A Dose Range Finding Study With Open-Label Extension to Evaluate the Safety of Oral LMI070/Branaplam in Early Manifest Huntington's Disease (VIBRANT-HD)

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

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.

Study Overview

• Status: Terminated
• Conditions: Early Manifest Huntington Disease
• Intervention / Treatment: Drug: Placebo; Drug: Branaplam

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:

Treatment Arm C: branaplam 154 mg oral solution or matching placebo, once weekly or Treatment Arm X: branaplam 84 mg oral solution or matching placebo, once weekly or Treatment Arm Y: branaplam 28 mg oral solution or matching placebo, once weekly

• The OLE was a one-year open-label extension to assess both long-term safety and tolerability, as well as the efficacy of the recommended optimal dose(s) for branaplam.

Due to safety concerns an urgent safety measure (USM) follow-up notification dated 06-Dec-2022 was issued to permanently discontinue the study treatment in all participants. At that point, only cohort 1 was enrolled. Therefore, only cohort 1 data is available for analysis (Treatment Arm A: branaplam 56 mg oral solution or matching placebo, once weekly). Participants who received active treatment (branaplam) were to remain in the study for follow-up for approximately one year following initial treatment discontinuation. The OLE part was not opened.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H2W 1T8
      • Novartis Investigative Site
• France
  • Angers Cedex 9, France, 49933
    • Novartis Investigative Site
  • Creteil, France, 94010
    • Novartis Investigative Site
  • Lille, France, 59037
    • Novartis Investigative Site
• Germany
  • Bochum, Germany, 44791
    • Novartis Investigative Site
  • Muenster, Germany, 48149
    • Novartis Investigative Site
  • Ulm, Germany, 89081
    • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, H-1083
    • Novartis Investigative Site
  • Szeged, Hungary, 6720
    • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08041
    • Novartis Investigative Site
  • Madrid, Spain, 28034
    • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08036
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

• Signed informed consent must be obtained prior to participation in the study.
• Clinically diagnosed Stage 1 or 2 Huntington's disease with a diagnostic confidence level (DCL) = 4 and a United Huntington's Disease Rating Scale (UHDRS) Total Functional Capacity (TFC) >8 at screening.
• Genetically confirmed Huntington's disease, with presence of ≥40 cytosine-adenineguanine (CAG) repeats in the huntingtin gene.
• Male and female participants between 25 to 75 years of age, inclusive, on the day of Informed Consent signature.

Exclusion Criteria

• Prior participation in clinical trial investigating a huntingtin-lowering therapy (unless participant received only placebo).
• Participants taking medications prohibited by the protocol.
• Any medical history, lumbar surgery or condition that would interfere with the ability to complete the protocol specified assessments.
• Participant has other severe, acute or chronic medical conditions including unstable psychiatric conditions, or laboratory abnormalities that in the opinion of the Investigator may increase the risk associated with study participation, or that may interfere with the interpretation of the study results.
• Any surgical or medical condition which might put the participant at risk in case of participation in the study. The Investigator should make this determination in consideration of the participant's medical history and/or clinical or laboratory evidence at the Screening visit.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Arm A; Branaplam 56 mg oral solution once weekly	Drug: Branaplam; messenger ribonucleic acid (RNA) splicing modifier. Branaplam was administered as an oral solution once weekly.; Other Names: LMI070
Experimental: Treatment Arm B; Branaplam 112 mg oral solution once weekly	Drug: Branaplam; messenger ribonucleic acid (RNA) splicing modifier. Branaplam was administered as an oral solution once weekly.; Other Names: LMI070
Experimental: 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	Drug: Branaplam; messenger ribonucleic acid (RNA) splicing modifier. Branaplam was administered as an oral solution once weekly.; Other Names: LMI070
Placebo Comparator: Placebo; Matching placebo oral solution once weekly	Drug: Placebo; Matching placebo oral solution once weekly

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change From Baseline to Week 17 in mHTT Protein in CSF	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.	Baseline, Week 17
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	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).	From first dose of study treatment up to Week 69

