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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01590888

Acronym

Reach2HD

Enrollment

109

Registered

2012-05-03

Start date

2012-04-30

Completion date

2014-02-28

Last updated

2016-07-18

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Huntington Disease

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.

Interventions

DRUGPBT2

250mg capsules administered orally once per day for 26 weeks

DRUGPlacebo

Matching capsules administered orally once per day for 26 weeks

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

25 Years to No maximum

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.

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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 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 Brain Function (MRI)	Baseline to 26 weeks	Measure of whole brain iron concentrations.
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.
Change From Baseline in Blood Biomarkers	Baseline to 26 weeks	Biomarkers assessed primarily with mutant huntingtin protein, normalised to lysate protein concentrations, as a change from baseline.

Countries

Australia, United States

Participant flow

Recruitment details

Twenty sites were initiated for the study, with participants enrolled at 14 sites in the US and 5 sites in Australia.

Participants by arm

Arm	Count
PBT2 250mg PBT2: 250mg capsules administered orally once per day for 26 weeks	36
PBT2 100mg PBT2: 100mg capsules administered orally once per day for 26 weeks	38
Sugar Pill Placebo: Matching capsules administered orally once per day for 26 weeks	35
Total	109

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Adverse Event	3	0	1
Overall Study	Lost to Follow-up	1	0	0

Baseline characteristics

Characteristic	PBT2 250mg	Total	Sugar Pill	PBT2 100mg
Age, Continuous	50.3 years STANDARD_DEVIATION 10.4	51.9 years STANDARD_DEVIATION 11	51.2 years STANDARD_DEVIATION 10.4	54.1 years STANDARD_DEVIATION 12.1
Body Mass Index	25.51 kg/m^2 STANDARD_DEVIATION 4.89	25.98 kg/m^2 STANDARD_DEVIATION 5.18	27.09 kg/m^2 STANDARD_DEVIATION 6.03	25.40 kg/m^2 STANDARD_DEVIATION 4.53
CAG Larger Allele Repeat Length	44.4 CAG repeats STANDARD_DEVIATION 4.6	43.9 CAG repeats STANDARD_DEVIATION 3.8	44.1 CAG repeats STANDARD_DEVIATION 3.9	43.2 CAG repeats STANDARD_DEVIATION 2.8
CAG Smaller Allele Repeat Length	18.8 CAG repeats STANDARD_DEVIATION 4.4	19.1 CAG repeats STANDARD_DEVIATION 4.1	20.0 CAG repeats STANDARD_DEVIATION 4.8	18.5 CAG repeats STANDARD_DEVIATION 3
Disease Burden	411.68 CAG repeats*years STANDARD_DEVIATION 104.96	404.49 CAG repeats*years STANDARD_DEVIATION 103.06	410.07 CAG repeats*years STANDARD_DEVIATION 110.02	392.54 CAG repeats*years STANDARD_DEVIATION 96.1
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants	2 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	34 Participants	107 Participants	35 Participants	38 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants	1 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	35 Participants	108 Participants	35 Participants	38 Participants
Region of Enrollment Australia	10 participants	30 participants	10 participants	10 participants
Region of Enrollment United States	26 participants	79 participants	25 participants	28 participants
Sex: Female, Male Female	17 Participants	55 Participants	19 Participants	19 Participants
Sex: Female, Male Male	19 Participants	54 Participants	16 Participants	19 Participants
Total Function Capacity	9.1 units on a scale STANDARD_DEVIATION 2.2	9.2 units on a scale STANDARD_DEVIATION 2	9.3 units on a scale STANDARD_DEVIATION 1.6	9.3 units on a scale STANDARD_DEVIATION 2.3

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	3 / 36	3 / 38	2 / 35
serious Total, serious adverse events	5 / 36	2 / 38	1 / 35

Outcome results

Primary

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,