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

Primary Purpose

Huntington Disease

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
PBT2
PBT2
Placebo
Sponsored by
Prana Biotechnology Limited
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Huntington Disease

Eligibility Criteria

25 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of California San Diego
  • Colorado Neurological Institute
  • University of Connecticut Health Center
  • University of Miami
  • University of Maryland School of Medicine
  • Johns Hopkins University
  • Massachusetts General Hospital East
  • Struthers Parkinson's Center
  • Washington University
  • Albany Medical College
  • Columbia University Medical Center
  • Ohio State University Medical Center
  • University of Tennessee Health Science Center
  • Booth Gardner Parkinson's Care Center
  • Westmead Hospital
  • Calvary Health Care Bethlehem
  • University of Melbourne Normanby Unit - St Vincents/St Georges
  • Royal Melbourne Hospital
  • Neurodegenerative Disorders Research

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Placebo Comparator

Arm Label

PBT2 250mg

PBT2 100mg

Sugar pill

Arm Description

Outcomes

Primary Outcome Measures

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,

Secondary Outcome Measures

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.
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).
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.
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.
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.
Change From Baseline in Blood Biomarkers
Biomarkers assessed primarily with mutant huntingtin protein, normalised to lysate protein concentrations, as a change from baseline.
Change From Baseline in Brain Function (MRI)
Measure of whole brain iron concentrations.
Change From Baseline in Blood Biomarkers
Biomarkers assessed primarily with soluble huntingtin protein, normalised to lysate protein concentrations, as a change from baseline.
Change From Baseline in Blood Biomarkers - Selenium
Biomarkers assessed primarily with plasma selenium as a change from baseline.
Change From Baseline in Urine Biomarkers
Biomarkers assessed primarily with 8-hydroxy-2'-deoxyguanosine, normalised to creatinine concentrations, as a change from baseline.
Change From Baseline in Brain Function (MRI)
Measure of the structural brain volume as assessed by the left caudate volume.
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.

Full Information

First Posted
April 18, 2012
Last Updated
June 7, 2016
Sponsor
Prana Biotechnology Limited
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1. Study Identification

Unique Protocol Identification Number
NCT01590888
Brief Title
Effect of PBT2 in Patients With Early to Mid Stage Huntington Disease
Acronym
Reach2HD
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2016
Overall Recruitment Status
Completed
Study Start Date
April 2012 (undefined)
Primary Completion Date
July 2013 (Actual)
Study Completion Date
February 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Prana Biotechnology Limited

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Huntington Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
109 (Actual)

8. Arms, Groups, and Interventions

Arm Title
PBT2 250mg
Arm Type
Experimental
Arm Title
PBT2 100mg
Arm Type
Experimental
Arm Title
Sugar pill
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
PBT2
Intervention Description
250mg capsules administered orally once per day for 26 weeks
Intervention Type
Drug
Intervention Name(s)
PBT2
Intervention Description
100mg capsules administered orally once per day for 26 weeks
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Matching capsules administered orally once per day for 26 weeks
Primary Outcome Measure Information:
Title
Safety and Tolerability of PBT2 in Patients With HD
Description
As measured by the total number of participants in each dose group who reported at least one adverse events during the study,
Time Frame
Baseline to 26 weeks
Secondary Outcome Measure Information:
Title
Change From Baseline in Cognitive Test Battery - Composite z Scores
Description
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.
Time Frame
Baseline to 26 weeks
Title
Change From Baseline in Motor Function
Description
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).
Time Frame
Baseline to 26 weeks
Title
Change From Baseline in Functional Abilities
Description
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.
Time Frame
Baseline to 26 weeks
Title
Change From Baseline in Behaviour
Description
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.
Time Frame
Baseline to 26 weeks
Title
Change From Baseline in Investigator Global Assessments by Efficacy Index
Description
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.
Time Frame
Baseline to 26 weeks
Title
Change From Baseline in Blood Biomarkers
Description
Biomarkers assessed primarily with mutant huntingtin protein, normalised to lysate protein concentrations, as a change from baseline.
Time Frame
Baseline to 26 weeks
Title
Change From Baseline in Brain Function (MRI)
Description
Measure of whole brain iron concentrations.
Time Frame
Baseline to 26 weeks
Title
Change From Baseline in Blood Biomarkers
Description
Biomarkers assessed primarily with soluble huntingtin protein, normalised to lysate protein concentrations, as a change from baseline.
Time Frame
Baseline to 26 weeks
Title
Change From Baseline in Blood Biomarkers - Selenium
Description
Biomarkers assessed primarily with plasma selenium as a change from baseline.
Time Frame
Baseline to 26 weeks
Title
Change From Baseline in Urine Biomarkers
Description
Biomarkers assessed primarily with 8-hydroxy-2'-deoxyguanosine, normalised to creatinine concentrations, as a change from baseline.
Time Frame
Baseline to 26 weeks
Title
Change From Baseline in Brain Function (MRI)
Description
Measure of the structural brain volume as assessed by the left caudate volume.
Time Frame
Baseline to 26 weeks
Title
Change From Baseline in Cognitive Test Battery - TMT Part B
Description
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.
Time Frame
Baseline to 26 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
25 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ray Dorsey
Organizational Affiliation
Johns Hopkins University
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California San Diego
City
San Diego
State/Province
California
ZIP/Postal Code
92161
Country
United States
Facility Name
Colorado Neurological Institute
City
Englewood
State/Province
Colorado
ZIP/Postal Code
80113
Country
United States
Facility Name
University of Connecticut Health Center
City
Farmington
State/Province
Connecticut
ZIP/Postal Code
06030
Country
United States
Facility Name
University of Miami
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
University of Maryland School of Medicine
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Massachusetts General Hospital East
City
Charlestown
State/Province
Massachusetts
ZIP/Postal Code
02129
Country
United States
Facility Name
Struthers Parkinson's Center
City
Golden Valley
State/Province
Minnesota
ZIP/Postal Code
55427
Country
United States
Facility Name
Washington University
City
St. Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Albany Medical College
City
Albany
State/Province
New York
ZIP/Postal Code
12208
Country
United States
Facility Name
Columbia University Medical Center
City
New York City
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Ohio State University Medical Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
University of Tennessee Health Science Center
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38163
Country
United States
Facility Name
Booth Gardner Parkinson's Care Center
City
Kirkland
State/Province
Washington
ZIP/Postal Code
98034
Country
United States
Facility Name
Westmead Hospital
City
Sydney
State/Province
New South Wales
ZIP/Postal Code
2145
Country
Australia
Facility Name
Calvary Health Care Bethlehem
City
Clayton
State/Province
Victoria
ZIP/Postal Code
3800
Country
Australia
Facility Name
University of Melbourne Normanby Unit - St Vincents/St Georges
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3101
Country
Australia
Facility Name
Royal Melbourne Hospital
City
Parkville
State/Province
Victoria
ZIP/Postal Code
3050
Country
Australia
Facility Name
Neurodegenerative Disorders Research
City
Perth
State/Province
Western Australia
ZIP/Postal Code
6008
Country
Australia

12. IPD Sharing Statement

Citations:
PubMed Identifier
18672400
Citation
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.
Results Reference
background
PubMed Identifier
20164561
Citation
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.
Results Reference
background
PubMed Identifier
25467848
Citation
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.
Results Reference
derived
PubMed Identifier
25063332
Citation
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.
Results Reference
derived

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

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