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| ID | Type | Description | Link |
|---|---|---|---|
| 2020-000105-92 | EudraCT Number |
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The trial was halted prematurely due to signs and symptoms that suggested the possibility of peripheral neuropathy. All participants who received branaplam continued to undergo routine (safety) evaluations for up to a year following their final dose
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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.
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:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment Arm A | Experimental | Branaplam 56 mg oral solution once weekly |
|
| Treatment Arm B | Experimental | Branaplam 112 mg oral solution once weekly |
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| Treatment Arm C or X or Y | Experimental | (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 Comparator | Matching placebo oral solution once weekly |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Branaplam | Drug | messenger ribonucleic acid (RNA) splicing modifier. Branaplam was administered as an oral solution once weekly. |
|
| 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 |
| 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. |
| 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:
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Inclusion Criteria
Exclusion Criteria
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Novartis Investigative Site | Montreal | Quebec | H2W 1T8 | Canada | ||
| Novartis Investigative Site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41491108 | Derived | Borowsky B, Ramos H, Caputo A, Hartmann A, Faller T, Peters T, Sui Y, Liu F, Meadowcroft M, David OJ, Laisney M, Kinhikar A, Marder KS, Tabrizi SJ, Landwehrmeyer GB, Leavitt BR. Oral splicing modulator branaplam in Huntington's disease: a phase 2 randomized controlled trial. Nat Med. 2026 Jan;32(1):103-112. doi: 10.1038/s41591-025-04117-4. Epub 2026 Jan 5. | |
| 38489195 |
| Label | URL |
|---|---|
| A Plain Language Trial Summary is available on www.novctrd.com | View source |
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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.
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The Screening period had a duration of up to 6 weeks. For eligible participants, the baseline measurements were performed within 6 days prior to the first dose of study treatment. At the Week 1 visit in the Core period participants were randomized (4:1) to receive either branaplam or placebo.
The last study visit was performed at Week 69. The open label extension (OLE) period was not opened.
Participants took part in 12 investigative sites in 5 countries.
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo | Treatment Arm A: matching placebo oral solution once weekly |
| FG001 | Branaplam 56 mg | Treatment Arm A: branaplam 56 mg oral solution once weekly |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jan 30, 2023 | Aug 27, 2024 |
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The study design used 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 was 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) reviewed the data separately. The decision to open a new cohort was planned to be made by the Sponsor in consultation with the DMC.
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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.
|
| Placebo | Drug | Matching placebo oral solution once weekly |
|
| 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 |
| From baseline (before first dose of study treatment) up to Week 17 (CSF) and Week 69 (serum) |
| Angers |
| 49933 |
| France |
| Novartis Investigative Site | Créteil | 94010 | France |
| Novartis Investigative Site | Lille | 59037 | France |
| Novartis Investigative Site | Bochum | 44791 | Germany |
| Novartis Investigative Site | Münster | 48149 | Germany |
| Novartis Investigative Site | Ulm | 89081 | Germany |
| Novartis Investigative Site | Budapest | H-1083 | Hungary |
| Novartis Investigative Site | Szeged | 6720 | Hungary |
| Novartis Investigative Site | Barcelona | Catalonia | 08036 | Spain |
| Novartis Investigative Site | Barcelona | 08041 | Spain |
| Novartis Investigative Site | Madrid | 28034 | Spain |
| Estevez-Fraga C, Tabrizi SJ, Wild EJ. Huntington's Disease Clinical Trials Corner: March 2024. J Huntingtons Dis. 2024;13(1):1-14. doi: 10.3233/JHD-240017. |
| 36463457 | Derived | Estevez-Fraga C, Tabrizi SJ, Wild EJ. Huntington's Disease Clinical Trials Corner: November 2022. J Huntingtons Dis. 2022;11(4):351-367. doi: 10.3233/JHD-229006. |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo | Treatment Arm A: matching placebo oral solution once weekly |
| BG001 | Branaplam 56 mg | Treatment Arm A: branaplam 56 mg oral solution once weekly |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Participants in the Safety Analysis Set (SAF) who had an available value for the outcome measure at baseline and Week 17. SAF included all participants who received at least one dose of study drug. | Posted | Mean | Standard Deviation | % change in mHTT protein | Baseline, Week 17 |
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| Primary | 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). | Safety Analysis Set including all participants who received at least one dose of study drug. | Posted | Count of Participants | Participants | From first dose of study treatment up to Week 69 |
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| Secondary | 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. | Participants in the Safety Analysis Set (SAF) who had an available value for the outcome measure at baseline and the corresponding study visit. SAF included all participants who received at least one dose of study drug. | Posted | Mean | Standard Deviation | % change in total brain volume | Baseline, Week 17, Week 33, Week 53, Week 69 |
