week 7, A Little Improved	10 37%	4 28.6%	4 15.4%
Week 7, No Change	11 40.7%	7 50%	15 57.7%
Week 7, A little Worse	2 7.4%	2 14.3%	2 7.7%
Week 12, Much Improved	2 7.4%	0 0%	0 0%
Week 12, Moderately Improved	6 22.2%	1 7.1%	1 3.8%
Week 12, A Little Improved	6 22.2%	4 28.6%	6 23.1%
Week 12, No Change	9 33.3%	7 50%	15 57.7%
Week 12, A little Worse	1 3.7%	0 0%	2 7.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.966
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.983
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.953
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.781
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.948
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.998
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

15. Secondary Outcome

Title	Number of Participants by Clinical Global Impression-Severity (CGI-S) (Global Severity) Score Categories Relative to Baseline
Description	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.
Time Frame	Baseline and Weeks 2, 7, and 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	TAK-831 75 mg	TAK-831 300 mg
Arm/Group Description	TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks.	TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.	TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
Measure Participants	27	14	26
Score at Baseline=0 (No Symptoms)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mild)	2 7.4%	2 14.3%	1 3.8%
Score at Baseline=2 (Moderate)	4 14.8%	2 14.3%	2 7.7%
Score at Baseline=3 (Severe)	0 0%	0 0%	0 0%
Score at Baseline=4 (Very Severe)	0 0%	0 0%	0 0%
Score at Baseline=0 (No Symptoms)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mild)	1 3.7%	0 0%	2 7.7%
Score at Baseline=2 (Moderate)	14 51.9%	6 42.9%	10 38.5%
Score at Baseline=3 (Severe)	2 7.4%	0 0%	1 3.8%
Score at Baseline=4 (Very Severe)	0 0%	0 0%	0 0%
Score at Baseline=0 (No Symptoms)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mild)	0 0%	0 0%	0 0%
Score at Baseline=2 (Moderate)	0 0%	0 0%	1 3.8%
Score at Baseline=3 (Severe)	3 11.1%	2 14.3%	8 30.8%
Score at Baseline=4 (Very Severe)	0 0%	0 0%	0 0%
Score at Baseline=0 (No Symptoms)	0 0%	0 0%
Score at Baseline=1 (Mild)	0 0%	0 0%
Score at Baseline=2 (Moderate)	0 0%	0 0%
Score at Baseline=3 (Severe)	0 0%	0 0%
Score at Baseline=4 (Very Severe)	1 3.7%	1 7.1%
Score at Baseline=0 (No Symptoms)	0 0%	0 0%
Score at Baseline=1 (Mild)	2 7.4%	1 7.1%
Score at Baseline=2 (Moderate)	3 11.1%	0 0%
Score at Baseline=3 (Severe)	0 0%	0 0%
Score at Baseline=4 (Very Severe)	0 0%	0 0%
Score at Baseline=0 (No Symptoms)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mild)	1 3.7%	1 7.1%	3 11.5%
Score at Baseline=2 (Moderate)	14 51.9%	8 57.1%	11 42.3%
Score at Baseline=3 (Severe)	3 11.1%	1 7.1%	2 7.7%
Score at Baseline=4 (Very Severe)	0 0%	0 0%	0 0%
Score at Baseline=0 (No Symptoms)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mild)	0 0%	0 0%	0 0%
Score at Baseline=2 (Moderate)	0 0%	0 0%	0 0%
Score at Baseline=3 (Severe)	2 7.4%	1 7.1%	7 26.9%
Score at Baseline=4 (Very Severe)	0 0%	0 0%	0 0%
Score at Baseline=0 (No Symptoms)	0 0%	0 0%
Score at Baseline=1 (Mild)	0 0%	0 0%
Score at Baseline=2 (Moderate)	0 0%	0 0%
Score at Baseline=3 (Severe)	0 0%	0 0%
Score at Baseline=4 (Very Severe)	1 3.7%	1 7.1%
Score at Baseline=0 (No Symptoms)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mild)	2 7.4%	1 7.1%	2 7.7%
Score at Baseline=2 (Moderate)	4 14.8%	0 0%	1 3.8%
Score at Baseline=3 (Severe)	0 0%	0 0%	0 0%
Score at Baseline=4 (Very Severe)	0 0%	0 0%	0 0%
Score at Baseline=0 (No Symptoms)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mild)	1 3.7%	0 0%	0 0%
Score at Baseline=2 (Moderate)	13 48.1%	8 57.1%	11 42.3%
Score at Baseline=3 (Severe)	2 7.4%	0 0%	0 0%
Score at Baseline=4 (Very Severe)	0 0%	0 0%	0 0%
Score at Baseline=0 (No Symptoms)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mild)	0 0%	0 0%	1 3.8%
Score at Baseline=2 (Moderate)	0 0%	0 0%	0 0%
Score at Baseline=3 (Severe)	1 3.7%	1 7.1%	9 34.6%
Score at Baseline=4 (Very Severe)	0 0%	0 0%	0 0%
Score at Baseline=0 (No Symptoms)	0 0%	0 0%
Score at Baseline=1 (Mild)	0 0%	0 0%
Score at Baseline=2 (Moderate)	0 0%	0 0%
Score at Baseline=3 (Severe)	0 0%	0 0%
Score at Baseline=4 (Very Severe)	1 3.7%	1 7.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.666
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.812
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.834
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.841
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.893
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.907
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

