Fenfluramine in CDKL5 Deficiency Disorder (CDD) | NCT03861871

NCT03861871

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

Status Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Fenfluramine Hydrochloride	Experimental	Study medication will be administered as equal doses twice a day in the morning and in the evening approximately 12 hours apart. Patients will first be titrated over 14 days to a dose of ZX008 0.8 mg/kg/day (maximum dose 30 mg/d). After completion of the Titration Period, patients will continue to receive the ZX008 0.8 mg/kg/day dose and be treated for an additional 12 weeks (Maintenance Period). Study medication will continue to be administered twice a day in the morning and in the evening, approximately 12 hours apart. After completion of the Maintenance Period, patients will enter the Taper Period, where they will decrease from 0.8 mg/kg twice a day to a dose of 0.4 mg/kg twice a day (maximum 30 mg/day). After 4 days at this dose level, patients will decrease their dose to 0.2 mg/kg/day. On day 9 of the Taper Period, all participants will stop taking study medication.	Drug: Fenfluramine Hydrochloride

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Fenfluramine Hydrochloride	Drug	Oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 and provided in concentrations of 2.5 mg/mL. Manufactured by Andersonbrecon, Inc. on behalf of Zogenix International Limited.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Change From Baseline in Median Monthly Convulsive Seizure Frequency	Change between baseline and Week 14 in the median number of monthly convulsive seizures.	Baseline, Week 14

Secondary Outcomes

Measure	Description	Time Frame
Change in Caregiver Global Impression of Change (CGIC) Score	The CGIC is a 1-item, parent/caregiver-completed assessment used determine how much their child/care-recipient has improved with treatment. The instrument asks parents/caregivers to rate their child's/care-recipient's improvement as: 1) very much improved; 2) much improved; 3) minimally improved; 4) unchanged; 5) a little worse; 6) much worse; 7) very much worse; the total score correspondingly ranges from 1-7.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Confirmed clinical/genetic diagnosis of CDKL5 Deficiency Disorder CDD
Ages 2-18 years old. Subject is male or non-pregnant, non-lactating female. Female subjects of childbearing potential must not be pregnant or breast-feeding. Female subjects of childbearing potential must have a negative urine pregnancy test. Subjects of childbearing or child-fathering potential must be willing to use medically acceptable forms of birth control, which includes abstinence, while being treated on this study and for 30 days after the last dose of study drug.
Subject has been informed of the nature of the study and informed consent has been obtained from the legally responsible parent/guardian.
Subject has provided assent in accordance with Investigational Review Board/Independent Ethics Committee (IRB/IEC) requirements, if capable.
Subject's caregiver is willing and able to be compliant with diary completion, visit schedule and study drug accountability.
Subjects must be receiving a therapeutically relevant and stable dose of anti-seizure medications, dietary therapies for epilepsy or vagus nerve stimulation settings for at least 4 weeks prior to screening and are expected to remain stable throughout the study.
≥4 convulsive seizures (tonic-clonic, tonic, atonic, clonic, focal motor) per 4-week period; each convulsive seizure must last ≥3 seconds.

Exclusion Criteria:

Subject has a known hypersensitivity to fenfluramine or any of the excipients in the study medication.
Subject has current or past history of cardiovascular or cerebrovascular disease, myocardial infarction or stroke.
Subject has current or past history of cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction or stroke, or clinically significant structural cardiac abnormality, including but not limited to mitral valve prolapse, atrial or ventricular septal defects, patent ductus arteriosis, and patent foramen ovale with reversal of shunt. (note: Patent foramen ovale or a bicuspid valve are is not considered exclusionary, but may be associated with the following diseases, which are exclusionary: coarctation of the aorta, Turner syndrome, supravalvular aortic stenosis, subvalvular aortic stenosis, patent ductus arteriosus, Sinus of Valsalva aneurysm, ventricular septal defect, Shone's complex, ascending aortic aneurysm, Loeys-Dietz syndrome, ACTA2 mutation familial thoracic aortic aneurysm syndrome, and MAT2A mutation familial thoracic aortic aneurysm syndrome).
Subject has 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.
Subjects who are currently on CBD/THC or any MMJ or those who have tested positive urine tetrahydrocannabinol (THC) Panel or whole blood cannabidiol (CBD).
Subject has participated in another clinical trial within the past 30 days (calculated from that study's last scheduled visit).
Subject is at imminent risk of self-harm or harm to others, in the investigator's opinion, based on clinical interview.
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; atomoxetine, or other centrally-acting noradrenergic agonist; or cyproheptadine. (see appendix 1)
Subject has moderate or severe hepatic impairment. Asymptomatic subjects with mild hepatic impairment (elevated liver enzymes <3x upper limited of normal [ULN] and/or elevated bilirubin <2x ULN) may be entered into the study after review and approval by the Medical Monitor in conjunction with the sponsor, in consideration of comorbidities and concomitant medications.

