A Randomized, Double-Blind, Placebo-Controlled Dose Range Finding Study With Open-Label Extension to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of LMI070/Branaplam Administered as Weekly Oral Doses in Participants With Early Manifest Huntington's Disease
Trial Snapshot
- Phase
- Phase 2
- Status
- Terminated
- Sponsor
- Novartis Pharmaceuticals
- Enrollment
- 26
- Locations
- 1
- Primary Endpoint
- Percentage Change From Baseline to Week 17 in mHTT Protein in CSF
Study Overview
Brief Summary
This is the first study of branaplam in adults with Huntington's Disease (HD) to determine the correct dose required to lower mutant huntingtin protein (mHTT) levels in the cerebrospinal fluid (CSF) to a degree expected to be efficacious over longer periods of time.
Detailed Description
This study was a randomized, double-blind, placebo-controlled study with a variable duration (between approximately 17 weeks to approximately 53 weeks) for the core period and a one-year open label extension (OLE) in early-stage manifest Huntington's disease (HD) participants.
After screening period and baseline assessments, the following two Treatment Periods were planned:
• The core period consisted of a 17-week double-blind, placebo-controlled, Dose Range Finding (DRF) portion of the study, followed by a blinded extension (BE) of variable duration (up to approximately 53 weeks). The DRF Period was to evaluate the safety, tolerability, pharmacokinetivs (PK) and pharmacodynamics (PD) of branaplam, as well as determine the optimal dose(s) to explore in further clinical evaluations.
The core period was planned to consist of 3 treatment arms:
- Cohort 1: Treatment Arm A: branaplam 56 mg oral solution or matching placebo, once weekly
- Cohort 2: Treatment Arm B: branaplam 112 mg oral solution or matching placebo, once weekly
- Cohort 3:
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description
This was a randomized double blind study. Participants were planned to be randomized in an equal randomization rate among the open treatment arms, and then in a 4:1 ratio for active vs. placebo within each arm.
Eligibility Criteria
- Ages
- 25 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Treatment Arm A
Branaplam 56 mg oral solution once weekly
Intervention: Branaplam (Drug)
Treatment Arm B
Branaplam 112 mg oral solution once weekly
Intervention: Branaplam (Drug)
Treatment Arm C or X or Y
(C) Branaplam 154 mg oral solution once weekly, OR (X) Branaplam 84 mg oral solution once weekly OR (Y) Branaplam 28 mg oral solution once weekly
Intervention: Branaplam (Drug)
Placebo
Matching placebo oral solution once weekly
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Percentage Change From Baseline to Week 17 in mHTT Protein in CSF
Time Frame: Baseline, Week 17
Mutant Huntingtin (mHTT) protein was measured in cerebrospinal fluid (CSF) obtained via lumbar puncture. The percentage change from baseline to Week 17 in mHTT protein in CSF was calculated with the following formula: (mHTTweek17 - mHTTbaseline)/ mHTTbaseline \* 100. Baseline value for mHTT is the last evaluable measurements prior to the first administration of study drug.
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame: From first dose of study treatment up to Week 69
Incidence of AEs (any AEs regardless of seriousness) and SAEs, including changes in vital signs, neurological examination, electrocardiograms (ECGs) and laboratory parameters qualifying and reported as AEs. Participants received study treatment up to maximum Week 20 (placebo) and Week 22 (branaplam).
Secondary Outcomes
- Percentage Change From Baseline in Total Brain Volume(Baseline, Week 17, Week 33, Week 53, Week 69)
- Percentage Change From Baseline in Total Brain Volume Excluding Patients With Subdural Hematoma(Baseline, Week 17, Week 33, Week 53, Week 69)
- Percentage Change From Baseline in Lateral Ventricles Volume(Baseline, Week 17, Week 33, Week 53, Week 69)
- Percentage Change From Baseline in Lateral Ventricles Volume Excluding Patients With Subdural Hematoma(Baseline, Week 17, Week 33, Week 53, Week 69)
- Percentage Change From Baseline in Left Caudate Volume(Baseline, Week 17, Week 33, Week 53, Week 69)
- Percentage Change From Baseline in Left Caudate Volume Excluding Patients With Subdural Hematoma(Baseline, Week 17, Week 33, Week 53, Week 69)
- Percentage Change From Baseline in Right Caudate Volume(Baseline, Week 17, Week 33, Week 53, Week 69)
- Percentage Change From Baseline in Right Caudate Volume Excluding Patients With Subdural Hematoma(Baseline, Week 17, Week 33, Week 53, Week 69)
- Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Functional Capacity (TFC)(Baseline, Week 17, Week 33 and Week 69)
- Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Motor Scale (TMS)(Baseline, Week 17, Week 33 and Week 69)
- Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Independence Scale (IS)(Baseline, Week 17, Week 33 and Week 69)
- Concentrations of mHTT Protein and Total HTT in CSF(Baseline, Week 9, Week 17)
- Concentrations of mHTT Protein and Total HTT in Plasma(Baseline, Week 17)
- Maximum Observed Plasma Concentration (Cmax) of Branaplam and Its Metabolite UFB112(pre-dose and 4, 7, 12, 22, 72 and 168 hours after branaplam dose at Week 1 and Week 17)
- Time to Reach Maximum Plasma Concentration (Tmax) of Branaplam and Its Metabolite UFB112(pre-dose and 4, 7, 12, 22, 72 and 168 hours after branaplam dose at Week 1 and Week 17)
- Area Under the Plasma Concentration-time Curve From Time Zero to 168 Hours (AUC0-168h) of Branaplam and Its Metabolite UFB112(pre-dose and 4, 7, 12, 22, 72 and 168 hours after branaplam dose at Week 1 and Week 17)
- Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of Branaplam and Its Metabolite UFB112(pre-dose and 4, 7, 12, 22, 72 and 168 hours after branaplam dose at Week 1)
- Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in Plasma(pre-dose at Weeks 2, 3, 5, 9, 13 and 17)
- Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in CSF(pre-dose at Weeks 9 and 17)
- Concentration Ratio CSF/Plasma of Branaplam and Its Metabolite UFB112(pre-dose at Weeks 9 and 17)