A Phase 3 Study to Examine the Efficacy and Safety of ZX008 in Subjects With CDKL5 Deficiency Disorder.

Phase 3Active Not RecruitingNCT05064878

Zogenix, Inc.87 enrolled

Overview

This is a Phase 3 Study to examine the efficacy and safety of ZX008 in children and adults with cyclin-dependent kinase like-5 (CDKL5) deficiency disorder (CDD).

This is an up to 3-part multicenter study: a double-blind, placebo-controlled part (Part 1) which includes Baseline Period (4 weeks), Titration Period (2 weeks), Maintenance Period (12 weeks) and Transition Period (2 weeks), followed by up to 2 open-label extension (OLE) parts: Part 2 of 54 weeks \[Treatment Period (52 weeks), Taper Period (2 weeks)\] and Part 3, i.e., OLE1 and OLE2, respectively, with the addition of the second OLE part (Part 3/OLE2) only for participants who will continue on fenfluramine and have no alternative treatment access from another source (e.g., a managed access program \[MAP\]). Participants can remain in Part 3 until MAP access or approval of fenfluramine (ZX008) has been obtained from regulatory authorities for CDD in the participant's country of residence, or until the investigational product development for CDD is stopped by the Sponsor, whichever comes first. Participants who discontinue early from Part 1, Part 2, or Part 3 will attend a Cardiac Follow-Up Visit 6 months after their last dose of study drug.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

CDKL5 Deficiency Disorder Generalized Tonic Clonic Seizure Epileptic Spasm Refractory Seizures

Interventions

FenfluramineDRUG

Fenfluramine is supplied as an oral aqueous solution of fenfluramine hydrochloride.

PlaceboDRUG

Matching fenfluramine (hydrochloride) placebo is supplied as an oral solution.

Eligibility

Sex: ALLMin age: 1 YearMax age: 35 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Subject has a confirmed pathogenic or likely pathogenic mutation in the CDKL5 gene and a clinical diagnosis of CDKL5 deficiency disorder (CDD) with epilepsy onset in the first year of life, plus motor and developmental delays. * Subject is male or female, aged 1 to 35 years, inclusive, as of the day of the Screening Visit. * Subject must have failed to achieve seizure control despite previous or current use of 2 or more antiepileptic treatments (AETs). * Subject is currently receiving at least 1 concomitant antiseizure treatment: antiseizure medication (ASM), vagus nerve stimulation (VNS), responsive neurostimulation (RNS), or ketogenic diet (KD). * All medications or interventions for epilepsy (including VNS, RNS, and KD) must be stable prior to screening and are expected to remain stable throughout the study. * At the Screening Visit, parent/caregiver reports that subject has ≥ 4 countable motor seizures (CMS) per week. Exclusion Criteria: * Subject has a known hypersensitivity to fenfluramine or any of the excipients in the study drug. * Subject has a diagnosis of pulmonary arterial hypertension. * Subject has a clinically significant medical condition, including chronic obstructive pulmonary disease, interstitial lung disease, or portal hypertension, or has had clinically relevant symptoms or a clinically significant illness currently or 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. * Subject has current or past history of cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction or stroke, severe ventricular arrhythmias, or clinically significant structural cardiac abnormality, including but not limited to mitral valve prolapse, atrial or ventricular septal defects, patent ductus arteriosus, and patent foramen ovale with reversal of shunt. (Note: Patent foramen ovale or a bicuspid aortic valve are not considered exclusionary). * Subject has current eating disorder that suggests anorexia nervosa or bulimia. * Subject has a current or past history of glaucoma. * Subject is taking \> 4 concomitant antiseizure medications (ASMs). Rescue medications are not included in the count. * Subject is receiving concomitant treatment with cannabidiol (CBD) other than Epidiolex/Epidyolex or is being actively treated with tetrahydrocannabinol (THC) or any marijuana product for any condition. * Subject has moderate to severe hepatic impairment. * Subject is currently receiving another investigational product(s) or has received another investigational product within 30 days or within \< 5 times the half-lives of the investigational product, whichever is longer, prior to the Screening Visit. * Subject has previously been treated with Fintepla® (fenfluramine) prior to the Screening Visit.

Locations (46)

Outcomes

Primary Outcomes

Percentage Change from Baseline in Countable Motor Seizure Frequency (CMSF) (Part 1)

The median percentage change from the Baseline in monthly (per 28 days) CMSF during the combined Titration and Maintenance Periods with the fenfluramine (ZX008) 0.8 mg/kg/day group compared with the placebo group will be reported.

Time frame: Baseline (28 days), Combined Titration and Maintenance (T+M) Periods (14 weeks)

Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) (Part 2)

An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. Treatment Emergent Adverse Events (TEAEs) are defined as any AEs reported on or after the first dose of study medication.

Time frame: Up to OLE1 Treatment Period Post-Dose Safety Follow-up Visit 17 (up to 70 weeks)

Percentage of Participants With Abnormal Physical Examination Findings (Part 2)

Abnormal findings of physical exam that is considered clinically significant by Principal Investigator (PI).

Time frame: Up to End of Treatment (EoT)/Early Termination (ET) Visit 16 of OLE1 Treatment Period (up to 68 weeks)

Percentage of Participants With Abnormal Neurological Examination Findings (Part 2)

Abnormal findings of neurological exam that is considered clinically significant by PI.