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| Secondary | 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. | Participants in the Safety Analysis Set (SAF) who had an available value for the outcome measure at baseline and the corresponding study visit, and who did not have subdural hematoma. SAF included all participants who received at least one dose of study drug. | Posted | Mean | Standard Deviation | % change in total brain volume | Baseline, Week 17, Week 33, Week 53, Week 69 |
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| Secondary | 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. | Participants in the Safety Analysis Set (SAF) who had an available value for the outcome measure at baseline and the corresponding study visit. SAF included all participants who received at least one dose of study drug. | Posted | Mean | Standard Deviation | % change in lateral ventricles volume | Baseline, Week 17, Week 33, Week 53, Week 69 |
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| Secondary | 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. | Participants in the Safety Analysis Set (SAF) who had an available value for the outcome measure at baseline and the corresponding study visit, and who did not have subdural hematoma. SAF included all participants who received at least one dose of study drug. | Posted | Mean | Standard Deviation | % change in lateral ventricles volume | Baseline, Week 17, Week 33, Week 53, Week 69 |
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| Secondary | 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. | Participants in the Safety Analysis Set (SAF) who had an available value for the outcome measure at baseline and the corresponding study visit. SAF included all participants who received at least one dose of study drug. | Posted | Mean | Standard Deviation | % change in left caudate volume | Baseline, Week 17, Week 33, Week 53, Week 69 |
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| Secondary | 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. | Participants in the Safety Analysis Set (SAF) who had an available value for the outcome measure at baseline and the corresponding study visit, and who did not have subdural hematoma. SAF included all participants who received at least one dose of study drug. | Posted | Mean | Standard Deviation | % change in left caudate volume | Baseline, Week 17, Week 33, Week 53, Week 69 |
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| Secondary | 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. | Participants in the Safety Analysis Set (SAF) who had an available value for the outcome measure at baseline and the corresponding study visit. SAF included all participants who received at least one dose of study drug. | Posted | Mean | Standard Deviation | % change in right caudate volume | Baseline, Week 17, Week 33, Week 53, Week 69 |
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| Secondary | 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. | Participants in the Safety Analysis Set (SAF) who had an available value for the outcome measure at baseline and the corresponding study visit, and who did not have subdural hematoma. SAF included all participants who received at least one dose of study drug. | Posted | Mean | Standard Deviation | % change in right caudate volume | Baseline, Week 17, Week 33, Week 53, Week 69 |
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| Secondary | 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. | Participants in the Safety Analysis Set (SAF) who had an available value for the outcome measure at baseline and the corresponding study visit. SAF included all participants who received at least one dose of study drug. | Posted | Mean | Standard Deviation | score on scale | Baseline, Week 17, Week 33 and Week 69 |
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| Secondary | 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. | Participants in the Safety Analysis Set (SAF) who had an available value for the outcome measure at baseline and the corresponding study visit. SAF included all participants who received at least one dose of study drug. | Posted | Mean | Standard Deviation | score on scale | Baseline, Week 17, Week 33 and Week 69 |
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| Secondary | 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. | Participants in the Safety Analysis Set (SAF) who had an available value for the outcome measure at baseline and the corresponding study visit. SAF included all participants who received at least one dose of study drug. | Posted | Mean | Standard Deviation | score on scale | Baseline, Week 17, Week 33 and Week 69 |
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| Secondary | 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. | Participants in the Safety Analysis Set (SAF) who had an available value for the outcome measure at the corresponding study visit. SAF included all participants who received at least one dose of study drug. | Posted | Mean | Standard Deviation | fmol | Baseline, Week 9, Week 17 |
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| Secondary | 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. | Safety Analysis Set (SAF) | Posted | Mean | Standard Deviation | fmol | Baseline, Week 17 |
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| Secondary | 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. | Patients in the PK analysis set with an available value for the outcome measure at each timepoint. The PK Analysis Set is only applicable to patients treated with branaplam and includes all participants with at least one evaluable concentration data sample. | Posted | Mean | Standard Deviation | ng/mL | pre-dose and 4, 7, 12, 22, 72 and 168 hours after branaplam dose at Week 1 and Week 17 |
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| Secondary | 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. | Patients in the PK analysis set with an available value for the outcome measure at each timepoint. The PK Analysis Set is only applicable to patients treated with branaplam and includes all participants with at least one evaluable concentration data sample. | Posted | Median | Full Range | hours | pre-dose and 4, 7, 12, 22, 72 and 168 hours after branaplam dose at Week 1 and Week 17 |
