The NAD-HD Study: A Study to Investigate Efficacy and Safety of Nicotinamide Riboside Compared With Placebo in Huntington's Disease

The goal of this clinical trial is to learn if oral supplement of nicotinamide riboside (NR), a form of vitamin B3, slows disease progression in adults with Huntington's disease. It will also learn about the safety of nicotinamide riboside. The main questions it aims to answer are:

* Does NR slow progression of overall symptom burden in Huntington's disease?
* Does NR have an effect on any specific symptom domain in Huntington's disease?
* Does supplementation with NR cause side-effects or safety issues when used for 2 years in Huntington's disease?
* Does NR have an effect on selected blood, imaging, and oculomotor biomarkers in Huntington's disease?

Researchers will compare NR to a placebo (a look-alike substance that contains no active compound) to see if NR works to treat Huntington's disease.

Participants will:

* Take 2000mg NR or a placebo every day for 2 years
* Visit the clinic once every 6 months for clinical investigations and tests
* Undergo brain imaging at baseline and upon completion of the study period


Eligibility Criteria:
Inclusion Criteria:

* Confirmed HD gene expansion carrier status with a diagnostic genetic test confirming ≥36 CAG-repeats in HTT.
* Clinically manifest HD with objective neurological signs corresponding to Diagnostic Confidence Level 4 based on the Total Motor Score of the UHDRS.
* Early or mid-stage disease corresponding to Shoulson-Fahn stage 1-340 and Total Functional Capacity (TFC) \> 2.
* Ability to walk indoors unassisted or by the help of walking aids only as determined at screening and baseline visits.
* Ability to write and perform pen-and-paper tests (SDMT, SWRT, MoCA) and complete questionnaires (HADS-SIS, SF-12) included in the study protocol.
* Ability to follow up telephone appointments and reliably attend study visits independently or with the assistance of a reliable partner (family member, friend, or assistant).
* Ability to tolerate blood draws.
* Participants who are women of childbearing potential should use an approved method for highly effective birth control throughout the study intervention period
* Capable of giving signed informed consent

Exclusion Criteria:

* Presence of other co-morbid neurological or psychiatric disorders considered clinically significant by the investigator, including, but not limited to psychotic disorders, brain tumor or inflammatory neurological disease.
* Attempted suicide or active suicidal ideation within 12 months prior to screening.
* A history of alcohol or substance use within a 12 month period prior to the baseline visit, fulfilling criteria of dependence or abuse under the International Classification of Diseases (ICD-10) F10-F19 (not including tobacco dependence).
* Any malignancy within 5 years prior to screening (except basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated) or history of a previously treated malignant disorder \> 5 years prior to screening with a remaining clinically significant recurrence risk.
* Established coronary artery disease or clinically significant cerebrovascular disease as deemed by the investigator.
* High age-specific cardiovascular risk as defined by the NORRISK2 algorithm based on smoking status, systolic blood pressure, serum total cholesterol and family history, modeled on the Norwegian population
* Any medical condition which, in the investigator's judgement, may preclude the subject's safe participation in the study, interfere with the ability to comply with study procedures or confound the interpretation of study results.
* Use of vitamin B3 supplements in any form or dose during the study or within 3 months prior to screening.
* Planned major surgery of any kind during the study period that is likely to affect clinical ratings, including, but not limited to, joint replacement and spinal surgery.
* Electroconvulsive therapy.
* Any medical therapy with known severe side effects that, in the investigator's judgement, may preclude the subject's safe participation in the study, interfere with the ability to comply with study procedures or confound the interpretation of study results.
* Any history of gene therapy exposure for the treatment of HD.