Time frame: Up to EoT/ET Visit 16 of OLE1 Treatment Period (up to 68 weeks)

Percentage of Participants with Positive Response to Self-harm Question (Part 2)

Time frame: OLE1 Treatment Period Day 1 to OLE1 Treatment Period Post-Dose Safety Follow-up Visit 17 (up to 70 weeks)

Percentage of Participants with Increase in Valvular Regurgitation from Baseline (except absent to trace) (Part 2)

Data from ClinicalTrials.gov

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Secondary Outcomes

Percentage of Participants Who Achieve a ≥ 50% Reduction from Baseline in CMSF (Part 1)

The percentage of participants who achieve a ≥ 50% reduction from Baseline in CMSF during T+M periods, in the fenfluramine 0.8 mg/kg/day group compared with the placebo group.

Time frame: Baseline (28 days), Combined T+M Periods (14 weeks)

Percentage of Participants with a Clinical Global Impression-Improvement (CGI-I) Rating of 'Much Improved' or 'Very Much Improved' as Assessed by Investigator (Part 1)

The percentage of participants who achieve a CGI-I rating of much or very much improved as assessed by the Investigator at the end of T+M periods, in the fenfluramine 0.8 mg/kg group compared with the placebo group. The CGI-I rating scale permits a global evaluation of the participant's improvement over time. The severity of a participant's condition is rated on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse) as follows: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse.

Time frame: At the end of the combined T+M Periods (14 weeks)

Percentage Change From Baseline in Monthly Generalized Tonic-Clonic (GTC) Seizure Frequency (Part 1)

The median percentage change from Baseline in monthly GTC seizure frequency during T+M periods, in the fenfluramine 0.8 mg/kg/day group compared with the placebo group.

Time frame: Baseline (28 days), Combined Titration and Maintenance (T+M) Periods (14 weeks)

Categorized Percentage Change in Seizures from Baseline in CMSF (Part 1)

The categorized median percentage change in seizures from the Baseline in monthly (per 28 days) CMSF during the combined T+ M periods will be presented in the following categories: no reduction or worsening, ≥25%, ≥75%, or 100% reduction.

Time frame: Baseline (28 days), Combined Titration and Maintenance (T+M) Periods (14 weeks)

Percentage of Participants who Achieve "Near Seizure Freedom" (Part 1)

The percentage of participants who achieve near seizure freedom, defined as 0 or 1 seizures, during T+M, in the fenfluramine 0.8 mg/kg/day group compared with the placebo group.

Time frame: Combined T+M Periods (14 weeks)

Percentage of Participants with a CGI-I Rating of 'Much Improved' or 'Very Much Improved' as Assessed by the Parent/Caregiver (Part 1)

The percentage of participants who achieve a CGI-I rating of much or very much improved as assessed by the by the parent/caregiver at the end of T+M periods, in the fenfluramine 0.8 mg/kg group compared with the placebo group.

Time frame: At the end of the combined T+M Periods (14 weeks)

Percentage of Participants with Improvement (Minimal, Much or Very Much Improved) on the CGI-I Rating as Assessed, Independently, by the Investigator (Part 1)

The percentage of participants who achieve a CGI-I rating of minimal, much or very much improved as assessed, independently, by the Investigator at the end of T+M periods, in the fenfluramine 0.8 mg/kg group compared with the placebo group.

Time frame: At the end of the combined T+M Periods (14 weeks)

Percentage of Participants with Improvement (Minimal, Much or Very Much Improved) on the CGI-I Rating as Assessed, Independently, by the Parent/Caregiver (Part 1)

The percentage of participants who achieve a CGI-I rating of minimal, much or very much improved as assessed, independently, by the parent/caregiver at the end of T+M periods, in the fenfluramine 0.8 mg/kg group compared with the placebo group.

Time frame: At the end of the combined T+M Periods (14 weeks)

Percentage Change from Baseline in the Monthly Frequency of all Seizures (Part 1)

The percentage change from the Baseline in the monthly (per 28 days) frequency of all seizures during the combined T+M period.

Time frame: Baseline (28 days), Combined Titration and Maintenance (T+M) Periods (14 weeks)

Change from Baseline in the Monthly Frequency of Countable Motor Seizure (CMS)-free Days (Part 1)

The change from the Baseline in the monthly (per 28 days) frequency of CMS-free days during the combined T+M periods.

Time frame: Baseline (28 days), Combined Titration and Maintenance (T+M) Periods (14 weeks)

Percentage of Participants with TEAEs (Part 1)

An AE is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. A TEAEs was defined as any adverse events with a start date/time on or after dosing of the study medication and up to end of the maintenance period (14 weeks) inclusive after dosing of the study medication.

Time frame: From Day of first dose to the End of the Maintenance Periods (up to 14 weeks)

Percentage of Participants With Abnormal Physical Examination Findings (Part 1)

Time frame: Baseline, Visit 6 (Day 43), Visit 7 (Day 71), Visit 8 (Day 99)

Percentage of Participants With Abnormal Neurological Examination Findings (Part 1)

Time frame: Baseline, Visit 6 (Day 43), Visit 8 (Day 99)

Percentage of Participants with Positive Response to Self-harm question (Part 1)

Time frame: Baseline, Visit 5 (Day 15), Visit 6 (Day 43), Visit 7 (Day 71), Visit 8 (Day 99)

Percentage of Participants with Increase in Valvular Regurgitation from Baseline (except absent to trace) (Part 1)

Valvular regurgitation will be assessed using a 2-D Color Doppler ECHO.

Time frame: From Day of first dose to the End of the Maintenance Period (up to 14 weeks)

Percentage of Participants with Pulmonary Arterial Hypertension (PASP > 35 mmHg) at any Time During Treatment on Repeat Testing (Part 1)

The safety and tolerability of fenfluramine (ZX008) will be assessed in pediatric and adult participants with CDD.

Time frame: From Day of first dose to the End of the Maintenance Period (up to 14 weeks)

Change from Baseline in Laboratory parameters (Hematology) (Part 1)