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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03214588
Recruitment Status : Completed
First Posted : July 11, 2017
Results First Posted : December 19, 2019
Last Update Posted : December 19, 2019
Sponsor:
Information provided by (Responsible Party):
Takeda

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.

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Study Type : Interventional  (Clinical Trial)
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 : November 8, 2017
Actual Primary Completion Date : December 27, 2018
Actual Study Completion Date : December 27, 2018


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




Primary Outcome Measures :
  1. Change From Baseline in the Inverse Time to Complete the 9-Hole Peg Test (9-HPT-1) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03214588


Locations
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United States, California
UCLA Ataxia Center
Los Angeles, California, United States, 90095
United States, Florida
University of Florida Center for Movement Disorders
Gainesville, Florida, United States, 32607
USF College of Medicine
Tampa, Florida, United States, 33612
United States, Iowa
University of Iowa Children's Hospital
Iowa City, Iowa, United States, 52242
United States, Ohio
Ohio State University Wexner Medical Center
Columbus, Ohio, United States, 43220
United States, Pennsylvania
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
Takeda
Investigators
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Study Director: Medical Director Clinical Science Takeda
  Study Documents (Full-Text)

Documents provided by Takeda:
Study Protocol  [PDF] October 6, 2017
Statistical Analysis Plan  [PDF] February 1, 2019


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Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT03214588    
Other Study ID Numbers: TAK-831-1501
U1111-1189-7951 ( Registry Identifier: WHO )
First Posted: July 11, 2017    Key Record Dates
Results First Posted: December 19, 2019
Last Update Posted: December 19, 2019
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Takeda:
Drug Therapy
Additional relevant MeSH terms:
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Ataxia
Cerebellar Ataxia
Friedreich Ataxia
Dyskinesias
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Cerebellar Diseases
Brain Diseases
Central Nervous System Diseases
Spinocerebellar Degenerations
Spinal Cord Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Mitochondrial Diseases
Metabolic Diseases