16. Secondary Outcome

Title	Number of Participants by Patient Global Impression-Severity (PGI-S) (Global Severity) Score Categories Relative to Baseline
Description	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.
Time Frame	Baseline and Weeks 2, 7, and 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	TAK-831 75 mg	TAK-831 300 mg
Arm/Group Description	TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks.	TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.	TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
Measure Participants	27	14	26
Score at Baseline=0 (No Symptoms)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mild)	5 18.5%	1 7.1%	2 7.7%
Score at Baseline=2 (Moderate)	2 7.4%	3 21.4%	3 11.5%
Score at Baseline=3 (Severe)	0 0%	0 0%	0 0%
Score at Baseline=4 (Very Severe)	0 0%	0 0%	0 0%
Score at Baseline=0 (No Symptoms)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mild)	2 7.4%	0 0%	0 0%
Score at Baseline=2 (Moderate)	11 40.7%	5 35.7%	16 61.5%
Score at Baseline=3 (Severe)	3 11.1%	3 21.4%	1 3.8%
Score at Baseline=4 (Very Severe)	0 0%	0 0%	0 0%
Score at Baseline=0 (No Symptoms)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mild)	0 0%	0 0%	0 0%
Score at Baseline=2 (Moderate)	0 0%	0 0%	0 0%
Score at Baseline=3 (Severe)	3 11.1%	1 7.1%	4 15.4%
Score at Baseline=4 (Very Severe)	0 0%	0 0%	0 0%
Score at Baseline=0 (No Symptoms)	0 0%
Score at Baseline=1 (Mild)	0 0%
Score at Baseline=2 (Moderate)	0 0%
Score at Baseline=3 (Severe)	1 3.7%
Score at Baseline=4 (Very Severe)	0 0%
Score at Baseline=0 (No Symptoms)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mild)	4 14.8%	1 7.1%	2 7.7%
Score at Baseline=2 (Moderate)	1 3.7%	2 14.3%	2 7.7%
Score at Baseline=3 (Severe)	0 0%	0 0%	0 0%
Score at Baseline=4 (Very Severe)	0 0%	0 0%	0 0%
Score at Baseline=0 (No Symptoms)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mild)	2 7.4%	0 0%	0 0%
Score at Baseline=2 (Moderate)	12 44.4%	4 28.6%	14 53.8%
Score at Baseline=3 (Severe)	4 14.8%	3 21.4%	2 7.7%
Score at Baseline=4 (Very Severe)	0 0%	0 0%	0 0%
Score at Baseline=0 (No Symptoms)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mild)	0 0%	0 0%	0 0%
Score at Baseline=2 (Moderate)	0 0%	2 14.3%	1 3.8%
Score at Baseline=3 (Severe)	3 11.1%	1 7.1%	3 11.5%
Score at Baseline=4 (Very Severe)	0 0%	0 0%	0 0%
Score at Baseline=0 (No Symptoms)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mild)	4 14.8%	1 7.1%	2 7.7%
Score at Baseline=2 (Moderate)	2 7.4%	2 14.3%	2 7.7%
Score at Baseline=3 (Severe)	0 0%	0 0%	0 0%
Score at Baseline=4 (Very Severe)	0 0%	0 0%	0 0%
Score at Baseline=0 (No Symptoms)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mild)	2 7.4%	0 0%	0 0%
Score at Baseline=2 (Moderate)	10 37%	4 28.6%	15 57.7%
Score at Baseline=3 (Severe)	4 14.8%	3 21.4%	3 11.5%
Score at Baseline=4 (Very Severe)	0 0%	0 0%	0 0%
Score at Baseline=0 (No Symptoms)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mild)	0 0%	0 0%	0 0%
Score at Baseline=2 (Moderate)	0 0%	1 7.1%	0 0%
Score at Baseline=3 (Severe)	2 7.4%	1 7.1%	2 7.7%
Score at Baseline=4 (Very Severe)	0 0%	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.032
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.216
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.215
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.411
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.194
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.408
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

