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

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ClinicalTrials.gov Identifier: NCT03214588
Recruitment Status : Active, not recruiting
First Posted : July 11, 2017
Last Update Posted : October 2, 2018
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.


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
Estimated Primary Completion Date : January 4, 2019
Estimated Study Completion Date : January 4, 2019


Arm Intervention/treatment
Experimental: TAK-831 High Dose
TAK-831 300 mg, tablets, orally, twice daily for up to 12 weeks.
Drug: TAK-831
TAK-831 tablets

Experimental: TAK-831 Low Dose
TAK-831 75 mg, tablets, orally, twice daily for up to 12 weeks.
Drug: TAK-831
TAK-831 tablets

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




Primary Outcome Measures :
  1. Change from Baseline in Inverse Time to Complete 9-Hole Peg Test (9-HPT-1) at Week 12 [ 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.


Secondary Outcome Measures :
  1. Change from Baseline on the Activities of Daily Living (ADL) Component of the Friedreich Ataxia Rating Scale (FARS) [ Time Frame: Baseline and Week 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.

  2. Change from Baseline on the 9-HPT-1 [ Time Frame: Baseline and Week 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.

  3. Change from Baseline on the ADL Individual Items [ Time Frame: Baseline and Week 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.

  4. Change from Baseline on the Modified Friedreich Ataxia Rating Scale Neurological Examination (mFARS-neuro) Total Score [ Time Frame: Baseline and Week 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.

  5. Change from Baseline on the mFARS-neuro Subscales and Individual Items [ Time Frame: Baseline and Week 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.

  6. Change from Baseline on the Timed 25-Foot Walk (T25FW) [ Time Frame: Baseline and Week 2, 7, and 12 ]
    The participant is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the instruction to start and ends when the participant has reached the 25-foot mark. The task is immediately administered again by having the participant walk back the same distance.

  7. Change from Baseline on the 9-HPT and T25FW Composite Score [ Time Frame: Baseline and Week 2, 7, and 12 ]
    9-HPT and T25FW will be evaluated together as a performance-based composite measure. The inverse transform of each score will be computed. The inverse scores from each test are 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 will be created by averaging the Z scores of the individual components. A larger Z-score represents a better outcome.

  8. Change from Baseline on Low-Contrast Letter Acuity (LCLA) Test Score [ Time Frame: Baseline and Week 2, 7, and, 12 ]
    The LCLA test assesses visual function in both eyes using the Low-Contrast Sloan Letter Charts at different contrast levels. The score ranges from 0 to 70, where 0=worst visual functioning and 70=best visual functioning.

  9. Clinical Global Impression-Improvement (CGI-I) (Global Change) [ Time Frame: Week 2, 7, and 12 ]
    The clinician uses the CGI-I scale to assess the participant's improvement (or worsening) overall relative to Baseline on a 7-point scale where 1=very much improved to 7=very much worse.

  10. Patient Global Impression-Improvement (PGI-I) (Global Change) [ Time Frame: Week 2, 7, and 12 ]
    The participant uses the PGI-I scale to assess their improvement (or worsening) overall relative to Baseline on a 7-point scale where 1=very much improved to 7=very much worse.

  11. CGI-I (Upper Extremity Functional Change) [ Time Frame: Week 2, 7, and 12 ]
    The clinician uses 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=very much improved to 7=very much worse.

  12. PGI-I (Upper Extremity Functional Change) [ Time Frame: Week 2, 7, and 12 ]
    The participant uses the PGI-I scale to assess their improvement (or worsening) in upper extremity function relative to Baseline on a 7-point scale where 1=very much improved to 7=very much worse.

  13. Change from Baseline on Clinical Global Impression-Severity (CGI-S) (Global Severity) [ Time Frame: Baseline and Week 2, 7, and 12 ]
    The clinician uses the CGI-S scale to assess the severity of the participant's disease overall on a 7-point scale where 1=normal to 7=extremely severe.

  14. Change from Baseline on Patient Global Impression-Severity (PGI-S) (Global Severity) [ Time Frame: Baseline and Week 2, 7, and 12 ]
    The participant assesses the severity of their disease overall using the PGI-S 7-point scale where 1=normal to 7=extremely severe.

  15. Change from Baseline on CGI-S (Upper Extremity Functional Severity) [ Time Frame: Baseline and Week 2, 7, and 12 ]
    The clinician uses the CGI-S scale to assess the severity of the participant's upper extremity function on a 7-point scale where 1=normal to 7=extremely severe.

  16. Change from Baseline on PGI-S (Upper Extremity Functional Severity) [ Time Frame: Baseline and Week 2, 7, and 12 ]
    The participant assesses the severity of their upper extremity function using the PGI-S 7-point scale where 1=normal to 7=extremely severe.

  17. Change from Baseline on the ADL Component of the Upper Limb Function items of the FARS [ Time Frame: Baseline and Week 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 36, with higher scores representing greater disability/dependency.

  18. Percentage of Participants with 15 Percent (%) and at Least 20% Reduced 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.


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
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
Study Director: Medical Director Clinical Science Takeda

Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT03214588     History of Changes
Other Study ID Numbers: TAK-831-1501
U1111-1189-7951 ( Registry Identifier: WHO )
First Posted: July 11, 2017    Key Record Dates
Last Update Posted: October 2, 2018
Last Verified: September 2018

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:
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