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

Phase 2

Terminated

• Conditions: Early Manifest Huntington Disease
• Interventions: Drug: Branaplam; Drug: Placebo

• Registration Number: NCT05111249
• Lead Sponsor: Novartis Pharmaceuticals

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:

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations
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Related News

Study Timeline

• Study First Submitted: 2021-10-15
• Study First Submitted QC: 2021-10-27
• Study First Posted: 2021-11-08
• Study Start: 2021-12-08
• Primary Completion: 2023-10-27
• Study Completion: 2023-10-27
• Results First Submitted: 2024-08-27
• Status Verified: 2024-10
• Results First Submitted QC: 2024-10-30
• Last Update Submitted: 2024-10-30
• Results First Posted: 2024-11-04
• Last Update Posted: 2024-11-04

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 26

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment Arm A	Branaplam	Branaplam 56 mg oral solution once weekly
Treatment Arm B	Branaplam	Branaplam 112 mg oral solution once weekly
Treatment Arm C or X or Y	Branaplam	(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
Placebo	Placebo	Matching placebo oral solution once weekly

Primary Outcome Measures

Name	Time	Method
Percentage Change From Baseline to Week 17 in mHTT Protein in CSF	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)	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 Outcome Measures

Name	Time	Method
Percentage Change From Baseline in Total Brain Volume	Baseline, Week 17, Week 33, Week 53, Week 69	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.
Percentage Change From Baseline in Total Brain Volume Excluding Patients With Subdural Hematoma	Baseline, Week 17, Week 33, Week 53, Week 69	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.
Percentage Change From Baseline in Lateral Ventricles Volume	Baseline, Week 17, Week 33, Week 53, Week 69	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.
Percentage Change From Baseline in Lateral Ventricles Volume Excluding Patients With Subdural Hematoma	Baseline, Week 17, Week 33, Week 53, Week 69	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.
Percentage Change From Baseline in Left Caudate Volume	Baseline, Week 17, Week 33, Week 53, Week 69	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.
Percentage Change From Baseline in Left Caudate Volume Excluding Patients With Subdural Hematoma	Baseline, Week 17, Week 33, Week 53, Week 69	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.
Percentage Change From Baseline in Right Caudate Volume	Baseline, Week 17, Week 33, Week 53, Week 69	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.
Percentage Change From Baseline in Right Caudate Volume Excluding Patients With Subdural Hematoma	Baseline, Week 17, Week 33, Week 53, Week 69	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.
Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Functional Capacity (TFC)	Baseline, Week 17, Week 33 and Week 69	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.
Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Motor Scale (TMS)	Baseline, Week 17, Week 33 and Week 69	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.
Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Independence Scale (IS)	Baseline, Week 17, Week 33 and Week 69	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 mHTT Protein and Total HTT in CSF	Baseline, Week 9, Week 17	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.
Concentrations of mHTT Protein and Total HTT in Plasma	Baseline, Week 17	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.
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	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.
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	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.
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	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.
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	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.
Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in Plasma	pre-dose at Weeks 2, 3, 5, 9, 13 and 17	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.
Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in CSF	pre-dose at Weeks 9 and 17	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.
Concentration Ratio CSF/Plasma of Branaplam and Its Metabolite UFB112	pre-dose at Weeks 9 and 17	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.

Trial Locations

Locations (1)

Novartis Investigative Site; 🇪🇸 Madrid, Spain