17. Secondary Outcome

Title	Number of Participants by CGI-S (Upper Extremity Functional Severity) Score Categories Relative to Baseline
Description	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.
Time Frame	Baseline and Week 2, 7, and 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	TAK-831 75 mg	TAK-831 300 mg
Arm/Group Description	TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks.	TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.	TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
Measure Participants	27	14	26
Score at Baseline=0 (Not Impaired)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mildly Impaired)	13 48.1%	3 21.4%	11 42.3%
Score at Baseline=2 (Moderately Impaired)	0 0%	2 14.3%	1 3.8%
Score at Baseline=3 (Severely Impaired)	0 0%	0 0%	1 3.8%
Score at Baseline=4 (Very Severely Impaired)	0 0%	0 0%	0 0%
Score at Baseline=0 (Not Impaired)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mildly Impaired)	2 7.4%	2 14.3%	2 7.7%
Score at Baseline=2 (Moderately Impaired)	11 40.7%	5 35.7%	8 30.8%
Score at Baseline=3 (Severely Impaired)	1 3.7%	0 0%	0 0%
Score at Baseline=4 (Very Severely Impaired)	0 0%	0 0%	1 3.8%
Score at Baseline=0 (Not Impaired)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mildly Impaired)	10 37%	4 28.6%	9 34.6%
Score at Baseline=2 (Moderately Impaired)	2 7.4%	3 21.4%	0 0%
Score at Baseline=3 (Severely Impaired)	0 0%	0 0%	0 0%
Score at Baseline=4 (Very Severely Impaired)	0 0%	0 0%	0 0%
Score at Baseline=0 (Not Impaired)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mildly Impaired)	4 14.8%	1 7.1%	3 11.5%
Score at Baseline=2 (Moderately Impaired)	9 33.3%	5 35.7%	8 30.8%
Score at Baseline=3 (Severely Impaired)	1 3.7%	0 0%	1 3.8%
Score at Baseline=4 (Very Severely Impaired)	0 0%	0 0%	1 3.8%
Score at Baseline=0 (Not Impaired)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mildly Impaired)	10 37%	3 21.4%	9 34.6%
Score at Baseline=2 (Moderately Impaired)	2 7.4%	2 14.3%	0 0%
Score at Baseline=3 (Severely Impaired)	0 0%	0 0%	1 3.8%
Score at Baseline=4 (Very Severely Impaired)	0 0%	0 0%	0 0%
Score at Baseline=0 (Not Impaired)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mildly Impaired)	4 14.8%	1 7.1%	4 15.4%
Score at Baseline=2 (Moderately Impaired)	7 25.9%	5 35.7%	8 30.8%
Score at Baseline=3 (Severely Impaired)	1 3.7%	0 0%	0 0%
Score at Baseline=4 (Very Severely Impaired)	0 0%	0 0%	1 3.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.406
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.235
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.225
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.434
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.249
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.380
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

