The purpose is to assess safety and tolerability of votoplam and to determine whether votoplam slows disease progression in patients with early symptomatic Huntington's disease (HD) compared to the control arm.
HTT227 - current compound code (former code is PTC518 from PTC Therapeutics), HTT227 is Novartis code under Novartis sponsorship.
Signed informed consents must be obtained prior to participation in the study
Ambulatory male or female participants between 21 to 70 years of age, inclusive, on the day of Informed Consent signature
Genetically confirmed HD diagnosis with a cytosine-adenine-guanine (CAG) repeat length of 40 or above. Participants must have prior genetic confirmation and known CAG repeat length obtained prior to screening.
UHDRS IS score ≥90
History of gene therapy or cell transplantation or any other experimental brain surgery for the treatment of HD
positive anti-HBc IgM
positive anti-HBc IgG confirmed by positive HBsAg and/or HBV DNA
positive HCV ab test confirmed by positive HCV RNA
Parallel
Votoplam (blinded)
DrugVotoplam (blinded) active treatment
Placebo
DrugPlacebo
Change from Baseline in cUHDRS score
The Composite Unified Huntingtons Disease Ratings Scale (cUHDRS) is an improved composite measure to assess multi-domain clinical progression in HD. The cUHDRS is a combined weighted score of measures of motor function (TMS), cognition (SDMT and SWRT) and overall functional capacity (TFC): cUHDRS = \[(TFC-10.4)/1.9 - (TMS-29.7)/14.9 + (SDMT-28.4)/11.3 + (SWRT - 66.1)/20.1\] + 10. In conjunction with one another, these measures provide a comprehensive, sensitive and specific tool for monitoring disease progression, with lower scores indicating more severe disease. cUHDRS score range from -8 to 25.
Change from Baseline in UHDRS-TFC
The UHDRS-Total Functional Capacity (TFC) focuses on the Investigator's assessment of the participant's capacity to perform a range of activities including occupation, finances, self-care, domestic chores and activities of daily living. The responses are derived from interview with the participant and/or companion, if applicable. Scores range from 0 to 13, with higher scores representing better functioning.
Change from Baseline in UHDRS-IS
The UHDRS-Independence Scale (IS) measures a patient's overall level of functional independence in activities of daily living. It provides a single score ranging from 10 (total dependence/bedbound) to 100 (no special care needed) in intervals of 10, with higher scores indicating better functioning. Scores can also be assigned in increments of 5 for intermediate levels of function.
The time to decline in TFC score by at least one or IS score by at least 10
The UHDRS-Total Functional Capacity (TFC) focuses on the Investigator's assessment of the participant's capacity to perform a range of activities including occupation, finances, self-care, domestic chores and activities of daily living. The responses are derived from interview with the participant and/or companion, if applicable. Scores range from 0 to 13, with higher scores representing better functioning. The UHDRS-Independence Scale (IS) measures a patient's overall level of functional independence in activities of daily living. It provides a single score ranging from 10 (total dependence/bedbound) to 100 (no special care needed) in intervals of 10, with higher scores indicating better functioning. Scores can also be assigned in increments of 5 for intermediate levels of function.
Change from Baseline in UHDRS-TMS
The UHDRS-Total Motor Score (TMS) is the cumulative sum of the individual motor ratings obtained during the administration of the motor assessment portion of the UHDRS. It includes items related to eye movements, speech, limb movements (including hand taps and pronation-supination), dystonia, chorea, and gait/balance. Scores range from 0 to 124, with higher scores indicating greater motor impairment.
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