An Open-Label Extension Trial to Assess the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride HCl) Oral Solution in Children and Young Adults With Dravet Syndrome

• ClinicalTrials.gov Identifier: NCT02823145
• Recruitment Status: Completed
• First Posted: July 6, 2016
• Results First Posted: September 25, 2023
• Last Update Posted: September 25, 2023
• Sponsor: Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.
• Information provided by (Responsible Party): UCB Pharma ( Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc. )

Tracking Information

• First Submitted Date: June 13, 2016
• First Posted Date: July 6, 2016
• Results First Submitted Date: July 27, 2023
• Results First Posted Date: September 25, 2023
• Last Update Posted Date: September 25, 2023
• Actual Study Start Date: June 8, 2016
• Actual Primary Completion Date: January 27, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 22, 2023)

• Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) During the Open-label Extension (OLE) Treatment Period [ Time Frame: From Day 1 to End of OLE Treatment Period - End of Study (EOS) Visit (Month 42) ]
  Treatment-emergent adverse events (TEAE) were defined as any AEs that based on start date information occurs after the first intake of study treatment.
• Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) Leading to Withdrawal From Investigational Medicinal Product (IMP) During the OLE Treatment Period [ Time Frame: From Day 1 to End of OLE Treatment Period - EOS Visit (Month 42) ]
  A TEAE was defined as any AE that based on start date information occurs after the first intake of study treatment. Percentage of participants with TEAEs leading to withdrawal from IMP during OLE Treatment Period were reported.
• Percentage of Participants With Serious Treatment-emergent Adverse Events (TEAEs) During the OLE Treatment Period [ Time Frame: From Day 1 to End of OLE Treatment Period - EOS Visit (Month 42) ]
  Serious Adverse event (SAE) was defined as any untoward medical occurrence that at any dose: • results in death, • is life-threatening threatening, • results in initial inpatient hospitalization or prolongation of hospitalization, •results in persistent or significant disability or incapacity, • results in a congenital anomaly/birth defect, • results in any medically significant event that did not meet any of the other 5 SAE criteria, but which was judged by a physician to potentially jeopardize the participant or require medical or surgical intervention to prevent one of the above outcomes listed as an SAE criterion.

Original Primary Outcome Measures (submitted: July 5, 2016)

Long-term safety and tolerability as measured by treatment emergent adverse events, including clinical labs, vital signs, and examination findings. [ Time Frame: Pre-baseline Up to 54 weeks ]

Sensitivity of the key efficacy analysis will be assessed for changes in dose or type of concomitant AED medications

Current Secondary Outcome Measures (submitted: September 22, 2023)

• Change From Baseline (Core) in Convulsive Seizure Frequency Per 28 Days From Day 1 to End of Study (EOS) Visit (Month 42) in the OLE Treatment Period [ Time Frame: From Day 1 to End of OLE Treatment Period (EOS Visit - up to Month 42), compared to Baseline (Core) ]
  Baseline (Core) was defined as Baseline prior to double-blind treatment in the core studies (ZX008-1501/ZX008-1502, and ZX008-1504 Cohort 2). Participants in 1504- Cohort 1 and de novo participants (who entered 1503 without having been in any of the core studies) did not have a Baseline (Core), and were not included in the analysis of this outcome measure. The total number of convulsive seizures from Day 1 to EOS was divided by the total number of days from Day 1 to EOS with nonmissing diary data and the result was then multiplied by 28 to get a 28-day convulsive seizure frequency (CSF). The change from Baseline for any individual participant was calculated by subtracting the Baseline (Core) from the post-baseline value. Monthly (28 day) CSF was based on electronic diary data obtained for each participant.
• Change From Baseline (Core) in Convulsive Seizure Frequency Per 28 Days From Month 2 to EOS (Month 42) in the OLE Treatment Period [ Time Frame: From Month 2 to End of OLE Treatment Period (EOS Visit - up to Month 42), compared to Baseline (Core) ]
  Baseline (Core) was defined as Baseline prior to double-blind treatment in the core studies. Participants in 1504-Cohort 1 and de novo participants did not have a Baseline (Core), and were not included in the analysis of this outcome measure. The total number of convulsive seizures from Month 2 to EOS was divided by the total number of days from Month 2 to EOS with nonmissing diary data and the result was then multiplied by 28 to get a 28-day CSF. The change from Baseline for any individual participant was calculated by subtracting the Baseline (Core) from the post-baseline value. Monthly (28 day) CSF was based on electronic diary data obtained for each participant.
• Convulsive Seizure Frequency (CSF) Per 28 Days During the OLE Treatment Period (to Month 36) [ Time Frame: At Month 1, Month 2, Month 3, Month 4-6, Month 7-9, Month 10-12, Month 13-15, Month 16-18, Month 19-21, Month 22-24, Month 25-27, Month 28-30, Month 31-33, and Month 34-36 ]
  Monthly (28 day) CSF was based on electronic diary data obtained for each participant. The total number of convulsive seizures in the ith interval (CSF in OLE, where, i=1, 2, 3, … , 14 ) was divided by the total number of days in the ith interval with nonmissing diary data and the result was then multiplied by 28 to get a 28-day CSF of OLE.
• Convulsive Seizure Frequency (CSF) by Mean Daily Dose During the Overall OLE Treatment Period [ Time Frame: From Day 1 to End of OLE Treatment Period - End of Study (EOS) Visit (Month 42) ]
  Convulsive seizure frequency over time, reported as per 28 days was analyzed by the actual dose administered. Participants were grouped into low (0.2 to <0.4 mg/kg), medium (0.4 to <0.6 mg/kg), and high dose (>0.6 mg/kg) groups depending on their mean daily doses of ZX008 during the OLE Treatment period. For each participant, the seizure frequency per 28 days was calculated as the number of seizures recorded during the period, divided by the number of days in the period and multiplied by 28. The convulsive seizure frequency was calculated from all available data collected.
• Percentage of Participants With Changes in Antiepileptic Drug (AED) Medications During First 6 Months of OLE Treatment Period [ Time Frame: At Month 1, 2, 3, 4 , 5, and 6 of OLE Treatment Period ]
  Participants in the study were required to be on stable background therapy for the first 6 months of treatment, after which background AEDs could be reduced or withdrawn so long as one background AED remained. The percentage of participants who had changes in dose or type of concomitant AED medications during the first, second, third, fourth, fifth, and sixth months were analyzed and reported.

