The primary goal of this study is to evaluate the safety and pharmacodynamic effects of PTC518 compared with placebo in participants with HD.
Participants will first be randomized to Part A or Part B or Parts D or E in a 1:1 randomization ratio, depending on their Huntington's disease Integrated Staging System (HD-ISS) staging criteria and then to active treatment (PTC518 5 mg in Parts A and D and 10 mg in Parts B and E) or matching placebo within each part in a 2:1 ratio of active treatment to placebo. A Drug Safety Monitoring Board (DSMB) Charter will undertake an unblinded review of safety data from the 5 and 10 mg dosing groups and provide a recommendation on when Parts C and F (with a 20 mg active treatment arm) can be initiated. At that time, participants will be randomized to any study Part that is currently open for enrollment, and then to either active treatment or placebo (in a 2:1 ratio) within that Part. Participants who complete this study and agree to participate in a long-term extension (LTE) study, will be enrolled in a separate LTE study PTC518-CNS-004-HD (NCT06254482).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
159
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A TEAE was defined as an AE that had an onset date or date of worsening on or after the first dose of study drug. A summary of other non-serious AEs and all serious adverse events (SAEs), regardless of causality is located in the 'Reported AE section'.
Time frame: Baseline up to Month 18
Percent Change From Baseline in Geometric Mean Blood tHTT Protein at Month 3
Least square (LS) mean and 95% confidence interval (CI) were calculated using mixed-model repeated measures (MMRM). The blood tHTT protein value was log-transformed before fitting the MMRM model. The LS means from MMRM model were back-transformed to present geometric mean percent changes.
Time frame: Baseline, Month 3
Percent Change From Baseline in Caudate Volume as Assessed Via Volumetric Magnetic Resonance Imaging (vMRI) at Month 12
LS mean and standard error (SE) were calculated using MMRM.
Time frame: Baseline, Month 12
Change From Baseline in Composite Unified Huntington's Disease Rating Scale (cUHDRS) Scores at Month 12
cUHDRS includes the Total Functional Capacity (range, 0-13; higher score means better functioning), Total Motor Score (range, 0-124; higher score means worse motor severity), Symbol Digit Modality Test (range, 0-110, correctly paired numbers-symbols in 90 seconds; higher score means better cognitive performance), and Stroop Word Reading (range, 0-no max value, correctly read colour words in 45 seconds; higher score means better cognitive performance) scores. The total score for the cUHDRS ranges from approximately 3 to 18, where higher scores indicated better functioning. LS mean and SE were calculated using analysis of covariance (ANCOVA) model.
Time frame: Baseline, Month 12
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University of California, San Diego
La Jolla, California, United States
Vanderbilt University Medical Center
Nashville, Tennessee, United States
The University of Texas Health Science Center at Houston; McGovern Medical School
Houston, Texas, United States
University of Washington Department of Neurology
Seattle, Washington, United States
Monash Health
Clayton, Australia
Westmead Hospital
Sydney, Australia
Medical University Innsbruck
Innsbruck, Austria
The Ottawa Hospital, Parkinson's and Movement Disorders Clinic
Ottawa, Canada
Centre Hospitalier Universitaire d'Angers
Angers, France
Hôpital Universitaire de Marseille Hôpital de la Timone
Marseille, France
...and 18 more locations
Percent Change From Baseline in Geometric Mean Blood tHTT Protein at Month 12
LS mean and 95% CI were calculated using MMRM. The blood tHTT protein value was log-transformed before fitting the MMRM model. The LS means from MMRM model were back-transformed to present geometric mean percent changes.
Time frame: Baseline, Month 12
Percent Change From Baseline in Cerebrospinal Fluid (CSF) Mutant Huntingtin Protein (mHTT) at Month 12
LS mean and 95% CI were calculated using MMRM. The CSF mHTT protein value was log-transformed before fitting the MMRM model. The LS means from MMRM model were back-transformed to present geometric mean percent changes.
Time frame: Baseline, Month 12
Percent Change From Baseline in Blood mHTT Protein at Month 12
LS mean and 95% CI were calculated using MMRM. The blood mHTT protein value was log-transformed before fitting the MMRM model. The LS means from MMRM model were back-transformed to present geometric mean percent changes.
Time frame: Baseline, Month 12