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)

• ClinicalTrials.gov Identifier: NCT05111249
• Recruitment Status: Recruiting
• First Posted: November 8, 2021
• Last Update Posted: June 3, 2022
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

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.

Condition or disease	Intervention/treatment	Phase
Early Manifest Huntington Disease	Drug: Branaplam; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 75 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention 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: Quadruple (Participant, Care Provider, Investigator, Outcomes 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.
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: December 8, 2021
• Estimated Primary Completion Date: February 17, 2025
• Estimated Study Completion Date: February 17, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment Arm A; Branaplam 56 mg oral solution once weekly	Drug: Branaplam; messenger ribonucleic acid (RNA) splicing modifier; Other Name: LMI070
Experimental: Treatment Arm B; Branaplam 112 mg oral solution once weekly	Drug: Branaplam; messenger ribonucleic acid (RNA) splicing modifier; Other Name: 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; Other Name: LMI070
Placebo Comparator: Placebo; Matching placebo oral solution once weekly	Drug: Placebo; Matching placebo oral solution once weekly

Outcome Measures

Primary Outcome Measures :

1. Reduction (%) of mHTT protein in cerebrospinal fluid (CSF) [ Time Frame: Baseline up to Week 17 ]
   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.
2. Number of treatment emergent adverse events and serious adverse events [ Time Frame: Baseline up to approximately 2 years ]
   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 :

1. Change from baseline in Ventricular Volume, Caudate Volume and Total Brain Volume [ Time Frame: Baseline up to approximately 2 years ]
   Ventricular, Caudate and Total Brain Volume will be measured by structural magnetic resonance imaging (MRI)
2. Concentrations of total HTT and mHTT protein in CSF [ Time Frame: Baseline up to approximately 2 years ]
   The concentrations of total HTT and mHTT protein will be measured in CSF samples obtained via lumbar puncture
3. Change from baseline in the Unified Huntington's Disease Rating Scale (UHDRS) Total Functional Capacity (TFC) [ Time Frame: Baseline up to approximately 2 years ]
   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.
4. Change from baseline in the Unified Huntington's Disease Rating Scale (UHDRS Total Motor Score (TMS) [ Time Frame: Baseline up to approximately 2 years ]
   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.
5. Change from baseline in the Unified Huntington's Disease Rating Scale (UHDRS) Independence Scale (IS) [ Time Frame: Baseline up to approximately 2 years ]
   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.
6. Concentrations of total HTT and mHTT protein in plasma [ Time Frame: Baseline up to approximately 2 years ]
   The concentrations of total HTT and mHTT protein will be measured in plasma from blood samples.
7. Concentrations of total HTT and mHTT protein in peripheral blood mononuclear cells (PBMCs) [ Time Frame: Baseline up to approximately 2 years ]
   The concentrations of total HTT and mHTT protein will be measured in PBMCs from blood samples.
8. Area under the curve (AUC) of branaplam in plasma [ Time Frame: Baseline up to approximately 2 years ]
   AUC will be calculated by measuring concentrations of branaplam in blood samples
9. Maximum concentration (Cmax) of branaplam in plasma [ Time Frame: Baseline up to approximately 2 years ]
   Cmax of branaplam will be calculated by measuring concentration in blood samples
10. Time taken to reach Cmx (Tmax) of branaplam in plasma. [ Time Frame: Baseline up to approximately 2 years ]
    Tmax will be calculated by measuring concentrations of branaplam in blood samples
11. Drug concentration observed at the last planned timepoint prior to dosing (Ctrough) of branaplam in plasma [ Time Frame: Baseline up to approximately 2 years ]
    Ctrough will be calculated by measuring concentrations of branaplam in blood samples
12. Concentrations of branaplam in CSF [ Time Frame: Baseline up to approximately 2 years ]
    The concentration of branaplam will be measured in CSF samples collected via lumbar puncture
13. Concentration ratio of branaplam in CSF/plasma. [ Time Frame: Baseline up to approximately 2 years ]
    Concentration ratio will be calculated by measuring branaplam in CSF samples collected via lumbar puncture and blood samples
14. Area under the curve (AUC) of UFB112 in plasma [ Time Frame: Baseline up to approximately 2 years ]
    AUC will be calculated by measuring concentrations of UFB112 in blood samples
15. Maximum concentration (Cmax) of UFB112 in plasma [ Time Frame: Baseline up to approximately 2 years ]
    Cmax of UFB112 will be calculated by measuring concentration in blood samples
16. Time taken to reach Cmx (Tmax) of UFB112 in plasma. [ Time Frame: Baseline up to approximately 2 years ]
    Tmax will be calculated by measuring concentrations of UFB112 in blood samples
17. Drug concentration observed at the last planned timepoint prior to dosing (Ctrough) of UFB112 in plasma [ Time Frame: Baseline up to approximately 2 years ]
    Ctrough will be calculated by measuring concentrations of UFB112 in blood samples
18. Concentrations of UFB112 in CSF [ Time Frame: Baseline up to approximately 2 years ]
    The concentration of UFB112 will be measured in CSF samples collected via lumbar puncture
19. Concentration ratio of UFB112 in CSF/plasma. [ Time Frame: Baseline up to approximately 2 years ]
    Concentration ratio will be calculated by measuring UFB112 in CSF samples collected via lumbar puncture and blood samples

