A Study to Investigate the Efficacy and Safety of ZX008 in Subjects With CDKL5 Deficiency Disorder

Study Overview
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Brief Summary
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This is a multicenter, double-blind, parallel-group, placebo controlled, 2-part study to evaluate the efficacy and safety of ZX008 when used as adjunctive therapy for the treatment of uncontrolled seizures in children and adults with cyclin-dependent kinase like-5 (CDKL5) deficiency disorder (CDD).

Detailed Description
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This is a 2-part multicenter trial. Part 1 is a 20-week randomized, double-blind, placebo-controlled, fixed-dose, parallel-group study to examine the efficacy and safety of ZX008 as an adjunctive therapy (to existing concomitant treatment with antiepileptic treatments [AETs]) in children and adults with a CDD diagnosis and uncontrolled seizures. Part 1 of the study is 20 weeks in duration and will consist of the following stages: Baseline Period (ie, Baseline [BL]; 4 weeks including the Screening Visit and baseline observation), Titration Period (ie, Titration; 2 weeks), Maintenance Period (ie, Maintenance; 12 weeks), and a 2-week Transition Period (ie, Transition; 2 weeks) to the open-label starting dose. Part 2 is a 54-week, open-label, flexible-dose, long-term extension for subjects who complete Part 1. Part 2 includes an Open-Label Extension (OLE) Treatment Period (52 weeks) with a Taper Period (ie, Taper; 2 weeks). The primary study analysis to evaluate the efficacy and safety of ZX008 in children and adults with CDD will be based on Part 1 data in all randomized subjects.

Official Title
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A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Fixed-Dose, Multicenter Study To Examine The Efficacy And Safety Of ZX008 In Subjects With CDKL5 Deficiency Disorder Followed By An Open-Label Extension

Conditions
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CDKL5 Deficiency Disorder, Generalized Tonic Clonic Seizure, Epileptic Spasm, Refractory Seizures

Intervention / Treatment
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* Drug: ZX008 (Fenfluramine Hydrochloride)
* Drug: Matching ZX008 Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has a confirmed pathogenic or likely pathogenic mutation in the CDKL5 gene and a clinical diagnosis of 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 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 moderate to severe hepatic impairment. 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 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 participated in another interventional clinical trial within 30 days of the Screening Visit or is currently receiving an investigational product. Subject has previously been treated with Fintepla® (fenfluramine) prior to the Screening Visit.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZX008 0.8 mg/kg/day<br>Part 1: ZX008 0.8 mg/kg/day will be administered twice a day (BID) in equally divided doses; maximum of 30 mg/day, (subjects taking concomitant stiripentol will receive 0.5 mg/kg/day, [maximum of 20 mg/day]) with or without food. | Drug: ZX008 (Fenfluramine Hydrochloride)<br>* ZX008 is supplied as an oral aqueous solution of Fenfluramine Hydrochloride.<br>|
| Placebo Comparator: Placebo<br>Part 1: Matching ZX008 placebo will be administered twice a day (BID) in equally divided doses with or without food. | Drug: Matching ZX008 Placebo<br>* Matching ZX008 placebo is supplied as an oral solution.<br>|
| Experimental: ZX008<br>Part 2: Open-label ZX008 will be administered using a flexible dosing regimen, up to ZX008 0.8 mg/kg/day; maximum dose: 30 mg/day (subjects taking concomitant stiripentol will receive 0.5 mg/kg/day, [maximum of 20 mg/day]). ZX008 will be administered twice a day (BID) in equally divided doses with or without food. | Drug: ZX008 (Fenfluramine Hydrochloride)<br>* ZX008 is supplied as an oral aqueous solution of Fenfluramine Hydrochloride.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The median percentage change from the Baseline Period (Baseline) in monthly (28 days) countable motor seizure frequency | The median percentage change from the Baseline Period (Baseline) in monthly (28 days) countable motor seizure frequency, or CMSF, during the combined Titration and Maintenance Periods (T+M) in the ZX008 0.8 mg/kg/day group compared with the placebo group | 14 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of subjects who achieve a ≥ 50% reduction from Baseline in CMSF | The percentage of subjects who achieve a ≥ 50% reduction from Baseline in CMSF during T+M in the ZX008 0.8 mg/kg/day group compared with the placebo group | 14 Weeks | 
| The percentage of subjects who achieve improvement in the Clinical Global Impression-Improvement (CGI-I) rating as assessed by the Investigator | The percentage of subjects who achieve a CGI-I rating of much or very much improved as assessed by the Investigator at the end of T+M in the ZX008 0.8 mg/kg group compared with the placebo group | 14 Weeks | 
| The median percentage change from Baseline in monthly Generalized Tonic-Clonic (GTC) seizure frequency | The median percentage change from Baseline in monthly GTC seizure frequency during T+M in the ZX008 0.8 mg/kg/day group compared with the placebo group | 14 Weeks |