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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)

Primary Purpose

Early Manifest Huntington Disease

Status
Active
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Branaplam
Placebo
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Early Manifest Huntington Disease focused on measuring Early Manifest, Huntington Disease, Branaplam, LMI070, Dose Range Finding, Safety, HD, mHTT, Pharmacokinetics, oral, Adult

Eligibility Criteria

25 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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:

Sites / Locations

  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Placebo Comparator

Arm Label

Treatment Arm A

Treatment Arm B

Treatment Arm C or X or Y

Placebo

Arm Description

Branaplam 56 mg oral solution once weekly

Branaplam 112 mg oral solution once weekly

(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

Matching placebo oral solution once weekly

Outcomes

Primary Outcome Measures

Reduction (%) of mHTT protein in cerebrospinal fluid (CSF)
To assess the dose-response relationship of branaplam administered over 16 weeks on mHTT protein change from baseline in cerebrospinal fluid (CSF) obtained via lumbar puncture. Treatment is administered for 16 weeks and assessments are done over a 17 week period.
Number of treatment emergent adverse events and serious adverse events
The occurrence of adverse events will be sought by non-directive questioning of the participant at each visit during the study. Adverse events also may be detected when volunteered by the participant during or between visits or through physical examination findings, laboratory test findings, or other assessments.

Secondary Outcome Measures

Change from baseline in Ventricular Volume, Caudate Volume and Total Brain Volume
Ventricular, Caudate and Total Brain Volume will be measured by structural magnetic resonance imaging (MRI)
Concentrations of total HTT and mHTT protein in CSF
The concentrations of total HTT and mHTT protein will be measured in CSF samples obtained via lumbar puncture
Change from baseline in the Unified Huntington's Disease Rating Scale (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. Scores range from 0 to 13, with higher scores representing better functioning.
Change from baseline in the Unified Huntington's Disease Rating Scale (UHDRS Total Motor Score (TMS)
The TMS is the cumulative sum of the individual motor ratings obtained during the administration of the motor assessment portion of the UHDRS. Scores range from 0 to 124; the higher score represents more significant impairment.
Change from baseline in the Unified Huntington's Disease Rating Scale (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.
Concentrations of total HTT and mHTT protein in plasma
The concentrations of total HTT and mHTT protein will be measured in plasma from blood samples.
Concentrations of total HTT and mHTT protein in peripheral blood mononuclear cells (PBMCs)
The concentrations of total HTT and mHTT protein will be measured in PBMCs from blood samples.
Area under the curve (AUC) of branaplam in plasma
AUC will be calculated by measuring concentrations of branaplam in blood samples
Maximum concentration (Cmax) of branaplam in plasma
Cmax of branaplam will be calculated by measuring concentration in blood samples
Time taken to reach Cmx (Tmax) of branaplam in plasma.
Tmax will be calculated by measuring concentrations of branaplam in blood samples
Drug concentration observed at the last planned timepoint prior to dosing (Ctrough) of branaplam in plasma
Ctrough will be calculated by measuring concentrations of branaplam in blood samples
Concentrations of branaplam in CSF
The concentration of branaplam will be measured in CSF samples collected via lumbar puncture
Concentration ratio of branaplam in CSF/plasma.
Concentration ratio will be calculated by measuring branaplam in CSF samples collected via lumbar puncture and blood samples
Area under the curve (AUC) of UFB112 in plasma
AUC will be calculated by measuring concentrations of UFB112 in blood samples
Maximum concentration (Cmax) of UFB112 in plasma
Cmax of UFB112 will be calculated by measuring concentration in blood samples
Time taken to reach Cmx (Tmax) of UFB112 in plasma.
Tmax will be calculated by measuring concentrations of UFB112 in blood samples
Drug concentration observed at the last planned timepoint prior to dosing (Ctrough) of UFB112 in plasma
Ctrough will be calculated by measuring concentrations of UFB112 in blood samples
Concentrations of UFB112 in CSF
The concentration of UFB112 will be measured in CSF samples collected via lumbar puncture
Concentration ratio of UFB112 in CSF/plasma.
Concentration ratio will be calculated by measuring UFB112 in CSF samples collected via lumbar puncture and blood samples

