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

Phase 2

Completed

• Conditions: Huntington Disease
• Interventions: Drug: PBT2; Drug: Placebo

• Registration Number: NCT01590888
• Lead Sponsor: Prana Biotechnology Limited

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2012-04
• Study First Submitted: 2012-04-18
• Study First Submitted QC: 2012-05-01
• Study First Posted: 2012-05-03
• Primary Completion: 2013-07
• Study Completion: 2014-02
• Results First Submitted: 2015-11-17
• Status Verified: 2016-06
• Results First Submitted QC: 2016-06-07
• Last Update Submitted: 2016-06-07
• Results First Posted: 2016-07-18
• Last Update Posted: 2016-07-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 109

Inclusion Criteria

• Patients who:

  1. Provide signed informed consent in accordance with local regulations.
  2. Have Huntington disease including clinical features of HD and a CAG repeat number ≥ 36.
  3. Have a Total Functional Capacity between 6 and 13, inclusive.
  4. Have cognitive impairment as demonstrated by a MoCA score of ≥ 12.
  5. Are ≥ 25 years of age.
  6. If taking tetrabenazine, have been on a stable dose for at least 3 months.
  7. If female, are either a) of childbearing potential and compliant in using adequate birth control or b) not of childbearing potential.
  8. If male, is either a) of reproductive potential and compliant in using adequate birth control or b) not of reproductive potential.
  9. 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.
  10. Are able to swallow oral capsules.
  11. 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:

  1. Have an allergy to PBT2 or its excipients.
  2. Have other known primary neurodegenerative disorders associated with dementia.
  3. Have known dementia syndromes due to non-primary CNS disease.
  4. Have another condition that in the investigator's judgment is resulting in clinically significant cognitive impairment.
  5. In the opinion of the investigator, have any clinically significant uncontrolled medical or psychiatric illness, including history of seizures.
  6. 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.
  7. Have a calculated creatinine clearance at Screening of <50mL/min.
  8. Have a history of malignancy diagnosed within 2 years of Screening.
  9. Are pregnant or lactating females.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
PBT2 250mg	PBT2	-
PBT2 100mg	PBT2	-
Sugar pill	Placebo	-

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Cognitive Test Battery - Composite z Scores	Baseline to 26 weeks	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.
Change From Baseline in Motor Function	Baseline to 26 weeks	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).
Change From Baseline in Functional Abilities	Baseline to 26 weeks	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.
Change From Baseline in Behaviour	Baseline to 26 weeks	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.
Change From Baseline in Investigator Global Assessments by Efficacy Index	Baseline to 26 weeks	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.
Change From Baseline in Blood Biomarkers	Baseline to 26 weeks	Biomarkers assessed primarily with soluble huntingtin protein, normalised to lysate protein concentrations, as a change from baseline.
Change From Baseline in Brain Function (MRI)	Baseline to 26 weeks	Measure of the structural brain volume as assessed by the left caudate volume.
Change From Baseline in Blood Biomarkers - Selenium	Baseline to 26 weeks	Biomarkers assessed primarily with plasma selenium as a change from baseline.
Change From Baseline in Urine Biomarkers	Baseline to 26 weeks	Biomarkers assessed primarily with 8-hydroxy-2'-deoxyguanosine, normalised to creatinine concentrations, as a change from baseline.
Change From Baseline in Cognitive Test Battery - TMT Part B	Baseline to 26 weeks	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.

Trial Locations

Locations (19)

University of Tennessee Health Science Center; 🇺🇸 Memphis, Tennessee, United States

Royal Melbourne Hospital; 🇦🇺 Parkville, Victoria, Australia

University of Miami; 🇺🇸 Miami, Florida, United States

University of Connecticut Health Center; 🇺🇸 Farmington, Connecticut, United States

Colorado Neurological Institute; 🇺🇸 Englewood, Colorado, United States

University of California San Diego; 🇺🇸 San Diego, California, United States

University of Maryland School of Medicine; 🇺🇸 Baltimore, Maryland, United States

Struthers Parkinson's Center; 🇺🇸 Golden Valley, Minnesota, United States

Washington University; 🇺🇸 St. Louis, Missouri, United States

Ohio State University Medical Center; 🇺🇸 Columbus, Ohio, United States

Columbia University Medical Center; 🇺🇸 New York City, New York, United States

Johns Hopkins University; 🇺🇸 Baltimore, Maryland, United States

Neurodegenerative Disorders Research; 🇦🇺 Perth, Western Australia, Australia

Albany Medical College; 🇺🇸 Albany, New York, United States

Massachusetts General Hospital East; 🇺🇸 Charlestown, Massachusetts, United States

Booth Gardner Parkinson's Care Center; 🇺🇸 Kirkland, Washington, United States

Calvary Health Care Bethlehem; 🇦🇺 Clayton, Victoria, Australia

University of Melbourne Normanby Unit - St Vincents/St Georges; 🇦🇺 Melbourne, Victoria, Australia

Westmead Hospital; 🇦🇺 Sydney, New South Wales, Australia