A Study of Pridopidine (ACR16) for the Treatment of Participants With Huntington's Disease

Study Overview
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Brief Summary
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The purpose of this study is to determine if ACR16 is effective and safe in the symptomatic treatment of Huntington's Disease.

Official Title
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A Multi-center, North American, Randomized, Double-blind, Parallel Group Study Comparing Three Doses of ACR16 Versus Placebo for the Symptomatic Treatment of Huntington Disease (HART)

Conditions
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Huntington Disease

Intervention / Treatment
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* Drug: ACR16
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to provide written Informed Consent prior to any study related procedure, including consent to genotyping of the CYP2D6 gene. Clinical features of HD, and a positive family history and/or the presence of ≥ 36 CAG repeats in the Huntington gene. Male or female age ≥ 30 years. Willing and able to take oral medication and to comply with the study specific procedures. Ambulatory, being able to travel to the assessment center, and judged by the Investigator as likely to be able to continue to travel for the duration of the study. Availability of a caregiver or family member to accompany the participant to two visits. A sum of ≥ 10 points on the mMS at the screening visit. For participants taking allowed antidepressants or other psychotropic medication , the dosing of medication must have been kept constant for at least 6 weeks before baseline visit. Exclusion Criteria: Treatment with any antipsychotic medication (neuroleptics) within 8 weeks of baseline visit, or at any time point during the study period. Use of tetrabenazine within 12 weeks of baseline visit, or at any time during the study period. Treatment with any investigational product within 4 weeks of baseline visit. Use of tricyclic antidepressants or class I antiarrhythmics within 6 weeks of baseline visit, or at any time during the study period. Use of concomitant medication that may lower the seizure threshold within 6 weeks of baseline visit, or at any time during the study period . Use of metoclopramide within 12 weeks of baseline visit, or at any time during the study period. Participants currently receiving deep brain stimulation (DBS). Participants with a history of surgical procedures aiming to improve the symptoms of Huntington disease, such as neural transplantations, lesions of the central nervous system, infusions of neurotrophic agents or previous attempts of deep brain stimulation. Participants previously randomized into this study. A prolonged QTc interval at Screening Visit (defined as a QTc interval of > 450 milliseconds [msec] for males or > 470 msec for females), or other clinically significant heart conditions as judged by the investigator. Creatinine clearance <40 milliliters (mL)/minute (min) as measured at the screening visit. Any clinically significant, abnormal, baseline laboratory result which in the opinion of the Investigator, affects the participant' suitability for the study or puts the participant at risk if he/she enters the study. Clinically significant hepatic or renal impairment. Participants with a known history of epilepsy or a history of febrile seizure(s) or seizure(s) of unknown cause. Severe intercurrent illness, which, in the opinion of the Investigator, may put the participant at risk when participating in the trial or may influence the results of the trial or affect the subjects' ability to take part in the trial. Alcohol and/or drug abuse as defined by Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM IV-TR) criteria for Substance Abuse - this includes the illicit use of cannabis within the last 12 months prior to Screening Visit Participants with suicidal ideation as defined as a positive score on criteria for major depressive episode, item A9 on the DSM -IV-TR criteria for a Major Depressive Episode Females who are pregnant or lactating or who intend to become pregnant during the study period. Females who are of child bearing potential and not taking adequate contraceptive precautions are excluded from the trial. (Females of childbearing potential taking acceptable contraceptive precautions can be included) Known allergy to any ingredients of the trial medication or placebo Any previous participation in a clinical study with ACR16.

