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    Summary
    EudraCT Number:2018-004496-12
    Sponsor's Protocol Code Number:1042-PCDH19-3002
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-08-01
    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 ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2018-004496-12
    A.3Full title of the trial
    A double-blind, randomized, placebo-controlled trial of adjunctive ganaxolone treatment in female children with protocadherin 19 (PCDH19)-related epilepsy followed by long-term open-label treatment
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study with an investigational drug called ganaxolone in female children with protocadherin 19 (PCDH19)-related epilepsy
    A.4.1Sponsor's protocol code number1042-PCDH19-3002
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03865732
    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 SponsorMarinus Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    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 supportMarinus Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMarinus Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointSafety Department
    B.5.3 Address:
    B.5.3.1Street Address5 Radnor Corporate Center 100 Matsonford Road
    B.5.3.2Town/ cityRadnor,
    B.5.3.3Post codePA 19087
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1 4846792138
    B.5.6E-mailsafetyPCDH193002@marinuspharma.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 nameGanaxolone
    D.3.2Product code CCD 1042, MD 9150000, Mepalon 1042, SPT3162
    D.3.4Pharmaceutical form Oral suspension
    D.3.4.1Specific paediatric formulation Yes
    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 INNGANAXOLONE
    D.3.9.1CAS number 383-98323-2
    D.3.9.2Current sponsor codeGNX
    D.3.9.4EV Substance CodeSUB07880MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 suspension
    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
    protocadherin 19 (PCDH19)-related epilepsy
    E.1.1.1Medical condition in easily understood language
    protocadherin 19 (PCDH19)-related epilepsy
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10032061
    E.1.2Term Other forms of epilepsy
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary:

    To assess the efficacy of Ganaxolone (GNX) compared with Placebo, in biomarker-positive subjects, as adjunctive therapy for the treatment of primary seizures types in children with genetically-confirmed PCDH19-related epilepsy at the end of the 17-week double-blind (DB) phase.
    E.2.2Secondary objectives of the trial
    Secondary:
    • •To assess the effect of GNX on primary seizure rate in biomarker negative subjects.
    • To assess behavioral/neuropsychiatric changes in subjects receiving GNX compared with subjects receiving PBO as adjunctive therapy at the end of the 17-week DB phase.
    • To assess the safety and tolerability of GNX compared with PBO as adjunctive therapy at the end of the 17-week DB phase.
    • To assess pharmacokinetic (PK) parameters in subjects receiving GNX doses up to 63 mg/kg/day ( or 1800 mg/day maximum) throughout the study.
    • To assess the long-term efficacy of GNX when administered as adjunctive therapy throughout the open-label (OL) phases.
    •To assess the long-term safety and tolerability of GNX when administered as adjunctive therapy throughout the open-label phases.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion Criteria:
    1. Molecular confirmation of a pathogenic or likely pathogenic PCDH19 variant. Genetic mutations will be confirmed by the sponsor's chosen central laboratory.
    2. Female subjects aged 1 through 17 years, inclusive.
    3. Subject/parent or LAR willing to give written informed consent/and subjects assent, after being properly informed of the nature and risks of the study and prior to engaging in any study related procedures.
    4. Failure to control seizures despite appropriate trial of 2 or more antiseizure mediations at therapeutic doses.
    5. Have at least 12 countable/witnessed primary seizures over an 84 day (12 week) period prior to the screening visit (pre-baseline screening). The primary seizure types are defined as countable focal
    seizures that include progressive hypotonia and impaired awareness, or any countable focal or generalized seizure with a clear motor component. Focal and generalized nonmotor seizures and myoclonic seizures do not count as the primary seizure types.
    6. Subject must be approved to participate by sponsor or its designee (eg, Epilepsy Consortium) after review of medical history, genetic testing, seizure classification video (if available), and historical seizure calendars.
    7. Concomitant AED regimens must have been stable for at least 1 month prior to the screening visit and must remain stable from screening to the end of the DB phase. Ketogenic diets and modified Atkins diet should be unchanged for 3 months prior to screening and must remain stable throughout baseline and the DB phase.
    8. Subjects with surgically implanted VNS will be allowed to enter the study provided that all of the following conditions are met:
    • The VNS has been in place for ≥ 1 year prior to the screening visit.
    • The settings must have remained constant for 3 months prior to the
    screening visit and remain constant throughout baseline and the DB phase.
    • The battery is expected to last for the duration of baseline and the DB phase.
    9. Parent/caregiver is able and willing to maintain an accurate and complete daily seizure diary for the duration of the study.
    10. Able and willing to take investigational product (suspension) with food 3 times daily. Ganaxolone must be administered with food.
    11. Sexually active female of childbearing potential must be using a medically acceptable method of birth control and have a negative quantitative serum β-human chorionic growth hormone (β-HCG) test collected at the initial screening visit. Childbearing potential is defined as a female who is biologically capable of becoming pregnant. A medically acceptable method of birth control includes intrauterine devices in place for at least 3 months prior to the screening visit, surgical sterilization, or adequate barrier methods (eg, diaphragm or condom and foam). An oral contraceptive alone is not considered adequate for the purpose of this study. Use of oral contraceptives in combination with another method (eg, a spermicidal cream) is acceptable. In subjects who are not sexually active, abstinence is an acceptable form.
    E.4Principal exclusion criteria
    Exclusion Criteria:
    1. Previous exposure to GNX.
    2. Pregnant or breastfeeding.
    3. Subjects with >8 consecutive weeks (56 consecutive days) of primary seizure freedom during the 12-week pre-baseline screening period.
    4. Subjects with ≤ 3 primary seizures during the 12-week baseline
    period.
    5. Concurrent use of strong inducers or inhibitors of CYP3A4/5/7 is not permitted. Any strong inhibitor or inducer of CYP3A4/5/7 must be discontinued at least 28 days before Baseline/Randomization Visit. This does not include approved AEDs.
    6. Subjects with a positive result on tetrahydrocannabinol (THC) or non-approved cannabidiol (CBD) test (via plasma drug screen). Tetrahydrocannabinol and/or non-approved CBD will be allowed in the
    OL phase.
    7. Chronic use of oral steroid medications, ketoconazole (except for topical formulations), St. John's Wort, or other investigational products is not permitted. Intermittent (<5 consecutive days/month or 10 cumulative days per month) use of corticosteroids as a rescue medication for breakthrough seizures may be allowed after sponsor approval.
    8. Changes in any chronic AED medication (i.e., changes in dose or starting a new chronic AED) within the last month prior to the screening visit (Visit 1) and during the 12 week baseline period (i.e., between Visit 1 and Visit 2). Changes in rescue AED medications to treat acute breakthrough seizures may be permitted with sponsor's approval. Changes in other (i.e., non-AED) chronic medications may be permitted with sponsor's approval.
    9. Have an active CNS infection, demyelinating disease, degenerative neurological disease, or CNS disease deemed progressive as evaluated by brain imaging (magnetic resonance imaging [MRI]).
    10. Have any disease or condition (medical or surgical; other than PCDH19) at the screening visit that might compromise the hematologic, cardiovascular, pulmonary, renal, gastrointestinal, or hepatic systems; or other conditions that might interfere with the absorption, distribution, metabolism, or excretion of the investigational product, or would place the subject at increased risk.
    11. An aspartate aminotransferase (AST/serum glutamic oxaloacetic transaminase [SGOT]) or alanine aminotransferase (ALT/serum glutamic pyruvic transaminase [SGPT]) > 3 × the upper limit of normal (ULN) at screening and if applicable, confirmed by a repeat test. If the subject has another reason to be excluded, repeated liver enzymes are not required.
    12. Total bilirubin levels > 1.5 × ULN at screening and if applicable confirmed by a repeat test. In cases of documented, stable medical condition (ie, Gilbert's Syndrome) resulting in levels of total bilirubin > ULN, the medical monitor can determine if a protocol exception can be made.
    13. Subjects with significant renal insufficiency, estimated glomerular filtration rate (eGFR) < 30 mL/min (calculated using the Cockcroft-Gault formula or Pediatric GFR calculator or Bedside Schwartz), will be excluded from study entry or will be discontinued if the criterion is met
    post baseline.
    14. Have been exposed to any other investigational drug within 30 days or fewer than 5 half lives prior to the screening visit.
    15. Unwillingness to withhold grapefruit, Seville oranges star fruit, or grapefruit containing products from diet 14 days prior to 1st dose and for the duration of the study
    16. Unwillingness to withhold alcohol throughout the entire clinical trial.
    17. Have active suicidal plan/intent or have had active suicidal thoughts in the past 6 months or a suicide attempt in the past 3 years.
    18. Known sensitivity or allergy to any component in the investigational product(s), progesterone or other related steroid compounds.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Endpoint (seizure control)
    The primary efficacy endpoint is the percent change in 28-day primary
    seizure frequency at the end of the 17-week DB phase relative to the
    baseline. The primary seizure types are defined as focal seizures that
    include progressive hypotonia and impaired awareness or any countable
    focal or generalized seizure with a clear motor component. Focal and
    generalized nonmotor seizures and myoclonic seizures do not count as
    the primary seizure types.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The analyses of the primary endpoint will be performed on the sum of the individual countable seizures and each series of continuous uncountable series of seizures (each contributes 1 to the sum).

