A study to evaluate the safety, tolerability and efficacy of weekly oral doses of branaplam in patients with Huntington's Disease

• Register: EUCTR
• Last refreshed on: 4 November 2024
• Main ID: EUCTR2020-000105-92-IT
• Date of registration: 20/09/2021
• Prospective Registration: Yes
• Primary sponsor: NOVARTIS PHARMA AG
• Public title: A study to evaluate the safety, tolerability and efficacy of weekly oral doses of branaplam in patients with Huntington's Disease
• Scientific title: A Randomized, Double-Blind, Placebo-Controlled Dose Range Finding Study with Open-Label Extension to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LMI070/branaplam when Administered as Weekly Oral Doses in Participants with Early Manifest Huntington's Disease - -
• Date of first enrolment: 26/11/2021
• Target sample size: 75
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2020-000105-92
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Canada, France, Germany, Hungary, Italy, Lithuania, Russian Federation, Spain, United Kingdom, United States

Contacts

• Name: Regulatory Affairs
• Affiliation: Novartis Farma S.p.A.

• Name: Regulatory Affairs
• Affiliation: Novartis Farma S.p.A.

Key inclusion & exclusion criteria

Inclusion criteria:
1. Signed informed consent must be obtained prior to participation in the study
2. Must be capable of providing informed consent
3. Clinically diagnosed Stage 1 or 2 HD with a diagnostic confidence interval (DCL) = 4 and a UHDRS Total Functional Capacity (TFC) >8 at screening
4. Genetically confirmed HD, with presence of =40 CAG repeats in the huntingtin gene
- For participants without prior documentation, a sample must be sent to the CAG lab vendor and confirmation of the CAG repeat length for these participants must be obtained prior to randomization
- For participants with previously existing documentation of their CAG repeat length, it is acceptable to use this prior data to qualify for randomization. These participants must also submit a sample for CAG repeat testing to be conducted by the central study laboratory.
5. Male and female participants between 25 to 75 years of age, inclusive, on the day of Informed Consent signature
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 50
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 25

Exclusion criteria:
1. Use of other investigational drugs within 5 half-lives of the first dose of study drug or within 30d, whichever is longer.
2. Prior participation in clinical trial investigating a huntingtin-lowering therapy (unless participant received only placebo)
3. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar chemical classes
4. Participants taking medications prohibited by the protocol
5. Any medical history, lumbar surgery or condition that would interfere with the ability to complete the protocol specified assessments
6. History of malignancy of any organ system, treated or untreated, regardless of whether there is evidence of local recurrence or metastases
7. 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 study results
8. Score yes on item 4 or 5 of the C-SSRS, if this ideation occurred in the past 6m from screening or yes on any item of the Suicidal Behavior section, except for the Non-Suicidal Self-Injurious Behavior, if this behavior occurred in the past 2y
9. Pregnant or nursing (lactating) women. WOCB potential should not become pregnant during the study or 7 months after stopping study medication.
10. Sexually active males unwilling to use a condom together with a spermicidal agent during intercourse while taking study drug and for 120d (in total) after the last dose of the study drug. A condom is required to be used also by vasectomized men as well during intercourse with a male partner of the study subject in order to prevent delivery of the genotoxic drug via semen.
11. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using one highly effective methods of contraception during dosing and for 7 months after stopping the study medication. Highly effective methods of birth control are those methods that have a less than 1% chance of an unwanted pregnancy during 1 year (see protocol). In addition to one highly effective method of contraception, a condom is
required for all male partners of female participants to prevent fathering a child AND to prevent exposure of study treatment via vaginal fluid to
your partner, until at least 7 months following the last dose of study treatment. Total abstinence, Periodic abstinence and withdrawal are NOT acceptable methods of contraception. Oral contraception cannot be considered due to potential decreased efficacy as potential DDI with branaplam. In case local regulations deviate from the contraception methods listed above, local regulations apply and will be described in the ICF.
12. History of:
- Gene therapy or cell transplantation or any other experimental brain surgery
- Hepatitis B or hepatitis C or serologic evidence for active viral hepatitis
- Immunodeficiency diseases, including a positive HIV test
- History or current evidence of drug or alcohol abuse in the 12m prior to screening, as defined by the DSM-V criteria for substance abuse. For former abusers, abstinence should be confirmed by laboratory tests
13. 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 l

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Huntington's disease
MedDRA version: 20.0 Level: PT Classification code 10070668 Term: Huntington's disease System Organ Class: 10010331 - Congenital, familial and genetic disorders