Full Information

First Posted
October 15, 2021
Last Updated
October 11, 2023
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT05111249
Brief Title
A Dose Range Finding Study With Open-Label Extension to Evaluate the Safety of Oral LMI070/Branaplam in Early Manifest Huntington's Disease
Acronym
VIBRANT-HD
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
December 8, 2021 (Actual)
Primary Completion Date
October 24, 2023 (Anticipated)
Study Completion Date
October 24, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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 is a randomized, double-blind, placebo-controlled study which will be conducted in approximately 75 early manifest HD participants. After screening and baseline assessments are completed, participants will enter the Core Treatment Period which is double-blinded and placebo-controlled. The Core Treatment Period includes a Dose Range Finding (DRF) period of 17 weeks, followed by a Blinded Extension period of up to 53 weeks. Three cohorts will be enrolled in the Core Treatment Period, and data from each cohort will be evaluated for efficacy and safety before proceeding to a new cohort with a higher dose. The Core Treatment Period will serve to evaluate the safety, tolerability, pharmacokinetic(s) (PK) and pharmacodynamic(s) (PD) and to find the best dose(s) to use in future studies. After the dose(s) is determined at the end of the Core Treatment Period, participants will roll over into the Open Label Extension (OLE) and will be given branaplam for approximately 1 year and attend clinic visits every 4 weeks. At the end of the OLE, the study may be amended to provide open-label branaplam beyond 1 year or a separate extension study may be initiated.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Early Manifest Huntington Disease
Keywords
Early Manifest, Huntington Disease, Branaplam, LMI070, Dose Range Finding, Safety, HD, mHTT, Pharmacokinetics, oral, Adult