    Post-baseline 28-day seizure frequency will be calculated as the total number of seizures in the 17-week DB treatment phase divided by the number of days with seizure data in the phase, multiplied by 28.
    Baseline 28-day seizure frequency will be calculated as the total number of seizures in the baseline phase divided by the number of days with seizure data in the phase, multiplied by 28.
    E.5.2Secondary end point(s)
    Secondary endpoints (seizure control):
    •Percentage of subjects experiencing a ≥ 50% reduction in 28-day primary seizure frequency compared to the 12 week baseline

    Secondary endpoints (behavioral/neuropsychiatric):
    • Behavior Rating Inventory of Executive Function (BRIEF, preschool version BRIEF-P)
    • Aberrant Behavior Check – Community (ABC-C)
    • Children’s Sleep Habit Questionnaire (CHSQ)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Seizure Frequency - Week -12 Screening Visit (start of Baseline); Wk0 baseline, Wks 1-5, 9, 13, 17

    and behavioral/neuropsychiatric
    Week 0 and 17
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    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 Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Open label - 17 weeks double blinded followed by up to 3 year open label
    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 trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA32
    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
    Australia
    Belgium
    Czechia
    Denmark
    France
    Germany
    Hungary
    Ireland
    Italy
    Netherlands
    Poland
    Spain
    United Kingdom
    United States
    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 years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days28
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial days20
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 30
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 27
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 3
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Paediatrics - Written informed consent will be obtained from the parent/legally authorized representative for all study
    subjects prior to any study-related procedures, including screening assessments.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 11
    F.4.2.2In the whole clinical trial 30
    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)
    Eligible subjects may participate in a long term open label phase of the study. The open-label phase will continue until the sponsor terminates the program or Ganaxolone has been approved and marketed the investigational product in the subjects' respective country. It is
    estimated to continue for 3 years.
    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 Decision2019-09-24
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial StatusCompleted
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