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change From Baseline in Total Brain Volume	Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment.	Baseline, Week 17, Week 33, Week 53, Week 69
Percentage Change From Baseline in Total Brain Volume Excluding Patients With Subdural Hematoma	Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment.	Baseline, Week 17, Week 33, Week 53, Week 69
Percentage Change From Baseline in Lateral Ventricles Volume	Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment.	Baseline, Week 17, Week 33, Week 53, Week 69
Percentage Change From Baseline in Lateral Ventricles Volume Excluding Patients With Subdural Hematoma	Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment.	Baseline, Week 17, Week 33, Week 53, Week 69
Percentage Change From Baseline in Left Caudate Volume	Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment.	Baseline, Week 17, Week 33, Week 53, Week 69
Percentage Change From Baseline in Left Caudate Volume Excluding Patients With Subdural Hematoma	Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment.	Baseline, Week 17, Week 33, Week 53, Week 69
Percentage Change From Baseline in Right Caudate Volume	Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment.	Baseline, Week 17, Week 33, Week 53, Week 69
Percentage Change From Baseline in Right Caudate Volume Excluding Patients With Subdural Hematoma	Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment.	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)	The TFC focuses on the investigator's assessment of the participant's capacity to perform a range of activities of daily living. The responses are derived from interview with the participant and/or companion, if applicable. TFC score range from 0 to 13, with higher scores representing better functioning.	Baseline, Week 17, Week 33 and Week 69
Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Motor Scale (TMS)	The TMS is the cumulative sum of the individual motor ratings obtained during the administration of the motor assessment portion of the UHDRS. TMS score range from 0 to 124 with higher scores representing more significant impairment.	Baseline, Week 17, Week 33 and Week 69
Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Independence Scale (IS)	The IS represents the investigator's assessment of the participant's level of independence, including topics of employment, finances, self-care and feeding. The scale has 19 discrete scores, from 10 (tube fed, total bed care) to 100 (no special care needed) with 5-point increments in between.	Baseline, Week 17, Week 33 and Week 69
Concentrations of mHTT Protein and Total HTT in CSF	Mutant Huntingtin (mHTT) protein and total HTT measured in cerebrospinal fluid (CSF) obtained via lumbar puncture. Baseline value is the last evaluable measurement prior to the first administration of study drug.	Baseline, Week 9, Week 17
Concentrations of mHTT Protein and Total HTT in Plasma	Mutant Huntingtin (mHTT) protein and total HTT measured in plasma. Baseline value is the last evaluable measurement prior to the first administration of study drug.	Baseline, Week 17
Maximum Observed Plasma Concentration (Cmax) of Branaplam and Its Metabolite UFB112	Pharmacokinetic (PK) parameters were calculated based on branaplam and its metabolite UFB112 plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose.	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	PK parameters were calculated based on branaplam and its metabolite UFB112 plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) concentration following a dose. Actual recorded sampling times were considered for the calculations.	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	PK parameters were calculated based on branaplam and its metabolite UFB112 plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-168h calculation.	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	PK parameters were calculated based on branaplam and its metabolite UFB112 plasma concentrations by using non-compartmental methods. The linear trapezoidal method and the regression analysis of the terminal elimination phase were used for AUCinf calculation.	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	Branaplam and its metabolite UFB112 concentrations were determined in plasma. Ctrough is defined as the concentration reached immediately before the next dose is administered. All drug concentrations below the lower limit of quantification were treated as zero for the calculation of PK parameters.	pre-dose at Weeks 2, 3, 5, 9, 13 and 17
Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in CSF	Branaplam and its metabolite UFB112 concentrations were determined in cerebrospinal fluid (CSF) obtained via lumbar puncture. Ctrough is defined as the concentration reached immediately before the next dose is administered. All drug concentrations below the lower limit of quantification were treated as zero for the calculation of PK parameters.	pre-dose at Weeks 9 and 17
Concentration Ratio CSF/Plasma of Branaplam and Its Metabolite UFB112	Branaplam and its metabolite UFB112 concentrations were determined plasma and in cerebrospinal fluid (CSF) obtained via lumbar puncture. Concentration ratios CSF/plasma were calculated for subjects for whom CSF and plasma concentrations were available at the respective time point.	pre-dose at Weeks 9 and 17

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With NfL Increase and Recovery	Neurofilament light chain (NfL) is a neuronal cytoplasmic protein highly expressed in large calibre myelinated axons. Its levels increase in cerebrospinal fluid (CSF) and serum in case of axonal damage in a variety of neurological disorders. The levels of NfL were determined in serum and CSF and the following 3 categories were defined: Serum NfL (sNfL) increase: > 100 pg/mL or > 2 x baseline (BL) sNfL; sNfL recovery: Worsening criteria are no longer met (sNfL <= 100 pg/mL or sNfL <= 2 x BL sNfL) for visits after last visit with increase; CSF NfL increase: > 10000 pg/mL or > 2 x BL CSF NfL or > 2 x CSF NfL of the previous assessment	From baseline (before first dose of study treatment) up to Week 17 (CSF) and Week 69 (serum)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• A Plain Language Trial Summary is available on www.novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): December 8, 2021
• Primary Completion (Actual): October 27, 2023
• Study Completion (Actual): October 27, 2023

Study Registration Dates

• First Submitted: October 15, 2021
• First Submitted That Met QC Criteria: October 27, 2021
• First Posted (Actual): November 8, 2021

Study Record Updates

• Last Update Posted (Actual): May 16, 2025
• Last Update Submitted That Met QC Criteria: May 14, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Safety; Pharmacokinetics; Adult; oral; HD; Huntington Disease; Early Manifest; Branaplam; LMI070; Dose Range Finding; mHTT
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Genetic Diseases, Inborn; Neurocognitive Disorders; Cognition Disorders; Dementia; Neurodegenerative Diseases; Movement Disorders; Heredodegenerative Disorders, Nervous System; Basal Ganglia Diseases; Dyskinesias; Chorea; Huntington Disease
• Other Study ID Numbers: CLMI070C12203; 2020-000105-92 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No