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
The study design uses a staggered cohort approach, allowing safety and tolerability of lower doses to be assessed before randomizing subjects to higher doses. At the time of the Cohort Gating Assessments (CGAs), all available data will be reviewed from a safety and dose finding perspective by an independent Sponsor team to support the decision to open the next cohort. The independent Data Monitoring Committee (DMC) will review the data separately. The decision to open a new cohort will be made by the Sponsor in consultation with the DMC.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
This is a randomized double blind study. Participants will 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.
Allocation
Randomized
Enrollment
26 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment Arm A
Arm Type
Experimental
Arm Description
Branaplam 56 mg oral solution once weekly
Arm Title
Treatment Arm B
Arm Type
Experimental
Arm Description
Branaplam 112 mg oral solution once weekly
Arm Title
Treatment Arm C or X or Y
Arm Type
Experimental
Arm Description
(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
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Matching placebo oral solution once weekly
Intervention Type
Drug
Intervention Name(s)
Branaplam
Other Intervention Name(s)
LMI070
Intervention Description
messenger ribonucleic acid (RNA) splicing modifier
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Matching placebo oral solution once weekly
Primary Outcome Measure Information:
Title
Reduction (%) of mHTT protein in cerebrospinal fluid (CSF)
Description
To assess the dose-response relationship of branaplam administered over 16 weeks on mHTT protein change from baseline in cerebrospinal fluid (CSF) obtained via lumbar puncture. Treatment is administered for 16 weeks and assessments are done over a 17 week period.
Time Frame
Baseline up to Week 17
Title
Number of treatment emergent adverse events and serious adverse events
Description
The occurrence of adverse events will be sought by non-directive questioning of the participant at each visit during the study. Adverse events also may be detected when volunteered by the participant during or between visits or through physical examination findings, laboratory test findings, or other assessments.
Time Frame
Baseline up to approximately 2 years
Secondary Outcome Measure Information:
Title
Change from baseline in Ventricular Volume, Caudate Volume and Total Brain Volume
Description
Ventricular, Caudate and Total Brain Volume will be measured by structural magnetic resonance imaging (MRI)
Time Frame
Baseline up to approximately 2 years
Title
Concentrations of total HTT and mHTT protein in CSF
Description
The concentrations of total HTT and mHTT protein will be measured in CSF samples obtained via lumbar puncture
Time Frame
Baseline up to approximately 2 years
Title
Change from baseline in the Unified Huntington's Disease Rating Scale (UHDRS) Total Functional Capacity (TFC)
Description
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. Scores range from 0 to 13, with higher scores representing better functioning.
Time Frame
Baseline up to approximately 2 years
Title
Change from baseline in the Unified Huntington's Disease Rating Scale (UHDRS Total Motor Score (TMS)
Description
The TMS is the cumulative sum of the individual motor ratings obtained during the administration of the motor assessment portion of the UHDRS. Scores range from 0 to 124; the higher score represents more significant impairment.
Time Frame
Baseline up to approximately 2 years
Title
Change from baseline in the Unified Huntington's Disease Rating Scale (UHDRS) Independence Scale (IS)
Description
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.
Time Frame
Baseline up to approximately 2 years
Title
Concentrations of total HTT and mHTT protein in plasma
Description
The concentrations of total HTT and mHTT protein will be measured in plasma from blood samples.
Time Frame
Baseline up to approximately 2 years
Title
Concentrations of total HTT and mHTT protein in peripheral blood mononuclear cells (PBMCs)
Description
The concentrations of total HTT and mHTT protein will be measured in PBMCs from blood samples.
Time Frame
Baseline up to approximately 2 years
Title
Area under the curve (AUC) of branaplam in plasma
Description
AUC will be calculated by measuring concentrations of branaplam in blood samples
Time Frame
Baseline up to approximately 2 years
Title
Maximum concentration (Cmax) of branaplam in plasma
Description
Cmax of branaplam will be calculated by measuring concentration in blood samples
Time Frame
Baseline up to approximately 2 years
Title
Time taken to reach Cmx (Tmax) of branaplam in plasma.
Description
Tmax will be calculated by measuring concentrations of branaplam in blood samples
Time Frame
Baseline up to approximately 2 years
Title
Drug concentration observed at the last planned timepoint prior to dosing (Ctrough) of branaplam in plasma
Description
Ctrough will be calculated by measuring concentrations of branaplam in blood samples
Time Frame
Baseline up to approximately 2 years
Title
Concentrations of branaplam in CSF
Description
The concentration of branaplam will be measured in CSF samples collected via lumbar puncture
Time Frame
Baseline up to approximately 2 years
Title
Concentration ratio of branaplam in CSF/plasma.
Description
Concentration ratio will be calculated by measuring branaplam in CSF samples collected via lumbar puncture and blood samples
Time Frame
Baseline up to approximately 2 years
Title
Area under the curve (AUC) of UFB112 in plasma
Description
AUC will be calculated by measuring concentrations of UFB112 in blood samples
Time Frame
Baseline up to approximately 2 years
Title
Maximum concentration (Cmax) of UFB112 in plasma
Description
Cmax of UFB112 will be calculated by measuring concentration in blood samples
Time Frame
Baseline up to approximately 2 years
Title
Time taken to reach Cmx (Tmax) of UFB112 in plasma.
Description
Tmax will be calculated by measuring concentrations of UFB112 in blood samples
Time Frame
Baseline up to approximately 2 years
Title
Drug concentration observed at the last planned timepoint prior to dosing (Ctrough) of UFB112 in plasma
Description
Ctrough will be calculated by measuring concentrations of UFB112 in blood samples
Time Frame
Baseline up to approximately 2 years
Title
Concentrations of UFB112 in CSF
Description
The concentration of UFB112 will be measured in CSF samples collected via lumbar puncture
Time Frame
Baseline up to approximately 2 years
Title
Concentration ratio of UFB112 in CSF/plasma.
Description
Concentration ratio will be calculated by measuring UFB112 in CSF samples collected via lumbar puncture and blood samples
Time Frame
Baseline up to approximately 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
25 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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:
Facility Information:
Facility Name
Novartis Investigative Site
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H2W 1T8
Country
Canada
Facility Name
Novartis Investigative Site
City
Angers Cedex 1
ZIP/Postal Code
49033
Country
France
Facility Name
Novartis Investigative Site
City
Creteil
ZIP/Postal Code
94010
Country
France
Facility Name
Novartis Investigative Site
City
Lille
ZIP/Postal Code
59037
Country
France
Facility Name
Novartis Investigative Site
City
Bochum
ZIP/Postal Code
44791
Country
Germany
Facility Name
Novartis Investigative Site
City
Muenster
ZIP/Postal Code
48149
Country
Germany
Facility Name
Novartis Investigative Site
City
Ulm
ZIP/Postal Code
89081
Country
Germany
Facility Name
Novartis Investigative Site
City
Budapest
ZIP/Postal Code
1085
Country
Hungary
Facility Name
Novartis Investigative Site
City
Szeged
ZIP/Postal Code
6725
Country
Hungary
Facility Name
Novartis Investigative Site
City
Barcelona
State/Province
Catalunya
ZIP/Postal Code
08036
Country
Spain
Facility Name
Novartis Investigative Site
City
Barcelona
ZIP/Postal Code
08041
Country
Spain
Facility Name
Novartis Investigative Site
City
Madrid
ZIP/Postal Code
28034
Country
Spain

12. IPD Sharing Statement

Learn more about this trial

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

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