18. Secondary Outcome

Title	Number of Participants by PGI-S (Upper Extremity Functional Severity) Score Categories
Description	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.
Time Frame	Baseline and Weeks 2, 7, and 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	TAK-831 75 mg	TAK-831 300 mg
Arm/Group Description	TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks.	TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.	TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
Measure Participants	27	14	26
Score at Baseline=0 (Not Impaired)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mildly Impaired)	0 0%	1 7.1%	0 0%
Score at Baseline=2 (Moderately Impaired)	0 0%	0 0%	0 0%
Score at Baseline=3 (Severely Impaired)	0 0%	0 0%	0 0%
Score at Baseline=4 (Very Severely Impaired)	0 0%	0 0%	0 0%
Score at Baseline=0 (Not Impaired)	1 3.7%	1 7.1%	0 0%
Score at Baseline=1 (Mildly Impaired)	11 40.7%	2 14.3%	9 34.6%
Score at Baseline=2 (Moderately Impaired)	2 7.4%	1 7.1%	2 7.7%
Score at Baseline=3 (Severely Impaired)	0 0%	0 0%	3 11.5%
Score at Baseline=4 (Very Severely Impaired)	0 0%	0 0%	0 0%
Score at Baseline=0 (Not Impaired)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mildly Impaired)	1 3.7%	1 7.1%	5 19.2%
Score at Baseline=2 (Moderately Impaired)	11 40.7%	5 35.7%	6 23.1%
Score at Baseline=3 (Severely Impaired)	0 0%	0 0%	1 3.8%
Score at Baseline=4 (Very Severely Impaired)	0 0%	0 0%	0 0%
Score at Baseline=0 (Not Impaired)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mildly Impaired)	0 0%	0 0%	0 0%
Score at Baseline=2 (Moderately Impaired)	0 0%	1 7.1%	0 0%
Score at Baseline=3 (Severely Impaired)	0 0%	0 0%	0 0%
Score at Baseline=4 (Very Severely Impaired)	0 0%	0 0%	0 0%
Score at Baseline=0 (Not Impaired)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mildly Impaired)	1 3.7%	0 0%	0 0%
Score at Baseline=2 (Moderately Impaired)	0 0%	0 0%	0 0%
Score at Baseline=3 (Severely Impaired)	0 0%	0 0%	1 3.8%
Score at Baseline=4 (Very Severely Impaired)	0 0%	0 0%	0 0%
Score at Baseline=0 (Not Impaired)	1 3.7%	1 7.1%	0 0%
Score at Baseline=1 (Mildly Impaired)	8 29.6%	1 7.1%	9 34.6%
Score at Baseline=2 (Moderately Impaired)	2 7.4%	3 21.4%	5 19.2%
Score at Baseline=3 (Severely Impaired)	0 0%	0 0%	2 7.7%
Score at Baseline=4 (Very Severely Impaired)	0 0%	0 0%	0 0%
Score at Baseline=0 (Not Impaired)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mildly Impaired)	3 11.1%	3 21.4%	4 15.4%
Score at Baseline=2 (Moderately Impaired)	11 40.7%	4 28.6%	3 11.5%
Score at Baseline=3 (Severely Impaired)	0 0%	0 0%	0 0%
Score at Baseline=4 (Very Severely Impaired)	0 0%	0 0%	0 0%
Score at Baseline=0 (Not Impaired)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mildly Impaired)	0 0%	0 0%	0 0%
Score at Baseline=2 (Moderately Impaired)	0 0%	1 7.1%	0 0%
Score at Baseline=3 (Severely Impaired)	0 0%	0 0%	0 0%
Score at Baseline=4 (Very Severely Impaired)	0 0%	0 0%	0 0%
Score at Baseline=0 (Not Impaired)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mildly Impaired)	1 3.7%	0 0%	0 0%
Score at Baseline=2 (Moderately Impaired)	0 0%	0 0%	0 0%
Score at Baseline=3 (Severely Impaired)	0 0%	0 0%	0 0%
Score at Baseline=4 (Very Severely Impaired)	0 0%	0 0%	0 0%
Score at Baseline=0 (Not Impaired)	1 3.7%	0 0%	0 0%
Score at Baseline=1 (Mildly Impaired)	9 33.3%	2 14.3%	11 42.3%
Score at Baseline=2 (Moderately Impaired)	3 11.1%	1 7.1%	2 7.7%
Score at Baseline=3 (Severely Impaired)	0 0%	0 0%	3 11.5%
Score at Baseline=4 (Very Severely Impaired)	0 0%	0 0%	0 0%
Score at Baseline=0 (Not Impaired)	0 0%	0 0%	0 0%
Score at Baseline=1 (Mildly Impaired)	2 7.4%	2 14.3%	2 7.7%
Score at Baseline=2 (Moderately Impaired)	8 29.6%	7 50%	6 23.1%
Score at Baseline=3 (Severely Impaired)	0 0%	0 0%	0 0%
Score at Baseline=4 (Very Severely Impaired)	0 0%	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.422
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.226
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.639
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.094
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.516
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.266
	Comments	The p-value was obtained using the Cochran-Mantel-Haenszel row mean score test stratified by ambulation status at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments