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Product Name: branaplam
Product Code: [LMI070]
Pharmaceutical Form: Oral solution
INN or Proposed INN: BRANAPLAM
CAS Number: 1562338-39-9
Current Sponsor code: LMI070
Concentration unit: µg/ml microgram(s)/millilitre
Concentration type: equal
Concentration number: 350-
Pharmaceutical form of the placebo: Oral solution
Route of administration of the placebo: Oral use

Product Name: branaplam
Product Code: [LMI070]
Pharmaceutical Form: Oral solution
INN or Proposed INN: BRANAPLAM
CAS Number: 1562338-39-9
Current Sponsor code: LMI070
Concentration unit: µg/ml microgram(s)/millilitre
Concentration type: equal
Concentration number: 350-

Product Name: branaplam
Product Code: [LMI070]
Pharmaceutical Form: Oral solution
INN or Proposed INN: BRANAPLAM
CAS Number: 1562338-39-9
Current Sponsor code: LMI070
Concentration unit: µg/ml microgram(s)/millilitre
Concentration type: equal
Concentration number: 350-

Product Name: branaplam
Product Code: [LMI070]
Pharmaceutical Form: Oral solution
INN or Proposed INN: BRANAPLAM
CAS Number: 1562338-39-9
Current Sponsor code: LMI070
Concentration unit: µg/ml microgram(s)/millilitre
Concentration type: equal
Concentration number: 350-

Product Name: branaplam
Product Code: [LMI070]
Pharmaceutical Form: Oral solution
INN or Proposed INN: BRANAPLAM
CAS Number: 1562338-39-9
Current Sponsor code: LMI070
Concentration unit: µg/ml microgram(s)/millilitre
Concentration type: equal
Concentration number: 350-

Primary Outcome(s)

Secondary Objective: - To assess the pharmacodynamics of branaplam when administered once weekly in participants with HD on clinical, imaging, and biomarker endpoints relevant to HD
- To assess pharmacokinetics of branaplam and its metabolite UFB112 in plasma and CSF

Main Objective: - To assess the dose-response relationship of branaplam administered over 16 weeks on mHTT protein change from baseline in cerebrospinal fluid (CSF)
- To evaluate the safety and tolerability of branaplam when administered for 16 weeks or longer in participants with HD

Primary end point(s): - Reduction (%) of mutant HTT protein in CSF
- Safety and tolerability parameters/assessments including but not limited to adverse events, physical exam findings, clinical laboratory assessments, HTT lowering etc.

Timepoint(s) of evaluation of this end point: - From baseline to week 17 of the Dose Range Finding (DRF)
- From baseline to week 17 of the DRF, from week 17 of the DRF to month 12 of the blinded extension (BE), from month 12 of the BE to 1 year of the open label extension (OLE)

Secondary Outcome(s)

Secondary end point(s): - Ventricular, Caudate and Total Brain Volume as measured by structural magnetic resonance imaging (MRI)
- Unified Huntington's Disease Rating Scale (UHDRS), Total Functional Capacity (TFC), UHDRS Total Motor Score (TMS), UHDRS Independence Scale (IS)
- Concentrations of total HTT and mHTT protein in CSF, PBMCs and plasma
- PK parameters (e.g. AUClast, AUCtau, Cmax, Tmax) of branaplam and its metabolite UFB112 in plasma
- Ctrough of branaplam and UFB112 in plasma across the study duration
- Concentrations of branaplam and its metabolite UFB112 in CSF and concentration ratio CSF/plasma of the analytes

Timepoint(s) of evaluation of this end point: - From baseline to week 17 of the DRF, from week 17 of the DRF to month 12 of the BE, from month 12 of the BE to 1 year of the OLE
- From baseline to week 17 of the DRF, from week 17 of the DRF to month 12 of the BE, from month 12 of the BE to 1 year of the OLE
- From baseline to week 17 of the DRF, from week 17 of the DRF to month 12 of the BE, from month 12 of the BE to 1 year of the OLE
- From baseline to week 17 of the DRF
- From baseline to week 17 of the DRF
- From baseline to week 17 of the DRF

Secondary ID(s)

2020-000105-92-DE

CLMI070C12203

Source(s) of Monetary Support

Novartis Pharma AG

Ethics review

Status: Approved
Approval date: 27/09/2021
Contact:

Results

• Results available: Yes
• Date Posted: 12/09/2024
• Date Completed: 23/10/2023
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-000105-92/results