Name	Affiliation	Role
Orrin Devinsky, MD	NYU Langone Health	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
New York Langone Health Comprehensive Epilespy Center		New York	New York	10016	United States

PubMed Identifier	Type	Citation	Retractions
33979451	Derived	Devinsky O, King L, Schwartz D, Conway E, Price D. Effect of fenfluramine on convulsive seizures in CDKL5 deficiency disorder. Epilepsia. 2021 Jul;62(7):e98-e102. doi: 10.1111/epi.16923. Epub 2021 May 12.

Arm/Group Information

ID	Title	Description
FG000	Fenfluramine Hydrochloride	Study medication will be administered as equal doses twice a day in the morning and in the evening approximately 12 hours apart. Patients will first be titrated over 14 days to a dose of ZX008 0.8 mg/kg/day (maximum dose 30 mg/d). After completion of the Titration Period, patients will continue to receive the ZX008 0.8 mg/kg/day dose and be treated for an additional 12 weeks (Maintenance Period). Study medication will continue to be administered twice a day in the morning and in the evening, approximately 12 hours apart. After completion of the Maintenance Period, patients will enter the Taper Period, where they will decrease from 0.8 mg/kg twice a day to a dose of 0.4 mg/kg twice a day (maximum 30 mg/day). After 4 days at this dose level, patients will decrease their dose to 0.2 mg/kg/day. On day 9 of the Taper Period, all participants will stop taking study medication. Fenfluramine Hydrochloride: Oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 and provided in concentrations of 2.5 mg/mL. Manufactured by Andersonbrecon, Inc. on behalf of Zogenix International Limited.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Fenfluramine Hydrochloride	Study medication will be administered as equal doses twice a day in the morning and in the evening approximately 12 hours apart. Patients will first be titrated over 14 days to a dose of ZX008 0.8 mg/kg/day (maximum dose 30 mg/d). After completion of the Titration Period, patients will continue to receive the ZX008 0.8 mg/kg/day dose and be treated for an additional 12 weeks (Maintenance Period). Study medication will continue to be administered twice a day in the morning and in the evening, approximately 12 hours apart. After completion of the Maintenance Period, patients will enter the Taper Period, where they will decrease from 0.8 mg/kg twice a day to a dose of 0.4 mg/kg twice a day (maximum 30 mg/day). After 4 days at this dose level, patients will decrease their dose to 0.2 mg/kg/day. On day 9 of the Taper Period, all participants will stop taking study medication. Fenfluramine Hydrochloride: Oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 and provided in concentrations of 2.5 mg/mL. Manufactured by Andersonbrecon, Inc. on behalf of Zogenix International Limited.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change From Baseline in Median Monthly Convulsive Seizure Frequency

Change between baseline and Week 14 in the median number of monthly convulsive seizures.

Posted

Median

Standard Deviation

Number of monthly seizures

Baseline, Week 14

ID	Title	Description
OG000	Fenfluramine Hydrochloride	Study medication will be administered as equal doses twice a day in the morning and in the evening approximately 12 hours apart. Patients will first be titrated over 14 days to a dose of ZX008 0.8 mg/kg/day (maximum dose 30 mg/d). After completion of the Titration Period, patients will continue to receive the ZX008 0.8 mg/kg/day dose and be treated for an additional 12 weeks (Maintenance Period). Study medication will continue to be administered twice a day in the morning and in the evening, approximately 12 hours apart. After completion of the Maintenance Period, patients will enter the Taper Period, where they will decrease from 0.8 mg/kg twice a day to a dose of 0.4 mg/kg twice a day (maximum 30 mg/day). After 4 days at this dose level, patients will decrease their dose to 0.2 mg/kg/day. On day 9 of the Taper Period, all participants will stop taking study medication. Fenfluramine Hydrochloride: Oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 and provided in concentrations of 2.5 mg/mL. Manufactured by Andersonbrecon, Inc. on behalf of Zogenix International Limited.

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Fenfluramine Hydrochloride	Study medication will be administered as equal doses twice a day in the morning and in the evening approximately 12 hours apart. Patients will first be titrated over 14 days to a dose of ZX008 0.8 mg/kg/day (maximum dose 30 mg/d). After completion of the Titration Period, patients will continue to receive the ZX008 0.8 mg/kg/day dose and be treated for an additional 12 weeks (Maintenance Period). Study medication will continue to be administered twice a day in the morning and in the evening, approximately 12 hours apart. After completion of the Maintenance Period, patients will enter the Taper Period, where they will decrease from 0.8 mg/kg twice a day to a dose of 0.4 mg/kg twice a day (maximum 30 mg/day). After 4 days at this dose level, patients will decrease their dose to 0.2 mg/kg/day. On day 9 of the Taper Period, all participants will stop taking study medication. Fenfluramine Hydrochloride: Oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 and provided in concentrations of 2.5 mg/mL. Manufactured by Andersonbrecon, Inc. on behalf of Zogenix International Limited.

ID	Term
D010627	Phenethylamines
D005021	Ethylamines
D000588	Amines
D009930	Organic Chemicals