Original Secondary Outcome Measures (submitted: July 5, 2016)

• Proportion of subjects who achieve reduction from baseline in convulsive seizure frequency [ Time Frame: Baseline up to 54 weeks ]
• The longest interval between convulsive seizures will be calculated for each subject over the entire open-label treatment period. [ Time Frame: Up to 54 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: An Open-Label Extension Trial to Assess the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride HCl) Oral Solution in Children and Young Adults With Dravet Syndrome
• Official Title: An Open-Label Extension Trial to Assess the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride HCl) Oral Solution as an Adjunctive Therapy in Children and Young Adults With Dravet Syndrome
• Brief Summary: This is an international, multicenter, open-label, long-term safety study of ZX008 in subjects with Dravet syndrome.
• Detailed Description: This is an international, multicenter, open-label, long-term safety study of ZX008 in pediatric and young adult subjects with Dravet syndrome who participated in one of the core studies (ZX008-1501 and ZX008-1502) and are candidates for continuous treatment for an extended period of time. This trial will consist of a 36-month Open-Label Extension (OLE) Treatment Period and a 2-week Post-Dosing Period.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Dravet Syndrome
• Intervention: Drug: ZX008 (Fenfluramine Hydrochloride)

Study Arms

Experimental: ZX008

ZX008 is supplied as an oral solution in a concentration of 2.5 mg/mL. Subjects will be titrated to an effective dose beginning with 0.2 mg/kg/day (maximum: 30 mg/day).

Intervention: Drug: ZX008 (Fenfluramine Hydrochloride)

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 22, 2023): 375
• Original Estimated Enrollment (submitted: July 5, 2016): 210
• Actual Study Completion Date: January 27, 2023
• Actual Primary Completion Date: January 27, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

• Male or non-pregnant, non-lactating female, age 2 to 18 years, inclusive as of the day of the core study Screening Visit.
• Satisfactory completion of the core study in the opinion of the investigator and the sponsor.
• Subjects who are >18 to ≤35 years of age at the time of screening and did not participate in one of the core studies may be eligible for participation.
• A documented medical history to support a clinical diagnosis of Dravet syndrome, where convulsive seizures are not completely controlled by current antiepileptic drugs.
• Parent/caregiver is willing and able to be compliant with diary completion, visit schedule and study drug accountability.
• 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).

Key Exclusion Criteria:

• Current or past history of cardiovascular or cerebrovascular disease, myocardial infarction or stroke.
• Current cardiac valvulopathy or pulmonary hypertension that is clinically significant and warrants discontinuation of study medication.
• Current or past history of glaucoma.
• Moderate or severe hepatic impairment.
• Receiving concomitant therapy with: centrally-acting anorectic agents; monoamineoxidase 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.
• Currently taking carbamazepine, oxcarbamazepine, eslicarbazepine, phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as maintenance therapy.
• A clinically significant condition, or has had clinically relevant symptoms or a clinically significant illness at Visit 1, other than epilepsy, that would negatively impact study participation, collection of study data, or pose a risk to the subject.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Years to 35 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Canada, Denmark, France, Germany, Italy, Japan, Netherlands, Spain, United Kingdom, United States
• Removed Location Countries: Norway, Sweden

Administrative Information

• NCT Number: NCT02823145
• Other Study ID Numbers: ZX008-1503; 2016-002804-14 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Data from this trial may be requested by qualified researchers six months after product approval in the US and/or Europe, or global development is discontinued, and 18 months after trial completion. Investigators may request access to anonymized individual patient-level data and redacted trial documents which may include: analysis-ready datasets, study protocol, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Prior to use of the data, proposals need to be approved by an independent review panel at www.Vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a prespecified time, typically 12 months, on a password protected portal. This plan may change if the risk of re-identifying trial participants is determined to be too high after the trial is completed; in this case and to protect participants, individual patient-level data would not be made available.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Data from this trial may be requested by qualified researchers six months after product approval in the US and/or Europe or global development is discontinued, and 18 months after trial completion.
• Access Criteria: Qualified researchers may request access to anonymized IPD and redacted study documents which may include: raw datasets, analysis-ready datasets, study protocol, blank case report form, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Prior to use of the data, proposals need to be approved by an independent review panel at www.Vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a pre-specified time, typically 12 months, on a password protected portal.
• URL: https://www.Vivli.org

• Current Responsible Party: UCB Pharma ( Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc. )
• Original Responsible Party: Same as current
• Current Study Sponsor: Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: UCB Cares; 001 844 599 2273

• PRS Account: UCB Pharma
• Verification Date: September 2023