Back to resultsA 2-Part Study to Investigate the Dose-Ranging Safety and Pharmacokinetics, Followed by the Efficacy and Safety of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children ≥ 2 Years Old and Young Adults With Dravet Syndrome
Primary Purpose
Dravet Syndrome
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
ZX008 (Fenfluramine Hydrochloride)
Matching Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Dravet Syndrome focused on measuring Seizure, Tonic clonic, Epilepsy, Myoclonic, Encephalopathy
Eligibility Criteria
Key Inclusion Criteria:
- Subject must be male or non-pregnant, non-lactating female, aged 2 to 18 years (inclusive).
- Subject must have documented medical history to support a clinical diagnosis of Dravet syndrome, where convulsive seizures are not completely controlled by current antiepileptic drugs.
- Subject must be receiving a therapeutically relevant and stable dose of stiripentol (STP) plus clobazam (CLB) and/or valproate (VPA), and for at least 4 weeks prior to screening and be expected to remain stable throughout the study (Cohort 2 only).
- Subject must be receiving a stable dose of CLB and VPA, administered twice daily (BID), to be eligible for Dose Regimen 1 and 2, or subject must be receiving a stable dose of CLB, VPA, and STP, administered BID, to be eligible for Dose Regimen 3 (Cohort 1 only).
Key Exclusion Criteria:
- Subject has a known hypersensitivity to fenfluramine or any of the excipients in the study medication.
- Subject has pulmonary arterial hypertension.
- Subject has a current or past history of cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction, or stroke.
- Subject has a 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.
- Subject has a current or past history of glaucoma.
- 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; triptans, atomoxetine, or other centrally acting noradrenergic agonists; cyproheptadine, and/or cytochrome P450 (CYP) 2D6/3A4/2B6 inhibitors/substrates.
- Subject is currently taking carbamazepine ,oxcarbazepine, eslicarbazepine, phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as maintenance therapy.
- Subject has a positive result on urine tetrahydrocannabinol (THC) panel or whole blood cannabidiol (CBD) at the Screening Visit.
- Subject has a clinically significant condition, or has had clinically relevant symptoms or a clinically significant illness in the 4 weeks prior to the Screening Visit, other than epilepsy, that would negatively impact study participation, collection of study data, or pose a risk to the subject.
Sites / Locations
- University of California San Francisco
- Children'S Hospital Colorado
- Ann & Robert H. Lurie Children'S Hospital of Chicago
- Children'S Hospital of Michigan
- Mayo Clinic
- Bc Children'S Hospital Division of Neurology
- Chu Sainte-Justine Hospital Neurology Clinic
- Chu Amiens Picardie Service de Neurologie Pédiatrique
- Chu de Bordeaux Hôpital Des Enfants
- HÔPITAL FEMME-MÈRE-ENFANT Hôpital Service de Neurologie Pédiatrique
- Chru de Lille Hôpital Roger Salengro
- Hôpital de La Timone, Service de Neuro-Métabolisme Pédiatrique
- Hôpital Necker-Enfants Malades
- Hôpital Robert-Debré
- Chu de Toulouse - Hôpital Des Enfants
- Hôpital D'Enfants Chur de Nancy
- Krankenhaus Mara, Epilepsie-Zentrum Bethel
- Universitätsklinikum Schleswig-Holstein, Klinik Für Neuropädiatrie
- Kleinwachau Sächsisches Epilepsiezentrum Radeberg
- Epilepsiecentrum Kempenhaeghe
- Stichting Epilepsie Instellingen Nederland
- Hospital Sant Joan de Déu Barcelona
- Hospital Ruber Internacional-Servicio de Neurología
- Cliníca Universidad de Navarra Nidad de Neuropediatría
- Royal Hospital For Children, Queen Elizabeth University, Institute of Neurosciences Hospital
- Alder Hey Children'S Nhs Foundation Trust, Littlewood'S Neurosciences Unit
- Evelina London Children'S Hospital, Paediatric Neurosciences
- Great Ormond Street Hospital For Children Nhs Foundation Trust
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Cohort 2: ZX008 0.5 mg/kg/day
Cohort 2: Matching Placebo
Arm Description
ZX008 0.5 mg/kg/day (maximum 20 mg/day) dose supplied as an oral solution administered twice a day (BID) in equally divided doses with food.
