Effect of PBT2 in Patients With Early to Mid Stage Huntington Disease

Study Overview
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Brief Summary
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Huntington disease (HD) is an inherited neurodegenerative disease which affects over 30,000 people in both the United States and Australia. HD is characterized by brain cell death that usually begins between the ages of 30 to 50, and results in motor, cognitive and behavioral signs and symptoms. While there are medications to help relieve some of the disease symptoms, there is no known treatment to address the cognitive impairment associated with HD. Normally occurring metals in the brain play a significant role in diseases such as Alzheimer disease and HD. PBT2 is a drug designed to interrupt interactions between these biological metals and target proteins in the brain, to prevent deterioration of brain cells. PBT2, has shown in animal models, and as well as in a small group of patients with Alzheimer's disease, it may improve cognition. There is some indication in animal models of HD, that the drug may improve motor function and control and reduce the amount of brain cell degeneration. PBT2-203 will evaluate how safe and well tolerated PBT2 is at a dose of 100 mg or 250 mg a day administered as oral daily capsules compared to a placebo over a six month treatment period. The trial will also measure whether there is an effect on cognitive abilities as well as other HD symptoms including motor and overall functioning of individuals with HD.

Official Title
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A Randomized, Double-blind, Placebo-controlled Study to Assess the Safety and Tolerability, and Efficacy of PBT2 in Patients With Early to Mid-stage Huntington Disease

Conditions
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Huntington Disease

Intervention / Treatment
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* Drug: PBT2
* Drug: PBT2
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who: Provide signed informed consent in accordance with local regulations. Have Huntington disease including clinical features of HD and a CAG repeat number ≥ 36. Have a Total Functional Capacity between 6 and 13, inclusive. Have cognitive impairment as demonstrated by a MoCA score of ≥ 12. Are ≥ 25 years of age. If taking tetrabenazine, have been on a stable dose for at least 3 months. If female, are either a) of childbearing potential and compliant in using adequate birth control or b) not of childbearing potential. If male, is either a) of reproductive potential and compliant in using adequate birth control or b) not of reproductive potential. Have a study partner who is willing to provide consent and spends on average at least two hours a day for at least four days a week with the patient, is fluent in the English language, and who agrees to attend certain study visits and provide accurate information about the patient. Are able to swallow oral capsules. Are fluent in the English language for the administration of rating scales and have sufficient visual, hearing and motor skills to complete procedures. Exclusion Criteria: Patients who: Have an allergy to PBT2 or its excipients. Have other known primary neurodegenerative disorders associated with dementia. Have known dementia syndromes due to non-primary CNS disease. Have another condition that in the investigator's judgment is resulting in clinically significant cognitive impairment. In the opinion of the investigator, have any clinically significant uncontrolled medical or psychiatric illness, including history of seizures. Have clinically significant cardiovascular, hepatic, renal, pulmonary, metabolic or endocrine disease that, in the opinion of the investigator, would interfere with an individual's participation in the study. Have a calculated creatinine clearance at Screening of <50mL/min. Have a history of malignancy diagnosed within 2 years of Screening. Are pregnant or lactating females.

Ages Eligible for Study
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Minimum Age: 25 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 |
| --- | --- |
| Experimental: PBT2 250mg<br> | Drug: PBT2<br>* 250mg capsules administered orally once per day for 26 weeks<br>|
| Experimental: PBT2 100mg<br> | Drug: PBT2<br>* 100mg capsules administered orally once per day for 26 weeks<br>|
| Placebo Comparator: Sugar pill<br> | Drug: Placebo<br>* Matching capsules administered orally once per day for 26 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of PBT2 in Patients With HD | As measured by the total number of participants in each dose group who reported at least one adverse events during the study, | Baseline to 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Cognitive Test Battery - Composite z Scores | Cognition composite z-scores were calculated for each participant. The composite scores were defined as the mean of the individual z-scores for the various cognition assessments. The Main Composite z-score was calculated for Category Fluency Test, Trail Making Test Part B, Map Search, Symbol Digit Modalities Test and Stroop Word Reading Test. The Exploratory Composite z-score was calculated for Category Fluency Test, Trail Making Test Part B, Map Search, Symbol Digit Modalities Test, Stroop Word Reading Test and Speeded Tapping test. The Executive Function Composite z-score was calculated from Category Fluency Test and Trail Making Test Part B. There is no unit of measure for the z score as it is the pure number calculated from the SD from the mean. A higher z score indicates an improvement. | Baseline to 26 weeks | 
| Change From Baseline in Motor Function | Total motor score calculated from the Unified Huntington Disease Rating Scale - Motor Function. The motor section of the UHDRS assesses motor features of HD with standardized ratings of oculomotor function, dysarthria, chorea, dystonia, gait, and postural stability. The total motor impairment scores is the sum of all the individual motor ratings, with higher scores indicating more severe motor impairment than lower scores. A maximum score of 60 is possible (range 0-60). | Baseline to 26 weeks | 
| Change From Baseline in Functional Abilities | Total Functional Capacity (TFC) assessment was based on an individual's ability to perform common daily tasks. TFC score range was 0 to 13. Higher scores on the function scales indicate better functioning than lower scores. | Baseline to 26 weeks | 
| Change From Baseline in Behaviour | Total Behavioural score from the Unified Huntington Disease Rating Scale. The behavioural assessment measures the frequency and severity of symptoms related to affect, thought content and coping styles. The total behaviour score is the sum of all responses, with scale range of 0 to 8. Higher scores on the behaviour assessments indicate more severe disturbance than lower scores. | Baseline to 26 weeks | 
| Change From Baseline in Investigator Global Assessments by Efficacy Index | Global function was assessed by the Investigator using the clinical global impression (CGI) scale which included assessing the severity of illness and global improvement and calculating the efficacy index for each participant. The efficacy index aims to relate therapeutic effects to reported side effects as assessed by the Investigator (range from 0 [marked improvement and no side effects] to 4 [unchanged or worse] and side effects outweigh therapeutic effects) and is calculated for each participant by dividing the therapeutic effect score by the side effects score. An improvement is reflected by CGI scale Efficacy Index values >1. | Baseline to 26 weeks | 
| Change From Baseline in Blood Biomarkers | Biomarkers assessed primarily with mutant huntingtin protein, normalised to lysate protein concentrations, as a change from baseline. | Baseline to 26 weeks | 
| Change From Baseline in Brain Function (MRI) | Measure of whole brain iron concentrations. | Baseline to 26 weeks | 
| Change From Baseline in Blood Biomarkers | Biomarkers assessed primarily with soluble huntingtin protein, normalised to lysate protein concentrations, as a change from baseline. | Baseline to 26 weeks | 
| Change From Baseline in Blood Biomarkers - Selenium | Biomarkers assessed primarily with plasma selenium as a change from baseline. | Baseline to 26 weeks | 
| Change From Baseline in Urine Biomarkers | Biomarkers assessed primarily with 8-hydroxy-2'-deoxyguanosine, normalised to creatinine concentrations, as a change from baseline. | Baseline to 26 weeks | 
| Change From Baseline in Brain Function (MRI) | Measure of the structural brain volume as assessed by the left caudate volume. | Baseline to 26 weeks | 
| Change From Baseline in Cognitive Test Battery - TMT Part B | Trail Making Test Part B was assessed by the number of seconds to complete the test (from 0 to 240 seconds). The Trails Making Test Part B actual change from baseline at Week 26 was analysed. | Baseline to 26 weeks |