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| Secondary | 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. | Patients in the PK analysis set with an available value for the outcome measure at each timepoint. The PK Analysis Set is only applicable to patients treated with branaplam and includes all participants with at least one evaluable concentration data sample. | Posted | Mean | Standard Deviation | hr*ng/mL | pre-dose and 4, 7, 12, 22, 72 and 168 hours after branaplam dose at Week 1 and Week 17 |
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| Secondary | 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. | Patients in the PK analysis set with an available value for the outcome measure at each timepoint. The PK Analysis Set is only applicable to patients treated with branaplam and includes all participants with at least one evaluable concentration data sample. | Posted | Mean | Standard Deviation | hr*ng/mL | pre-dose and 4, 7, 12, 22, 72 and 168 hours after branaplam dose at Week 1 |
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| Secondary | 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. | Patients in the PK analysis set with an available value for the outcome measure at each timepoint. The PK Analysis Set is only applicable to patients treated with branaplam and included all participants with at least one evaluable concentration data sample. | Posted | Mean | Standard Deviation | ng/mL | pre-dose at Weeks 2, 3, 5, 9, 13 and 17 |
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| Secondary | 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. | Patients in the PK analysis set with an available value for the outcome measure at each timepoint. The PK Analysis Set is only applicable to patients treated with branaplam and included all participants with at least one evaluable concentration data sample. | Posted | Mean | Standard Deviation | ng/mL | pre-dose at Weeks 9 and 17 |
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| Secondary | 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. | Patients in the PK analysis set with an available value for the outcome measure at each timepoint. The PK Analysis Set is only applicable to patients treated with branaplam and included all participants with at least one evaluable concentration data sample. | Posted | Mean | Standard Deviation | concentration ratio | pre-dose at Weeks 9 and 17 |
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| Other Pre-specified | 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:
| Safety Analysis Set including all participants who received at least one dose of study drug. sNfL recovery was assessed in participants meeting the criterion for sNfL increase. | Posted | Count of Participants | Participants | From baseline (before first dose of study treatment) up to Week 17 (CSF) and Week 69 (serum) |
|
From first dose of study treatment up to Week 69
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo | Treatment Arm A: matching placebo oral solution once weekly | 0 | 5 | 0 | 5 | 2 | 5 |
| EG001 | Branaplam 56 mg | Treatment Arm A: branaplam 56 mg oral solution once weekly | 0 | 21 | 4 | 21 | 15 | 21 |
| EG002 | Overall | All participants | 0 | 26 | 4 | 26 | 17 | 26 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vestibular neuronitis | Infections and infestations | MedDRA (26.1) | Systematic Assessment |
| |
| Subdural haematoma | Injury, poisoning and procedural complications | MedDRA (26.1) | Systematic Assessment |
| |
| Uterine polyp | Reproductive system and breast disorders | MedDRA (26.1) | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA (26.1) | Systematic Assessment |
| |
| Thrombocytosis | Blood and lymphatic system disorders | MedDRA (26.1) | Systematic Assessment |
| |
| Diarrhoea | Gastrointestinal disorders | MedDRA (26.1) | Systematic Assessment |
| |
| Puncture site pain | General disorders | MedDRA (26.1) | Systematic Assessment |
| |
| COVID-19 | Infections and infestations | MedDRA (26.1) | Systematic Assessment |
| |
| Cystitis | Infections and infestations | MedDRA (26.1) | Systematic Assessment |
| |
| Urinary tract infection | Infections and infestations | MedDRA (26.1) | Systematic Assessment |
| |
| Head injury | Injury, poisoning and procedural complications | MedDRA (26.1) | Systematic Assessment |
| |
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (26.1) | Systematic Assessment |
| |
| Muscular weakness | Musculoskeletal and connective tissue disorders | MedDRA (26.1) | Systematic Assessment |
| |
| Balance disorder | Nervous system disorders | MedDRA (26.1) | Systematic Assessment |
| |
| Headache | Nervous system disorders | MedDRA (26.1) | Systematic Assessment |
| |
| Neuropathy peripheral | Nervous system disorders | MedDRA (26.1) | Systematic Assessment |
| |
| Paraesthesia | Nervous system disorders | MedDRA (26.1) | Systematic Assessment |
| |
| Polyneuropathy | Nervous system disorders | MedDRA (26.1) | Systematic Assessment |
| |
| Delusional disorder, persecutory type | Psychiatric disorders | MedDRA (26.1) | Systematic Assessment |
| |
| Benign prostatic hyperplasia | Reproductive system and breast disorders | MedDRA (26.1) | Systematic Assessment |
| |
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA (26.1) | Systematic Assessment |
|
The terms and conditions of Novartis' agreements with its investigators may vary. Novartis does not prohibit any investigator from publishing. Any publications from a single site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Novartis Pharmaceuticals | 862-778-8300 | Novartis.email@novartis.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Oct 30, 2023 | Aug 27, 2024 | SAP_001.pdf |
Not provided
| ID | Term |
|---|---|
| D006816 | Huntington Disease |
| ID | Term |
|---|---|
| D001480 | Basal Ganglia Diseases |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D003704 | Dementia |
| D002819 | Chorea |
| D020820 | Dyskinesias |
| D009069 | Movement Disorders |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D019636 | Neurodegenerative Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D003072 | Cognition Disorders |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
Not provided
Not provided
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