Matching placebo administered twice a day (BID) in equally divided doses with food.
Outcomes
Primary Outcome Measures
Change in Convulsive Seizure Frequency (CSF) From the Baseline Period (Baseline) to the Combined Titration + Maintenance (T+M) Period
Monthly (28 day) convulsive seizure frequency (CSF) was based on electronic diary data obtained for each participant. Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). The number of convulsive seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day CSF.
Secondary Outcome Measures
Percentage of Participants Who Achieved ≥ a 50% Reduction in Convulsive Seizure Frequency From Baseline to the Combined Titration + Maintenance Period
Percentage of participants who achieved ≥ a 50% reduction in convulsive seizure frequency from Baseline compared to the combined Titration + Maintenance Periods in the ZX008 0.5 mg/kg/day vs placebo groups.
Longest Convulsive Seizure-Free Interval (Days)
Comparison of the duration of the longest convulsive seizure-free interval (days) during the combined Titration + Maintenance Periods for the ZX008 0.5 mg/kg/day and placebo groups.
Full Information
NCT ID
NCT02926898
First Posted
August 10, 2016
Last Updated
October 31, 2022
Sponsor
Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT02926898
Brief Title
A 2-Part Study to Investigate the Dose-Ranging Safety and Pharmacokinetics, Followed by the Efficacy and Safety of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children ≥ 2 Years Old and Young Adults With Dravet Syndrome
Official Title
A Multicenter, 2-Cohort Trial to First Assess the Pharmacokinetic and Safety Profile of a Single Dose of ZX008 (Fenfluramine Hydrochloride) Oral Solution When Added to Standard of Care (Cohort 1), Followed by a Randomized, Double-blind, Placebo-controlled Parallel Group Evaluation of the Efficacy, Safety, and Tolerability of ZX008 as Adjunctive Antiepileptic Therapy to Stiripentol Treatment in Children and Young Adults With Dravet Syndrome (Cohort 2)
Study Type
Interventional
2. Study Status
Record Verification Date
October 2022
Overall Recruitment Status
Completed
Study Start Date
January 27, 2017 (Actual)
Primary Completion Date
June 5, 2018 (Actual)
Study Completion Date
June 5, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The primary purpose of this study is to evaluate the safety, tolerability, and efficacy of ZX008 (fenfluramine hydrochloride) when added to adjunctive antiepileptic stiripentol treatment in children and young adults with Dravet syndrome.
Detailed Description
This is a multicenter, 2-cohort trial to first assess the pharmacokinetic and safety profile of a single dose of ZX008 (fenfluramine hydrochloride) oral solution when added to a standard Dravet syndrome treatment regimen containing valproate (VPA) and clobazam (CLB), with or without stiripentol (STP) (Cohort 1), followed by a randomized, double-blind, placebo-controlled parallel group evaluation of the efficacy, safety, and tolerability of ZX008 as adjunctive therapy for seizures in children and young adults with Dravet syndrome (Cohort 2).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Dravet Syndrome
Keywords
Seizure, Tonic clonic, Epilepsy, Myoclonic, Encephalopathy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
87 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Cohort 2: ZX008 0.5 mg/kg/day
Arm Type
Experimental
Arm Description
ZX008 0.5 mg/kg/day (maximum 20 mg/day) dose supplied as an oral solution administered twice a day (BID) in equally divided doses with food.
Arm Title
Cohort 2: Matching Placebo
Arm Type
Placebo Comparator
Arm Description
Matching placebo administered twice a day (BID) in equally divided doses with food.
Intervention Type
Drug
Intervention Name(s)
ZX008 (Fenfluramine Hydrochloride)
Intervention Description
ZX008 0.5 mg/kg/day (maximum 20 mg/day). ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 and provided in concentrations of 2.5 mg/mL.
*Note: The 0.5 mg/kg/day dose of ZX008 fenfluramine hydrochloride in this study is equivalent to 0.4 mg/kg/day (maximum 17 mg/day) dose of fenfluramine base.
