Clinical trial NCT05111249: A Dose Range Finding Study With Open-Label Extension to Evaluate the Safety of Oral LMI070/Branaplam in Early Manifest Huntington's Disease
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
Overall status: TERMINATED
Phase: PHASE2
Conditions: Early Manifest Huntington Disease
Keywords: Early Manifest
Huntington Disease
Branaplam
LMI070
Dose Range Finding
Safety
HD
mHTT
Pharmacokinetics
oral
Adult
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2021-11-08
Enrollment: 26
Sex: ALL
Minimum age (years): 25
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Percentage Change From Baseline to Week 17 in mHTT Protein in CSF
timeFrame: Baseline, Week 17
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From first dose of study treatment up to Week 69
Secondary outcomes:
measure: Percentage Change From Baseline in Total Brain Volume
timeFrame: Baseline, Week 17, Week 33, Week 53, Week 69
measure: Percentage Change From Baseline in Total Brain Volume Excluding Patients With Subdural Hematoma
timeFrame: Baseline, Week 17, Week 33, Week 53, Week 69
measure: Percentage Change From Baseline in Lateral Ventricles Volume
timeFrame: Baseline, Week 17, Week 33, Week 53, Week 69
measure: Percentage Change From Baseline in Lateral Ventricles Volume Excluding Patients With Subdural Hematoma
timeFrame: Baseline, Week 17, Week 33, Week 53, Week 69
measure: Percentage Change From Baseline in Left Caudate Volume
timeFrame: Baseline, Week 17, Week 33, Week 53, Week 69
measure: Percentage Change From Baseline in Left Caudate Volume Excluding Patients With Subdural Hematoma
timeFrame: Baseline, Week 17, Week 33, Week 53, Week 69
measure: Percentage Change From Baseline in Right Caudate Volume
timeFrame: Baseline, Week 17, Week 33, Week 53, Week 69
measure: Percentage Change From Baseline in Right Caudate Volume Excluding Patients With Subdural Hematoma
timeFrame: Baseline, Week 17, Week 33, Week 53, Week 69
measure: Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Functional Capacity (TFC)
timeFrame: Baseline, Week 17, Week 33 and Week 69
measure: Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Motor Scale (TMS)
timeFrame: Baseline, Week 17, Week 33 and Week 69
measure: Change From Baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Independence Scale (IS)
timeFrame: Baseline, Week 17, Week 33 and Week 69
measure: Concentrations of mHTT Protein and Total HTT in CSF
timeFrame: Baseline, Week 9, Week 17
measure: Concentrations of mHTT Protein and Total HTT in Plasma
timeFrame: Baseline, Week 17
measure: Maximum Observed Plasma Concentration (Cmax) of Branaplam and Its Metabolite UFB112
timeFrame: pre-dose and 4, 7, 12, 22, 72 and 168 hours after branaplam dose at Week 1 and Week 17
measure: Time to Reach Maximum Plasma Concentration (Tmax) of Branaplam and Its Metabolite UFB112
timeFrame: pre-dose and 4, 7, 12, 22, 72 and 168 hours after branaplam dose at Week 1 and Week 17
measure: Area Under the Plasma Concentration-time Curve From Time Zero to 168 Hours (AUC0-168h) of Branaplam and Its Metabolite UFB112
timeFrame: pre-dose and 4, 7, 12, 22, 72 and 168 hours after branaplam dose at Week 1 and Week 17
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of Branaplam and Its Metabolite UFB112
timeFrame: pre-dose and 4, 7, 12, 22, 72 and 168 hours after branaplam dose at Week 1
measure: Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in Plasma
timeFrame: pre-dose at Weeks 2, 3, 5, 9, 13 and 17
measure: Trough Concentration (Ctrough) of Branaplam and Its Metabolite UFB112 in CSF
timeFrame: pre-dose at Weeks 9 and 17
measure: Concentration Ratio CSF/Plasma of Branaplam and Its Metabolite UFB112
timeFrame: pre-dose at Weeks 9 and 17
Other outcomes:
measure: Number of Participants With NfL Increase and Recovery
timeFrame: From baseline (before first dose of study treatment) up to Week 17 (CSF) and Week 69 (serum)
Locations:
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Angers Cedex 9
country: France
facility: Novartis Investigative Site
city: Creteil
country: France
facility: Novartis Investigative Site
city: Lille
country: France
facility: Novartis Investigative Site
city: Bochum
country: Germany
facility: Novartis Investigative Site
city: Muenster
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Szeged
country: Hungary
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
Study officials:
References: