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    Summary
    EudraCT Number:2016-002804-14
    Sponsor's Protocol Code Number:ZX008-1503
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-09-07
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2016-002804-14
    A.3Full title of the trial
    An Open-Label Extension Trial to Assess the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children and Young Adults with Dravet Syndrome
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical Study to evaluate the safety and effectiveness of Fenfluramine as adjunct therapy in children and young adults with Dravet Syndrome
    A.4.1Sponsor's protocol code numberZX008-1503
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02823145
    A.5.4Other Identifiers
    Name:IND NumberNumber:125797
    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 SponsorZogenix International Limited
    B.1.3.4CountryUnited Kingdom
    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 supportZogenix, Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationZogenix, Inc.
    B.5.2Functional name of contact pointAJ Acker
    B.5.3 Address:
    B.5.3.1Street Address5858 Horton Street, Suite 455
    B.5.3.2Town/ cityEmeryville
    B.5.3.3Post codeCA 94608
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1510550 8331
    B.5.5Fax number+1510550 8341
    B.5.6E-mailajacker@zogenix.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1219
    D.3 Description of the IMP
    D.3.1Product nameFenfluramine hydrochloride (red)
    D.3.2Product code ZX008
    D.3.4Pharmaceutical form Oral solution
    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 INNFENFLURAMINE HYDROCHLORIDE
    D.3.9.1CAS number 404-82-0
    D.3.9.2Current sponsor codeZX008
    D.3.9.3Other descriptive nameFENFLURAMINE HYDROCHLORIDE (red)
    D.3.9.4EV Substance CodeSUB02115MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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.IMP: 2
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1219
    D.3 Description of the IMP
    D.3.1Product nameFenfluramine hydrochloride (colorless)
    D.3.2Product code ZX008
    D.3.4Pharmaceutical form Oral solution
    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 INNFENFLURAMINE HYDROCHLORIDE
    D.3.9.1CAS number 404-82-0
    D.3.9.2Current sponsor codeZX008
    D.3.9.3Other descriptive nameFENFLURAMINE HYDROCHLORIDE (colorless)
    D.3.9.4EV Substance CodeSUB02115MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Dravet's syndrome
    E.1.1.1Medical condition in easily understood language
    Dravet's syndrome
    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 19.0
    E.1.2Level LLT
    E.1.2Classification code 10073682
    E.1.2Term Dravet syndrome
    E.1.2System Organ Class 100000004850
    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 long-term safety and tolerability of ZX008.
    E.2.2Secondary objectives of the trial
    •To assess the effect of ZX008 relative to the pre-ZX008 baseline on the following effectiveness measures:
    -The change in the frequency of convulsive seizures
    -The proportion of subjects who achieve a ≥40%, ≥50%, and ≥75% reduction in convulsive seizure frequency
    -The longest convulsive seizure-free interval
    -The percentage of convulsive seizure-free days
    -The non-convulsive seizure frequency
    -The convulsive + non-convulsive seizure frequency.
    •To estimate the incidence of the following on subjects receiving ZX008:
    -Use of rescue medication
    -Hospitalization to treat seizures
    -Status epilepticus.

    Please refer to the Clinical Study Protocol, Section 2 Study Objectives and Endpoints for complete list of Secondary Endpoints
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject is aged 2 to 18 years inclusive, as of the day of the core study Screening Visit. Subject is male or non-pregnant, non-lactating female. Female subjects of childbearing potential must not be pregnant or breast-feeding. Female subjects of childbearing potential must have a negative urine pregnancy test. Subjects of childbearing or child-fathering potential must be willing to use medically acceptable forms of birth control, which includes abstinence, while being treated on this study and for 30 days after the last dose of study drug.
    2. Subject has satisfactorily completed the core study in the opinion of the investigator and the sponsor.
    3. Subject has documented medical history to support a clinical diagnosis of Dravet syndrome, where convulsive seizures are not completely controlled by current antiepileptic drugs.
    4. Subject has been informed of the nature of the study and informed consent has been obtained from the legally responsible parent/guardian.
    5. Subject has provided assent in accordance with IRB/IEC requirements, if capable.
    6. Subject’s caregiver is willing and able to be compliant with diary completion, visit schedule and study drug accountability.
    7. Subject’s parent/caregiver has been compliant with diary completion during the core study, in the opinion of the investigator (eg, at least 90% compliant).
    8. Subjects entering from study ZX008-1504 must be receiving a therapeutically relevant and stable dose of clobazam, valproic acid, and stiripentol (Cohort 1 Dose Regimen 3 and Cohort 2 only) for at least 4 weeks prior to screening and are expected to remain stable throughout the study.
    E.4Principal exclusion criteria
    1. Subject has a known hypersensitivity to fenfluramine or any of the excipients in the study medication.
    2. Subject has current or past history of cardiovascular or cerebrovascular disease, myocardial infarction or stroke.
    3. Subject with current cardiac valvulopathy or pulmonary hypertension that the investigator, parent, IPCAB, IDSMC, or sponsor deems clinically significant and warrants discontinuation of study medication.
    4. Subject has current or recent history of Anorexia Nervosa, bulimia, or depression within the prior year that required medical treatment or psychological treatment for a duration greater than 1 month.
    5. Subject is at imminent risk of self-harm or harm to others, in the investigator’s opinion, based on clinical interview and responses provided on the Columbia-Suicide Severity Rating Scale (C-SSRS). Subjects must be excluded if they report suicidal behavior as measured by the C-SSRS Since Last Visit, which includes suicidal ideation with intent and plan (Item #5). If a subject reports suicidal ideation on Item 4 without specific plan, and the investigator feels that the subject is appropriate for the study considering the potential risks, the investigator must document appropriateness for inclusion, and discuss with the parent/caregiver to be alert to mood or behavioral changes, especially around times of dose adjustment.
    6. Subject has a current or past history of glaucoma.
    7. Subject has moderate or severe hepatic impairment. Asymptomatic subjects with mild hepatic impairment (elevated liver enzymes <3x upper limited of normal [ULN] and/or elevated bilirubin <2x ULN) may be entered into the study after review and approval by the Medical Monitor in conjunction with the sponsor, in consideration of comorbidities and concomitant medications.
    8. Subject is receiving concomitant therapy with: centrally-acting anorectic agents; monoamine-oxidase inhibitors; any centrally-acting compound with clinically appreciable amount of serotonin agonist or antagonist properties, including serotonin reuptake inhibition; atomoxetine, or other centrally-acting noradrenergic agonist; cyproheptadine, and/or cytochrome P450 (CYP) 2D6/3A4/2B6 inhibitors/substrates (see Appendix 1). (Note: Short-term medication requirements will be handled on a per case basis by the Medical Monitor.)
    9. Subject is currently taking carbamazepine, oxcarbamazepine, eslicarbazepine, phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as maintenance therapy.
    10. For subjects entering from core studies ZX008-1501, ZX008-1502, or ZX008-1504 (Cohort 1/Dose Regimens 1 &2): Subject is currently receiving or has received stiripentol in the past 21 days prior to core study Visit 1.
    11. Subject is unwilling to refrain from large or daily servings of grapefruits and/or Seville oranges, and their juices beginning with Visit 1 and throughout the study.
    12. Subject has positive result on urine THC Panel or whole blood CBD at Visit 1.
    13. Subject is unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.
    14. Subject has a clinically significant condition, or has had clinically relevant symptoms or a clinically significant illness in the 4 weeks prior to Visit 1, other than epilepsy, that would negatively impact study participation, collection of study data, or pose a risk to the subject.
    E.5 End points
    E.5.1Primary end point(s)
    The effectiveness endpoints of the study are:
    •Number of seizures by type
    •Convulsive seizure-free interval
    •Clinical Global Impression – Improvement as assessed by parent/caregiver
    •Clinical Global Impression – Improvement as assessed by principal investigator
    •QOLCE to measure changes in quality of life of the subject
    •PedsQL to measure changes in quality of life of the subject
    •QoL of parent/caregiver using the EQ-5D-5L scale
    •Affective symptoms of parent/caregiver using the HADS (in parents/caregivers from core studies ZX008-1501 and ZX008-1502 only)
    •Duration of prolonged seizures (seizure type that, during pre-Z008 baseline, had duration >2 minutes)
    •Number of episodes of status epilepticus
    •Number of instances of rescue medication use and number of doses
    •Number of inpatient hospital admissions due to seizures
    E.5.1.1Timepoint(s) of evaluation of this end point
    Please refer to study protocol
    E.5.2Secondary end point(s)
    The safety endpoints of the study are:
    •AEs
    •Laboratory safety (hematology, chemistry, urinalysis)
    •Vital signs (blood pressure, heart rate, temperature, and respiratory rate)
    •Physical examination
    •Neurological examination
    •12-lead ECGs
    •Doppler ECHOs
    •Body weight
    •BRIEF to measure cognition.

    For subjects from core study ZX008-1504 only, the exploratory endpoints of this study are:
    •Health and social care resource use, including GP visits, speech and language, occupational and physical therapy, in addition to acute hospital and institutional length of stay, loss of work, etc
    •Sleep quality
    •Mealtime behavior
    •Karolinska Sleepiness Scale to measure the effect of study medication on sleepiness
    E.5.2.1Timepoint(s) of evaluation of this end point
    Please refer to study protocol
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Information not present in EudraCT
    E.8.4 The trial involves multiple sites in the Member State concerned Information not present in EudraCT
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA35
    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
    Canada
    Denmark
    France
    Germany
    Italy
    Norway
    Spain
    Sweden
    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 years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    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: 310
    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: 217
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 93
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2016-09-07. Yes
    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
    Children and adolescents
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 310
    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)
    standard care
    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 Decision2017-04-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-11-03
    P. End of Trial
    P.End of Trial StatusCompleted
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