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants will receive a placebo capsule once daily for the first 4 weeks. After 4 weeks (Weeks 5 to 12), placebo capsule will be taken twice daily (BID) as 2 separate doses. | Other: Placebo<br>* Placebo matching to ACR16 will be administered per schedule specified in the arm description.<br>|
| Experimental: ACR16 10 mg BID<br>Participants will receive ACR16 10 milligrams (mg) capsule orally once daily for the first 4 weeks. After 4 weeks (Weeks 5 to 12), ACR16 10 mg capsule will be taken twice daily (BID) as 2 separate doses (total dose: 20 mg). | Drug: ACR16<br>* ACR16 will be administered per dose and schedule specified in the arm description.<br>* Other names: pridopidine;|
| Experimental: ACR16 22.5 mg BID<br>Participants will receive ACR16 22.5 mg capsule orally once daily for the first 4 weeks. After 4 weeks (Weeks 5 to 12), ACR16 22.5 mg capsule will be taken twice daily (BID) as 2 separate doses (total dose: 45 mg). | Drug: ACR16<br>* ACR16 will be administered per dose and schedule specified in the arm description.<br>* Other names: pridopidine;|
| Experimental: ACR16 45 mg BID<br>Participants will receive ACR16 45 mg capsule once daily for the first 4 weeks. After 4 weeks (Weeks 5 to 12), ACR16 45 mg capsule will be taken twice daily (BID) as 2 separate doses (total dose: 90 mg). | Drug: ACR16<br>* ACR16 will be administered per dose and schedule specified in the arm description.<br>* Other names: pridopidine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Modified Motor Score (mMS) (Sum of Score of Items 4-10 and 13-15 of the UHDRS Motor Assessments) at Week 12 | The mMS is a subscale of the UHDRS total motor score and comprises 13 responses from the 10 items, 4-10 and 13-15, from the UHDRS motor assessment. The items for mMS included dysarthria, tongue protrusion, finger taps (right and left), pronate/supinate hands (right and left), luria - first-hand-palm sequencing, arms rigidity (right and left), body bradykinesia, gait, tandem walking, and retropulsion pull test. Each of these items were rated on a scale of 0 (normal) to 4 (marked impairment). Total score ranged from 0 to 52, with higher scores indicating more severe motor impairment. The last observation carried forward (LOCF) method was used to generate an mMS score for each participant for Week 12 assessment. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Total Motor Score (TMS) | The UHDRS Motor Assessment comprises 31 responses from the 15 items, where each response is rated on a 5-point scale from 0 (normal) to 4 (maximally abnormal). The Total Motor Score (TMS) is the sum of all the 31 responses with higher scores indicating more severe motor impairment than lower scores. | Basline, Week 12 | 
| Number of Participants in Each of the Ratings of the Clinical Global Impression of Change (CGI-C) Scale | The CGI-C was rated by the investigator on a 7-point scale as: 1 = Very much improved; 2 = Much improved; 3 = Minimally improved; 4 = No change; 5 = Minimally worse; 6 = Much worse; and 7 = Very much worse. | Week 12 | 
| Change From Baseline in Stroop Word Reading Test | The Stroop test measures the ability to concentrate and ward off distractions. The test consists of three items: (i) colour naming; (ii) word reading; (iii) interference. The word reading test requires participants to read colour words written in black and each response is scored as the number of correct answers made in 45 seconds. Higher scores indicate less severe disease, and an increase in score represents an improvement. | Baseline, Week 12 | 
| Change From Baseline in Total UHDRS Behavioral Assessment Score | The total behavioral assessment score is the sum of the 11 products (depressed mood, apathy, low self-esteem/guilt, compulsive behavior, anxiety, irritable behavior, perseverative/obsessive thinking, disruptive/aggressive behavior, suicidal thoughts, delusions, and hallucinations) of frequency and severity symptom scores and excluded the 3 yes/no questions relating to confusion, dementia, and depression. Frequency is rated on a scale of 0 (never or almost never) to 4 (very frequently, most of the time). Severity is rated on a scale of 0 (no evidence) to 4 (severe). Total behavior score ranges from 0 (no impairment) to 88 (severe impairment), with higher scores indicating greater behavioral impairments. | Baseline, Week 12 | 
| Change From Baseline in Total Hospital Anxiety and Depression Scale (HADS) Score | HADS is a self-administered instrument reliable for detecting states of depression and anxiety. It includes 2 subscales: Hospital Anxiety and Depression Scale - anxiety (HADS-A) assesses state of generalized anxiety (anxious mood, restlessness, anxious thoughts, panic attacks); Hospital Anxiety and Depression Scale - depression (HADS-D) assesses state of lost interest and diminished pleasure response (lowering of hedonic tone). Each subscale is comprised of 7 items with range 0 (no presence of anxiety or depression) to 3 (severe feeling of anxiety or depression). Total score ranges from 0 to 21 for each subscale where higher scores indicate greater severity of anxiety and depression symptoms. The total HADS score was a composite score summed of all 14 items for a total range of 0-42. Lower change from baseline scores indicate improvement. | Baseline, Week 12 | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | An adverse event (AE) was defined as any change from the participant's baseline (pre-treatment) condition, other than improvement, that did not necessarily have causal relationship with the study drug. TEAEs were defined as adverse events that began after ACR16/placebo administration. AEs included both SAEs and non-serious AEs. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'. | Baseline up to Week 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Huntington Disease