A Randomised Controlled Trial, Of N-Acetyl Cysteine (NAC), for Premanifest Huntingtin Gene Expansion Carriers

Study Overview
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Brief Summary
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NAC-preHD is a phase II randomized placebo controlled study of oral NAC among premanifest HD gene expansion carriers, with clinical and radiological outcome at three years.

Official Title
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A Randomised Controlled Trial, Of N-Acetyl Cysteine (NAC), for Premanifest Huntingtin Gene Expansion Carriers

Conditions
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Huntington Disease

Intervention / Treatment
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* Drug: NAC
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to provide informed consent Huntingtin gene expansion carrier with >= 39 CAG repeats Absence of unequivocal motor signs of HD - that is, UHDRS Diagnostic Confidence Level needs to be <4 upon enrolment Expected to develop clinical HD within 10 years of trial enrolment using the Langbehn formula Availability of an informant for corroborative history Negative serum pregnancy test for women of childbearing potential If of childbearing potential, is able and agrees to remain abstinent or use adequate contraceptive methods Ability to tolerate MRI scans Ability to tolerate blood draws Able to comply with all study protocol requirements, according to the investigators judgement In the opinion of the investigator, medically, psychiatrically and neurologically stable at the time of enrolment Exclusion Criteria: Diagnosis of clinical HD Known hypersensitivity to NAC Pregnancy, breastfeeding or intention to do so prior to the end of the study Exposure to any investigational drugs within 30 days of Baseline Visit Use of supplemental NAC Abnormalities in laboratory measurements, ECG or vital signs at screening, which precludes safe participation in the study Current or history of substance abuse within one year of Baseline visit Unstable psychiatric or acute medical illness including cancer, as determined by investigator Current use of antipsychotic medications or Tetrabenazine History of gene therapy, cell transplantation, or any experimental brain surgery History of attempted suicide or suicidal ideation within 12 months prior to screening Pre-existing structural brain lesion as assessed by a centrally read MRI scan during the screening period

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: Participants will be randomly allocated to either the NAC arm or the placebo arm using Block Randomisation, stratified by site, through a centralised process, with allocation concealment.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NAC<br>1g N-Acetylcysteine capsules, taken orally twice a day. | Drug: NAC<br>* 1g of clinical grade N-Acetylcysteine capsules, taken orally twice a day<br>* Other names: N-Acetylcysteine;|
| Placebo Comparator: Placebo<br>Coated Placebo capsules, taken orally twice a day | Drug: Placebo<br>* Coated Placebo capsules, manufactured to match appearance and taste, taken orally twice a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Caudate Atrophy Rate on volumetric MRI | Blinded assessment | Baseline through end of study (up to 3 years) | 
| Rate of motor phenoconversion | Defined by conversion to Diagnostic Confidence Level 4, upon blinded assessment using the UHDRS motor subscale | Baseline through end of study (up to 3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| UHDRS motor subscale (total score) | Measuring changes in motor function | Baseline through end of study (up to 3 years) | 
| Stroop Word | Change in cognition as measured by Stroop Word | Baseline through end of study (up to 3 years) | 
| Trail Making Test | Change in cognition as measured by Trail Making Test | Baseline through end study (up to 3 years) | 
| Montreal Cognitive Assessment | Change in cognition as measured by Montreal Cognitive Assessment | Baseline through end of study (up to 3 years) | 
| Symbol Digit Modality Test | Change in cognition as measured by Symbol Digit Modality Test | Baseline through end of study (up to 3 years) | 
| Changes in Mood and Behavioural symptoms | Evaluated using the PBA-s, a semi-structured interview behavioural scale | Baseline through end of study (up to 3 years) | 
| Changes in Daily Function | Measured using the Total Functional Capacity and Independent Scale from the broader UHDRS and the Functional Rating Scale for HD | Baseline through end of study (up to 3 years) | 
| Change to Quality of Life | As measured by the standardised questionnaires, HDQoL and EQ-5D | Baseline through end of study (up to 3 years) | 
| Study completion (Safety and Tolerability) | Measured by the proportion of participants completing NAC arm of study | Baseline through end of study (up to 3 years) | 
| Incidence of abnormal laboratory values and/or 12-lead ECG changes (Safety and Tolerability) | Measured by the Number of participants with abnormal laboratory values and/or 12-lead ECG changes compared to baseline | Baseline through end of study (up to 3 years) | 
| Incidence of adverse and/or serious adverse events (Safety and Tolerability) | Measured by the number of adverse and/or serious adverse events | Baseline through end of study (up to 3 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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N-Acetylcysteine