Effect of PBT2 in Patients With Early to Mid Stage Huntington Disease (Reach2HD)

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

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.

Study Overview

• Status: Completed
• Conditions: Huntington Disease
• Intervention / Treatment: Drug: PBT2; Drug: PBT2; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 109
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2145
      • Westmead Hospital
  • Victoria
    • Clayton, Victoria, Australia, 3800
      • Calvary Health Care Bethlehem
    • Melbourne, Victoria, Australia, 3101
      • University of Melbourne Normanby Unit - St Vincents/St Georges
    • Parkville, Victoria, Australia, 3050
      • Royal Melbourne Hospital
  • Western Australia
    • Perth, Western Australia, Australia, 6008
      • Neurodegenerative Disorders Research
• United States
  • California
    • San Diego, California, United States, 92161
      • University of California San Diego
  • Colorado
    • Englewood, Colorado, United States, 80113
      • Colorado Neurological Institute
  • Connecticut
    • Farmington, Connecticut, United States, 06030
      • University of Connecticut Health Center
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
    • Baltimore, Maryland, United States, 21201
      • University of Maryland School of Medicine
  • Massachusetts
    • Charlestown, Massachusetts, United States, 02129
      • Massachusetts General Hospital East
  • Minnesota
    • Golden Valley, Minnesota, United States, 55427
      • Struthers Parkinson's Center
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical College
    • New York City, New York, United States, 10032
      • Columbia University Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Medical Center
  • Tennessee
    • Memphis, Tennessee, United States, 38163
      • University of Tennessee Health Science Center
  • Washington
    • Kirkland, Washington, United States, 98034
      • Booth Gardner Parkinson's Care Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Sugar pill	Drug: Placebo; Matching capsules administered orally once per day for 26 weeks
Experimental: PBT2 250mg	Drug: PBT2; 250mg capsules administered orally once per day for 26 weeks; Drug: PBT2; 100mg capsules administered orally once per day for 26 weeks
Experimental: PBT2 100mg	Drug: PBT2; 250mg capsules administered orally once per day for 26 weeks; Drug: PBT2; 100mg capsules administered orally once per day for 26 weeks

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Prana Biotechnology Limited
• Investigators: Principal Investigator: Ray Dorsey, Johns Hopkins University

Publications and helpful links

General Publications

• Lannfelt L, Blennow K, Zetterberg H, Batsman S, Ames D, Harrison J, Masters CL, Targum S, Bush AI, Murdoch R, Wilson J, Ritchie CW; PBT2-201-EURO study group. Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2008 Sep;7(9):779-86. doi: 10.1016/S1474-4422(08)70167-4. Epub 2008 Jul 30. Erratum In: Lancet Neurol. 2009 Nov;8(11):981.
• Faux NG, Ritchie CW, Gunn A, Rembach A, Tsatsanis A, Bedo J, Harrison J, Lannfelt L, Blennow K, Zetterberg H, Ingelsson M, Masters CL, Tanzi RE, Cummings JL, Herd CM, Bush AI. PBT2 rapidly improves cognition in Alzheimer's Disease: additional phase II analyses. J Alzheimers Dis. 2010;20(2):509-16. doi: 10.3233/JAD-2010-1390.
• Huntington Study Group Reach2HD Investigators. Safety, tolerability, and efficacy of PBT2 in Huntington's disease: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2015 Jan;14(1):39-47. doi: 10.1016/S1474-4422(14)70262-5. Epub 2014 Nov 14.
• Cherny RA, Ayton S, Finkelstein DI, Bush AI, McColl G, Massa SM. PBT2 Reduces Toxicity in a C. elegans Model of polyQ Aggregation and Extends Lifespan, Reduces Striatal Atrophy and Improves Motor Performance in the R6/2 Mouse Model of Huntington's Disease. J Huntingtons Dis. 2012;1(2):211-9. doi: 10.3233/JHD-120029.

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): July 1, 2013
• Study Completion (Actual): February 1, 2014

Study Registration Dates

• First Submitted: April 18, 2012
• First Submitted That Met QC Criteria: May 1, 2012
• First Posted (Estimate): May 3, 2012

Study Record Updates

• Last Update Posted (Estimate): July 18, 2016
• Last Update Submitted That Met QC Criteria: June 7, 2016
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Genetic Diseases, Inborn; Basal Ganglia Diseases; Movement Disorders; Neurodegenerative Diseases; Dyskinesias; Heredodegenerative Disorders, Nervous System; Dementia; Cognition Disorders; Chorea; Huntington Disease
• Other Study ID Numbers: PBT2-203