Eligibility Criteria

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

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:

Contacts and Locations

Contacts

Contact: Novartis Pharmaceuticals; 1-888-669-6682; novartis.email@novartis.com

Contact: Novartis Pharmaceuticals; +41613241111

Locations

United States, Alabama

Novartis Investigative Site; Recruiting

Birmingham, Alabama, United States, 35294-0111

United States, Florida

Novartis Investigative Site; Recruiting

Tampa, Florida, United States, 33612

United States, Maryland

Novartis Investigative Site; Recruiting

Baltimore, Maryland, United States, 21287

United States, New York

Novartis Investigative Site; Recruiting

New York, New York, United States, 10033

United States, Pennsylvania

Novartis Investigative Site; Recruiting

Philadelphia, Pennsylvania, United States, 19107

Canada, Quebec

Novartis Investigative Site; Recruiting

Montreal, Quebec, Canada, H2W 1T8

France

Novartis Investigative Site; Recruiting

Angers Cedex 1, France, 49033

Novartis Investigative Site; Recruiting

Creteil, France, 94010

Novartis Investigative Site; Recruiting

Lille Cedex, France, 59037

Germany

Novartis Investigative Site; Recruiting

Bochum, Germany, 44791

Novartis Investigative Site; Recruiting

Erlangen, Germany, 91054

Novartis Investigative Site; Recruiting

Muenster, Germany, 48149

Novartis Investigative Site; Recruiting

Ulm, Germany, 89081

Hungary

Novartis Investigative Site; Recruiting

Budapest, Hungary, 1085

Novartis Investigative Site; Recruiting

Szeged, Hungary, 6725

Italy

Novartis Investigative Site; Recruiting

Milano, MI, Italy, 20133

Spain

Novartis Investigative Site; Recruiting

Barcelona, Catalunya, Spain, 08036

Novartis Investigative Site; Recruiting

Barcelona, Spain, 08041

Novartis Investigative Site; Recruiting

Madrid, Spain, 28034

Sponsors and Collaborators

Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT05111249
• Other Study ID Numbers: CLMI070C12203
• First Posted: November 8, 2021
• Last Update Posted: June 3, 2022
• Last Verified: June 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Huntington Disease; Early Manifest; Branaplam; LMI070; Dose Range Finding; Safety; HD; mHTT; Pharmacokinetics; oral; Adult

Additional relevant MeSH terms:

Huntington Disease; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Dementia; Chorea; Dyskinesias