19. Secondary Outcome

Title	Change From Baseline in the ADL Component Score for Upper Limb Function Items of the FARS
Description	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.
Time Frame	Baseline and Weeks 2, 7 and 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	TAK-831 75 mg	TAK-831 300 mg
Arm/Group Description	TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks.	TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.	TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
Measure Participants	27	14	26
Change from Baseline at Week 2	-0.21 (0.213)	-0.40 (0.308)	0.34 (0.212)
Change from Baseline at Week 7	-0.17 (0.202)	-0.14 (0.289)	0.16 (0.203)
Change from Baseline at Week 12	-0.15 (0.240)	-0.05 (0.345)	0.19 (0.240)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change from Baseline at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.299
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.19
	Confidence Interval	(2-Sided) 90%; -0.80 to 0.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.362
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change from Baseline at Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.967
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.55
	Confidence Interval	(2-Sided) 90%; 0.06 to 1.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.293
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change from Baseline at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.529
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 90%; -0.54 to 0.59
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.338
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change from Baseline at Week 7
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.880
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.33
	Confidence Interval	(2-Sided) 90%; -0.13 to 0.80
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.279
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	Change from Baseline at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.599
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.10
	Confidence Interval	(2-Sided) 90%; -0.58 to 0.79
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.408
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	Change from Baseline at Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.846
	Comments	P-values are 1-sided, with the alternative hypothesis that TAK-831 is superior to placebo in the clinically favorable direction.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.34
	Confidence Interval	(2-Sided) 90%; -0.21 to 0.90
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.333
	Estimation Comments

