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

Phase 3

Recruiting

• Conditions: CDKL5 Deficiency Disorder; Generalized Tonic Clonic Seizure; Epileptic Spasm; Refractory Seizures
• Interventions: Drug: ZX008 (Fenfluramine Hydrochloride); Drug: Matching ZX008 Placebo

• Registration Number: NCT05064878
• Lead Sponsor: Zogenix, Inc.

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2021-09-22
• Study First Submitted QC: 2021-09-22
• Study First Posted: 2021-10-01
• Study Start: 2022-03-08
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-07
• Last Update Posted: 2024-11-11
• Primary Completion: 2025-02-05
• Study Completion: 2026-06-16

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 100

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ZX008 0.8 mg/kg/day	ZX008 (Fenfluramine Hydrochloride)	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.
Placebo	Matching ZX008 Placebo	Part 1: Matching ZX008 placebo will be administered twice a day (BID) in equally divided doses with or without food.
ZX008	ZX008 (Fenfluramine Hydrochloride)	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.

Primary Outcome Measures

Name	Time	Method
The median percentage change from the Baseline Period (Baseline) in "monthly (28 days) countable motor seizure frequency	14 Weeks	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

Secondary Outcome Measures

Name	Time	Method
The percentage of subjects who achieve a ≥ 50% reduction from Baseline in CMSF	14 Weeks	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
The percentage of subjects who achieve improvement in the Clinical Global Impression-Improvement (CGI-I) rating as assessed by the Investigator	14 Weeks	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
The median percentage change from Baseline in monthly Generalized Tonic-Clonic (GTC) seizure frequency	14 Weeks	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

Trial Locations

Locations (63)

Ep0216 901; 🇩🇪 Vogtareuth, Germany

Ep0216 1909; 🇮🇱 Petah tikva, Israel

Ep0216 1201; 🇮🇹 Florence, Italy

Ep0216 1204; 🇮🇹 Genova, Italy

Ep0216 1212; 🇮🇹 Modena, Italy

Ep0216 164; 🇺🇸 Cleveland, Ohio, United States

Ep0216 1505; 🇯🇵 Niigata, Japan

Ep0216 1502; 🇯🇵 Shizuoka, Japan

Ep0216 1518; 🇯🇵 Ōmura, Japan

Ep0216 1401; 🇳🇱 Zwolle, Netherlands

Ep0216 2104; 🇵🇹 Lisboa, Portugal

Ep0216 2105; 🇵🇹 Porto, Portugal

Ep0216 1103; 🇪🇸 Barcelona, Spain

Ep0216 1114; 🇪🇸 Madrid, Spain

Ep0216 1116; 🇪🇸 Madrid, Spain

Ep0216 1117; 🇪🇸 Madrid, Spain

Ep0216 1118; 🇪🇸 Santiago De Compostela, Spain

Ep0216 1115; 🇪🇸 Valencia, Spain

Ep0216 607; 🇬🇧 Bristol, United Kingdom

Ep0216 602; 🇬🇧 London, United Kingdom

Ep0216 604; 🇬🇧 Sheffield, United Kingdom

Ep0216 1904; 🇮🇱 Tel Aviv, Israel

Ep0216 1512; 🇯🇵 Hiroshima, Japan

Ep0216 1206; 🇮🇹 Roma, Italy

Ep0216 1208; 🇮🇹 Roma, Italy

Ep0216 1202; 🇮🇹 Verona, Italy

Ep0216 3101; 🇦🇪 Dubai, United Arab Emirates

Ep0216 611; 🇬🇧 Manchester, United Kingdom

Ep0216 154; 🇺🇸 Birmingham, Alabama, United States

Ep0216 122; 🇺🇸 Los Angeles, California, United States

Ep0216 144; 🇺🇸 Los Angeles, California, United States

Ep0216 130; 🇺🇸 Orange, California, United States

Ep0216 101; 🇺🇸 San Francisco, California, United States

Ep0216 173; 🇺🇸 Aurora, Colorado, United States

Ep0216 149; 🇺🇸 Washington, District of Columbia, United States

Ep0216 165; 🇺🇸 Orlando, Florida, United States

Ep0216 151; 🇺🇸 Atlanta, Georgia, United States

Ep0216 157; 🇺🇸 Atlanta, Georgia, United States

Ep0216 113; 🇺🇸 Boston, Massachusetts, United States

Ep0216 134; 🇺🇸 Detroit, Michigan, United States

Ep0216 136; 🇺🇸 Grand Rapids, Michigan, United States

Ep0216 109; 🇺🇸 Rochester, Minnesota, United States

Ep0216 118; 🇺🇸 New York, New York, United States

Ep0216 166; 🇺🇸 Chapel Hill, North Carolina, United States

Ep0216 133; 🇺🇸 Cincinnati, Ohio, United States

Ep0216 120; 🇺🇸 Philadelphia, Pennsylvania, United States

Ep0216 160; 🇺🇸 Charleston, South Carolina, United States

Ep0216 124; 🇺🇸 Memphis, Tennessee, United States

Ep0216 153; 🇺🇸 Nashville, Tennessee, United States

Ep0216 171; 🇺🇸 Austin, Texas, United States

Ep0216 146; 🇺🇸 Dallas, Texas, United States

Ep0216 126; 🇺🇸 Fort Worth, Texas, United States

Ep0216 125; 🇺🇸 Tacoma, Washington, United States

Ep0216 2505; 🇦🇹 Linz, Austria

Ep0216 804; 🇧🇪 Brussels, Belgium

Ep0216 801; 🇧🇪 Edegem, Belgium

Ep0216 2802; 🇬🇪 Tbilisi, Georgia

Ep0216 902; 🇩🇪 Bielefeld, Germany

Ep0216 909; 🇩🇪 Kehl-Kork, Germany

Ep0216 908; 🇩🇪 Kiel, Germany

Ep0216 1801; 🇮🇪 Cork, Ireland

Ep0216 1803; 🇮🇪 Dublin, Ireland

Ep0216 1906; 🇮🇱 Ramat Gan, Israel