Intervention Type
Drug
Intervention Name(s)
Matching Placebo
Intervention Description
Matching Placebo
Primary Outcome Measure Information:
Title
Change in Convulsive Seizure Frequency (CSF) From the Baseline Period (Baseline) to the Combined Titration + Maintenance (T+M) Period
Description
Monthly (28 day) convulsive seizure frequency (CSF) was based on electronic diary data obtained for each participant. Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). The number of convulsive seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day CSF.
Time Frame
15 weeks (combined Titration + Maintenance Period)
Secondary Outcome Measure Information:
Title
Percentage of Participants Who Achieved ≥ a 50% Reduction in Convulsive Seizure Frequency From Baseline to the Combined Titration + Maintenance Period
Description
Percentage of participants who achieved ≥ a 50% reduction in convulsive seizure frequency from Baseline compared to the combined Titration + Maintenance Periods in the ZX008 0.5 mg/kg/day vs placebo groups.
Time Frame
15 weeks (combined Titration + Maintenance Period)
Title
Longest Convulsive Seizure-Free Interval (Days)
Description
Comparison of the duration of the longest convulsive seizure-free interval (days) during the combined Titration + Maintenance Periods for the ZX008 0.5 mg/kg/day and placebo groups.
Time Frame
15 weeks (combined Titration + Maintenance Period)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Key Inclusion Criteria:
Subject must be male or non-pregnant, non-lactating female, aged 2 to 18 years (inclusive).
Subject must have documented medical history to support a clinical diagnosis of Dravet syndrome, where convulsive seizures are not completely controlled by current antiepileptic drugs.
Subject must be receiving a therapeutically relevant and stable dose of stiripentol (STP) plus clobazam (CLB) and/or valproate (VPA), and for at least 4 weeks prior to screening and be expected to remain stable throughout the study (Cohort 2 only).
Subject must be receiving a stable dose of CLB and VPA, administered twice daily (BID), to be eligible for Dose Regimen 1 and 2, or subject must be receiving a stable dose of CLB, VPA, and STP, administered BID, to be eligible for Dose Regimen 3 (Cohort 1 only).
Key Exclusion Criteria:
Subject has a known hypersensitivity to fenfluramine or any of the excipients in the study medication.
Subject has pulmonary arterial hypertension.
Subject has a current or past history of cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction, or stroke.
Subject has a 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.
Subject has a current or past history of glaucoma.
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; triptans, atomoxetine, or other centrally acting noradrenergic agonists; cyproheptadine, and/or cytochrome P450 (CYP) 2D6/3A4/2B6 inhibitors/substrates.
Subject is currently taking carbamazepine ,oxcarbazepine, eslicarbazepine, phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as maintenance therapy.
Subject has a positive result on urine tetrahydrocannabinol (THC) panel or whole blood cannabidiol (CBD) at the Screening Visit.
Subject has a clinically significant condition, or has had clinically relevant symptoms or a clinically significant illness in the 4 weeks prior to the Screening Visit, other than epilepsy, that would negatively impact study participation, collection of study data, or pose a risk to the subject.
Facility Information:
Facility Name
University of California San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94158
Country
United States
Facility Name
Children'S Hospital Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Ann & Robert H. Lurie Children'S Hospital of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Children'S Hospital of Michigan
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Bc Children'S Hospital Division of Neurology
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V6H 3V4
Country
Canada
Facility Name
Chu Sainte-Justine Hospital Neurology Clinic
