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.
This study will have a variable double-blind treatment duration of up to 36 months. As part of the study design, not every participant will complete 36 months of treatment. The study consists of 3 periods: * Screening Period: A period of up to 42-days to assess participants eligibility * Double-blind Treatment Period: This period will have variable individual treatment duration, up to 36 months. The double-blind treatment period concludes when ≥50% patients complete Month 36. The maximum treatment duration for an individual participant is 36 months. * Safety Follow-up Period: A period consisting of one safety follow-up visit, conducted on site or by phone call, for all participants not continuing treatment in the separate open-label extension study or discontinuing early. The visit/phone call will take place 30 days after End of Study (EOS)
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
770
Votoplam (blinded) active treatment
Placebo
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.
Time frame: Baseline, Month 36
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.
Time frame: Baseline, Month 36
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.
Time frame: Baseline, Month 36
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.
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University of Alabama Birmingham
Birmingham, Alabama, United States
RECRUITINGUniv of Arkansas for Med Sciences
Little Rock, Arkansas, United States
RECRUITINGUniversity of CA San Diego
La Jolla, California, United States
RECRUITINGUC Davis Health System
Sacramento, California, United States
RECRUITINGUCSF
San Francisco, California, United States
RECRUITINGStanford Healthcare
Stanford, California, United States
RECRUITINGCenExcel Rocky Mtn Clin Research
Englewood, Colorado, United States
RECRUITINGU Conn Health
Farmington, Connecticut, United States
RECRUITINGGeorgetown University
Washington D.C., District of Columbia, United States
RECRUITINGUM Department Of Neurology
Miami, Florida, United States
RECRUITING...and 107 more locations
Time frame: Baseline to end of treatment up to 36 months
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.
Time frame: Baseline, Month 36
Change from Baseline in SDMT
The Symbol Digit Modality Test (SDMT) is used to assess attention, working memory, psychomotor speed and visual perceptual processing. Participants are presented with a translation key of specific numbers paired with unique abstract symbols. Below the translation key is an array of symbols paired with empty spaces, the participant's task is to match the number for each symbol as quickly as possible in a given time frame. Scores are based on number of correctly paired items and range from 0 to 110, with higher scores representing better performance.
Time frame: Baseline, Month 36
Change from Baseline in SWRT
The Stroop Word Reading Test (SWRT) is a measure of processing and psychomotor speed. Participants are presented with a list or words (color names) printed in black ink and asked to read aloud as many words as possible within a set timeframe. Scores are based on the number of words read correctly and range from 0 to 60, with higher scores representing better performance.
Time frame: Baseline, Month 36
Percent change from Baseline in blood mHTT protein
The mutant huntington protein (mHTT) which is detectable both in blood and cerebrospinal fluid (CSF), represents a reliable biomarker for HD due to its direct involvement in disease pathology. Blood mHTT is a direct product of the pathogenic HTT gene mutation and represents a proximal marker of Huntington's disease (HD) biology.
Time frame: Baseline to steady state and up to 36 months in blood mHTT protein
Change from Baseline in serum NfL
Serum Neurofilament light chain NfL is a component of the neuronal cytoskeleton, released into CSF and blood after neuro-axonal damage, serving as a marker of neurodegeneration and disease progression in HD.
Time frame: Baseline, Month 36
Incidence and severity of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) and TEAEs leading to participant withdrawal
Number of participants with AEs and SAEs, including notable findings on physical examination, changes in vital signs, laboratory parameters, ECG, etc.
Time frame: Baseline to up to 36 months