20. Secondary Outcome

Title	Number of Participants With at Least a 15 Percent (%) or at Least a 20% Reduction in 9-HPT Completion Time From Baseline
Description	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.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	TAK-831 75 mg	TAK-831 300 mg
Arm/Group Description	TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks.	TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.	TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
Measure Participants	27	14	26
At Least 15% Reduction from Baseline	3 11.1%	0 0%	0 0%
At Least 20% Reduction from Baseline	2 7.4%	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	At Least 15% Reduction from Baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments	P-value was from Fisher's exact test. Odds ratio was obtained from Cochran-Mantel-Haenszel with ambulation status at randomization as a stratification factor.
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.00
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	At Least 15% Reduction from Baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments	P-value was from Fisher's exact test. Odds ratio was obtained from Cochran-Mantel-Haenszel with ambulation status at randomization as a stratification factor.
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.00
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 75 mg
	Comments	At Least 20% Reduction from Baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments	P-value was from Fisher's exact test. Odds ratio was obtained from Cochran-Mantel-Haenszel with ambulation status at randomization as a stratification factor.
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.00
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, TAK-831 300 mg
	Comments	At Least 20% Reduction from Baseline
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.999
	Comments	P-value was from Fisher's exact test. Odds ratio was obtained from Cochran-Mantel-Haenszel with ambulation status at randomization as a stratification factor.
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.00
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	First dose of study drug to up to 17 days past last dose (up to 14.4 weeks)
Adverse Event Reporting Description	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.
Arm/Group Title	Placebo		TAK-831 75 mg		TAK-831 300 mg
Arm/Group Description	TAK-831 placebo-matching tablets, orally, twice daily for up to 12 weeks.		TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.		TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
All Cause Mortality
	Placebo		TAK-831 75 mg		TAK-831 300 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		0/14 (0%)		0/26 (0%)
Serious Adverse Events
	Placebo		TAK-831 75 mg		TAK-831 300 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		0/14 (0%)		0/26 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		TAK-831 75 mg		TAK-831 300 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/27 (77.8%)		10/14 (71.4%)		24/26 (92.3%)
Cardiac disorders
Angina pectoris	0/27 (0%)		1/14 (7.1%)		0/26 (0%)
Ear and labyrinth disorders
Vertigo	1/27 (3.7%)		1/14 (7.1%)		0/26 (0%)
Eye disorders
Altered visual depth perception	0/27 (0%)		1/14 (7.1%)		0/26 (0%)
Gastrointestinal disorders
Nausea	4/27 (14.8%)		1/14 (7.1%)		8/26 (30.8%)
Vomiting	3/27 (11.1%)		1/14 (7.1%)		1/26 (3.8%)
Abdominal discomfort	2/27 (7.4%)		1/14 (7.1%)		1/26 (3.8%)
Abdominal pain upper	1/27 (3.7%)		1/14 (7.1%)		1/26 (3.8%)
Constipation	2/27 (7.4%)		0/14 (0%)		1/26 (3.8%)
General disorders
Fatigue	4/27 (14.8%)		0/14 (0%)		3/26 (11.5%)
Pain	1/27 (3.7%)		0/14 (0%)		2/26 (7.7%)
Pyrexia	0/27 (0%)		0/14 (0%)		3/26 (11.5%)
Infections and infestations
Urinary tract infection	0/27 (0%)		0/14 (0%)		3/26 (11.5%)
Gastroenteritis viral	0/27 (0%)		0/14 (0%)		2/26 (7.7%)
Nasopharyngitis	2/27 (7.4%)		0/14 (0%)		0/26 (0%)
Sinusitis	0/27 (0%)		0/14 (0%)		2/26 (7.7%)
Upper respiratory tract infection	2/27 (7.4%)		0/14 (0%)		0/26 (0%)
Injury, poisoning and procedural complications
Fall	6/27 (22.2%)		1/14 (7.1%)		6/26 (23.1%)
Laceration	1/27 (3.7%)		1/14 (7.1%)		1/26 (3.8%)
Skin abrasion	2/27 (7.4%)		0/14 (0%)		1/26 (3.8%)
Head injury	1/27 (3.7%)		1/14 (7.1%)		0/26 (0%)
Metabolism and nutrition disorders
Decreased appetite	0/27 (0%)		1/14 (7.1%)		0/26 (0%)
Musculoskeletal and connective tissue disorders
Muscle spasms	2/27 (7.4%)		1/14 (7.1%)		1/26 (3.8%)
Arthralgia	1/27 (3.7%)		0/14 (0%)		2/26 (7.7%)
Back pain	1/27 (3.7%)		1/14 (7.1%)		1/26 (3.8%)
Flank pain	0/27 (0%)		1/14 (7.1%)		0/26 (0%)
Musculoskeletal pain	0/27 (0%)		1/14 (7.1%)		0/26 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic naevus	0/27 (0%)		1/14 (7.1%)		0/26 (0%)
Nervous system disorders
Headache	8/27 (29.6%)		4/14 (28.6%)		11/26 (42.3%)
Dizziness	2/27 (7.4%)		1/14 (7.1%)		1/26 (3.8%)
Aphonia	2/27 (7.4%)		0/14 (0%)		0/26 (0%)
Balance disorder	0/27 (0%)		0/14 (0%)		2/26 (7.7%)
Coordination abnormal	0/27 (0%)		1/14 (7.1%)		1/26 (3.8%)
Migraine	0/27 (0%)		1/14 (7.1%)		1/26 (3.8%)
Aphasia	0/27 (0%)		1/14 (7.1%)		0/26 (0%)
Hypoaesthesia	0/27 (0%)		1/14 (7.1%)		0/26 (0%)
Paraesthesia	0/27 (0%)		1/14 (7.1%)		0/26 (0%)
Tremor	0/27 (0%)		1/14 (7.1%)		0/26 (0%)
Visual field defect	0/27 (0%)		1/14 (7.1%)		0/26 (0%)
Renal and urinary disorders
Pollakiuria	0/27 (0%)		1/14 (7.1%)		1/26 (3.8%)
Urinary incontinence	2/27 (7.4%)		0/14 (0%)		0/26 (0%)
Micturition urgency	0/27 (0%)		1/14 (7.1%)		0/26 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	2/27 (7.4%)		1/14 (7.1%)		5/26 (19.2%)
Oropharyngeal pain	3/27 (11.1%)		1/14 (7.1%)		4/26 (15.4%)
Nasal congestion	1/27 (3.7%)		1/14 (7.1%)		4/26 (15.4%)
Rhinorrhoea	3/27 (11.1%)		0/14 (0%)		1/26 (3.8%)
Throat irritation	2/27 (7.4%)		0/14 (0%)		0/26 (0%)
Dysphonia	0/27 (0%)		1/14 (7.1%)		0/26 (0%)
Skin and subcutaneous tissue disorders
Eczema	0/27 (0%)		1/14 (7.1%)		0/26 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Generally, the PI may publish results of the study following the publication of results by the Sponsor.