City
Montréal
State/Province
Quebec
ZIP/Postal Code
H3T 1C5
Country
Canada
Facility Name
Chu Amiens Picardie Service de Neurologie Pédiatrique
City
Amiens
ZIP/Postal Code
80480
Country
France
Facility Name
Chu de Bordeaux Hôpital Des Enfants
City
Bordeaux
ZIP/Postal Code
33076
Country
France
Facility Name
HÔPITAL FEMME-MÈRE-ENFANT Hôpital Service de Neurologie Pédiatrique
City
Bron
ZIP/Postal Code
69677
Country
France
Facility Name
Chru de Lille Hôpital Roger Salengro
City
Lille
ZIP/Postal Code
59037
Country
France
Facility Name
Hôpital de La Timone, Service de Neuro-Métabolisme Pédiatrique
City
Marseille
ZIP/Postal Code
13385
Country
France
Facility Name
Hôpital Necker-Enfants Malades
City
Paris
ZIP/Postal Code
75015
Country
France
Facility Name
Hôpital Robert-Debré
City
Paris
ZIP/Postal Code
75019
Country
France
Facility Name
Chu de Toulouse - Hôpital Des Enfants
City
Toulouse
ZIP/Postal Code
31059
Country
France
Facility Name
Hôpital D'Enfants Chur de Nancy
City
Vandœuvre-lès-Nancy
ZIP/Postal Code
54511
Country
France
Facility Name
Krankenhaus Mara, Epilepsie-Zentrum Bethel
City
Bielefeld
ZIP/Postal Code
33617
Country
Germany
Facility Name
Universitätsklinikum Schleswig-Holstein, Klinik Für Neuropädiatrie
City
Kiel
ZIP/Postal Code
24105
Country
Germany
Facility Name
Kleinwachau Sächsisches Epilepsiezentrum Radeberg
City
Radeberg
ZIP/Postal Code
01454
Country
Germany
Facility Name
Epilepsiecentrum Kempenhaeghe
City
Heeze
ZIP/Postal Code
5591 VE
Country
Netherlands
Facility Name
Stichting Epilepsie Instellingen Nederland
City
Zwolle
ZIP/Postal Code
8025 BV
Country
Netherlands
Facility Name
Hospital Sant Joan de Déu Barcelona
City
Barcelona
ZIP/Postal Code
08950
Country
Spain
Facility Name
Hospital Ruber Internacional-Servicio de Neurología
City
Madrid
ZIP/Postal Code
28034
Country
Spain
Facility Name
Cliníca Universidad de Navarra Nidad de Neuropediatría
City
Pamplona
ZIP/Postal Code
31008
Country
Spain
Facility Name
Royal Hospital For Children, Queen Elizabeth University, Institute of Neurosciences Hospital
City
Glasgow
State/Province
Scotland
ZIP/Postal Code
G51 4TF
Country
United Kingdom
Facility Name
Alder Hey Children'S Nhs Foundation Trust, Littlewood'S Neurosciences Unit
City
Liverpool
ZIP/Postal Code
L12 2AP
Country
United Kingdom
Facility Name
Evelina London Children'S Hospital, Paediatric Neurosciences
City
London
ZIP/Postal Code
SE1 7EH
Country
United Kingdom
Facility Name
Great Ormond Street Hospital For Children Nhs Foundation Trust
City
London
ZIP/Postal Code
WC1N 3JH
Country
United Kingdom
12. IPD Sharing Statement
Citations:
PubMed Identifier
31790543
Citation
Nabbout R, Mistry A, Zuberi S, Villeneuve N, Gil-Nagel A, Sanchez-Carpintero R, Stephani U, Laux L, Wirrell E, Knupp K, Chiron C, Farfel G, Galer BS, Morrison G, Lock M, Agarwal A, Auvin S; FAiRE, DS Study Group. Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens: A Randomized Clinical Trial. JAMA Neurol. 2020 Mar 1;77(3):300-308. doi: 10.1001/jamaneurol.2019.4113.
Results Reference
result
PubMed Identifier
34768178
Citation
Cross JH, Galer BS, Gil-Nagel A, Devinsky O, Ceulemans B, Lagae L, Schoonjans AS, Donner E, Wirrell E, Kothare S, Agarwal A, Lock M, Gammaitoni AR. Impact of fenfluramine on the expected SUDEP mortality rates in patients with Dravet syndrome. Seizure. 2021 Dec;93:154-159. doi: 10.1016/j.seizure.2021.10.024. Epub 2021 Nov 2.
Results Reference
derived
PubMed Identifier
33540241
Citation
Sullivan J, Perry MS, Wheless JW, Galer B, Gammaitoni A. Fenfluramine responder analyses and numbers needed to treat: Translating epilepsy trial data into clinical practice. Eur J Paediatr Neurol. 2021 Mar;31:10-14. doi: 10.1016/j.ejpn.2021.01.005. Epub 2021 Jan 22.
Results Reference
derived
Learn more about this trial
A 2-Part Study to Investigate the Dose-Ranging Safety and Pharmacokinetics, Followed by the Efficacy and Safety of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children ≥ 2 Years Old and Young Adults With Dravet Syndrome
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