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    Summary
    EudraCT Number:2020-000105-92
    Sponsor's Protocol Code Number:CLMI070C12203
    National Competent Authority:Lithuania - SMCA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2021-10-28
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedLithuania - SMCA
    A.2EudraCT number2020-000105-92
    A.3Full title of the trial
    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
    Atsitiktinių imčių, dvigubai koduotas, placebu kontroliuojamas dozių ribų nustatymo tyrimas su atviru pratęsimu, siekiant įvertinti kartą per savaitę per burną vartojamo branaplamo (LMI070) saugumą, toleravimą, farmakokinetiką ir farmakodinamiką tiriamiesiems, sergantiems ankstyvojo pasireiškimo Hantingtono liga
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to evaluate the safety, tolerability and efficacy of weekly oral doses of branaplam in patients with Huntington's Disease
    A.4.1Sponsor's protocol code numberCLMI070C12203
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNovartis Pharma AG
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNovartis Pharma AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSIA Novartis Baltics Lithuanian Branch
    B.5.2Functional name of contact pointClinical Trial Information Desk
    B.5.3 Address:
    B.5.3.1Street AddressUpės str. 19
    B.5.3.2Town/ cityVilnius
    B.5.3.3Post codeLT-08128
    B.5.3.4CountryLithuania
    B.5.4Telephone number+370 5 269 1650
    B.5.6E-mailDRA.Lithuania@novartis.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namebranaplam
    D.3.2Product code LMI070
    D.3.4Pharmaceutical form Oral solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBRANAPLAM
    D.3.9.1CAS number 1562338-39-9
    D.3.9.2Current sponsor codeLMI070
    D.3.9.4EV Substance CodeSUB188600
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboOral solution
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Huntington's disease
    E.1.1.1Medical condition in easily understood language
    Huntington's disease
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10070668
    E.1.2Term Huntington's disease
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - 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
    E.2.2Secondary objectives of the trial
    - 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
    E.2.3Trial contains a sub-study No
    E.3Principal 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
    E.4Principal 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 laboratory evidence (see protocol) at screening
    14. Cardiovascular exclusion criteria:
    - History or current diagnosis of ECG abnormalities indicating significant risk or safety concern for study participants (see protocol)
    - History or concomitant clinically significant cardiac arrhythmias, complete left bundle branch block, high-grade AV block
    - History of familial long QT syndrome or known family history of TdP, risks for TdP including uncorrected hypokalemia or hypomagnesemia, history of clinically significant/symptomatic bradycardia and a family history of idiopathic sudden death.
    - Resting QTcF ≥450msec (male) or ≥460msec (female) at pretreatment or inability to determine the QTcF interval
    - Use of agents known to prolong the QT interval or with a known risk of TdP unless it can be permanently discontinued for the duration of study
    - Uncontrolled hypertension at screening >140mmHg or average diastolic blood pressure > 90mmHg
    15. Any clinically significant hematological abnormality at screening and/or laboratory evidence (see protocol)
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(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)
    E.5.2Secondary 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
    E.5.2.1Timepoint(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
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA23
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Canada
    Russian Federation
    United States
    Belgium
    France
    Germany
    Hungary
    Italy
    Lithuania
    United Kingdom
    Spain
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days11
    E.8.9.2In all countries concerned by the trial years4
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 52
    F.4.2.2In the whole clinical trial 75
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    By the end of the study, either the protocol will be amended to extend the open-label extension beyond a year, or a separate extension study will be initiated to offer continued access to branaplam.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-03-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-02-24
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2023-10-27
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