A 2-Part Study to Investigate the Dose-Ranging Safety and... | NCT02926898

NCT02926898

Status Module

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Cohort 2: ZX008 0.5 mg/kg/day	Experimental	ZX008 0.5 mg/kg/day (maximum 20 mg/day) dose supplied as an oral solution administered twice a day (BID) in equally divided doses with food.	Drug: ZX008 (Fenfluramine Hydrochloride)
Cohort 2: Matching Placebo	Placebo Comparator	Matching placebo administered twice a day (BID) in equally divided doses with food.	Drug: Matching Placebo

Interventions

Name	Type	Description	Arm Group Labels	Other Names
ZX008 (Fenfluramine Hydrochloride)	Drug	ZX008 0.5 mg/kg/day (maximum 20 mg/day). ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 and provided in concentrations of 2.5 mg/mL. *Note: The 0.5 mg/kg/day dose of ZX008 fenfluramine hydrochloride in this study is equivalent to 0.4 mg/kg/day (maximum 17 mg/day) dose of fenfluramine base.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Change in Convulsive Seizure Frequency (CSF) From the Baseline Period (Baseline) to the Combined Titration + Maintenance (T+M) Period	Monthly (28 day) convulsive seizure frequency (CSF) was based on electronic diary data obtained for each participant. Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). The number of convulsive seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day CSF.	15 weeks (combined Titration + Maintenance Period)

Secondary Outcomes

Measure	Description	Time Frame
Percentage of Participants Who Achieved ≥ a 50% Reduction in Convulsive Seizure Frequency From Baseline to the Combined Titration + Maintenance Period	Percentage of participants who achieved ≥ a 50% reduction in convulsive seizure frequency from Baseline compared to the combined Titration + Maintenance Periods in the ZX008 0.5 mg/kg/day vs placebo groups.	15 weeks (combined Titration + Maintenance Period)

Eligibility Module

Eligibility Criteria

Key Inclusion Criteria:

Subject must be male or non-pregnant, non-lactating female, aged 2 to 18 years (inclusive).
Subject must have documented medical history to support a clinical diagnosis of Dravet syndrome, where convulsive seizures are not completely controlled by current antiepileptic drugs.
Subject must be receiving a therapeutically relevant and stable dose of stiripentol (STP) plus clobazam (CLB) and/or valproate (VPA), and for at least 4 weeks prior to screening and be expected to remain stable throughout the study (Cohort 2 only).
Subject must be receiving a stable dose of CLB and VPA, administered twice daily (BID), to be eligible for Dose Regimen 1 and 2, or subject must be receiving a stable dose of CLB, VPA, and STP, administered BID, to be eligible for Dose Regimen 3 (Cohort 1 only).

Key Exclusion Criteria:

Subject has a known hypersensitivity to fenfluramine or any of the excipients in the study medication.
Subject has pulmonary arterial hypertension.
Subject has a current or past history of cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction, or stroke.
Subject has a 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.
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; triptans, atomoxetine, or other centrally acting noradrenergic agonists; cyproheptadine, and/or cytochrome P450 (CYP) 2D6/3A4/2B6 inhibitors/substrates.
Subject is currently taking carbamazepine ,oxcarbazepine, eslicarbazepine, phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as maintenance therapy.
Subject has a positive result on urine tetrahydrocannabinol (THC) panel or whole blood cannabidiol (CBD) at the Screening Visit.
Subject has a clinically significant condition, or has had clinically relevant symptoms or a clinically significant illness 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.

Facility	Status	City	State	ZIP	Country	Contacts
University of California San Francisco		San Francisco	California	94158	United States
Children'S Hospital Colorado

PubMed Identifier	Type	Citation	Retractions
31790543	Result	Nabbout R, Mistry A, Zuberi S, Villeneuve N, Gil-Nagel A, Sanchez-Carpintero R, Stephani U, Laux L, Wirrell E, Knupp K, Chiron C, Farfel G, Galer BS, Morrison G, Lock M, Agarwal A, Auvin S; FAiRE, DS Study Group. Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens: A Randomized Clinical Trial. JAMA Neurol. 2020 Mar 1;77(3):300-308. doi: 10.1001/jamaneurol.2019.4113.
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Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Cohort 2: ZX008 0.5 mg/kg/Day	ZX008 0.5 mg/kg/day (maximum 20 mg/day) administered twice a day (BID) in equally divided doses.
FG001	Cohort 2: Matching Placebo	Matching placebo administered twice a day (BID) in equally divided doses.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Feb 2, 2018	Jun 10, 2021

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 in Convulsive Seizure Frequency (CSF) From the Baseline Period (Baseline) to the Combined Titration + Maintenance (T+M) Period

Monthly (28 day) convulsive seizure frequency (CSF) was based on electronic diary data obtained for each participant. Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). The number of convulsive seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day CSF.

Modified intent-to-treat (mITT) Population, defined as all randomized subjects who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.

Posted

Mean

Standard Deviation

Convulsive seizures per 28 days

15 weeks (combined Titration + Maintenance Period)

ID	Title	Description
OG000	Cohort 2: ZX008 0.5 mg/kg/Day	ZX008 0.5 mg/kg/day (maximum 20 mg/day) administered twice a day (BID) in equally divided doses.
OG001	Cohort 2: Matching Placebo	Matching placebo administered twice a day (BID) in equally divided doses.

Units	Counts
Participants	OG00043 OG00144

Title

Denominators

Categories

Title	Measurements
	OG000-3.18± 44.121 OG001-0.65± 8.767

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		ANCOVA		<0.001	Analysis of covariance (ANCOVA) model with treatment group (ZX008 or placebo) and age group (< 6 years, ≥ 6 years) as factors, and with log baseline frequency as a covariate, and log CSF as the outcome variable.	Percent difference	-54.0			2-Sided	95	-67.2	-35.6					Superiority

Secondary

Percentage of Participants Who Achieved ≥ a 50% Reduction in Convulsive Seizure Frequency From Baseline to the Combined Titration + Maintenance Period

Percentage of participants who achieved ≥ a 50% reduction in convulsive seizure frequency from Baseline compared to the combined Titration + Maintenance Periods in the ZX008 0.5 mg/kg/day vs placebo groups.

Modified intent-to-treat (mITT) Population, defined as all randomized subjects who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.

Posted

Number

Percentage of participants

15 weeks (combined Titration + Maintenance Period)

ID	Title	Description
OG000	Cohort 2: ZX008 0.5 mg/kg/Day	ZX008 0.5 mg/kg/day (maximum 20 mg/day) administered twice a day (BID) in equally divided doses.
OG001	Cohort 2: Matching Placebo	Matching placebo administered twice a day (BID) in equally divided doses.

Units	Counts
Participants

Secondary

Longest Convulsive Seizure-Free Interval (Days)

Comparison of the duration of the longest convulsive seizure-free interval (days) during the combined Titration + Maintenance Periods for the ZX008 0.5 mg/kg/day and placebo groups.

Modified intent-to-treat (mITT) Population, defined as all randomized subjects who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.

Posted

Median

Full Range

Days

15 weeks (combined Titration + Maintenance Period)

ID	Title	Description
OG000	Cohort 2: ZX008 0.5 mg/kg/Day	ZX008 0.5 mg/kg/day (maximum 20 mg/day) administered twice a day (BID) in equally divided doses.
OG001	Cohort 2: Matching Placebo	Matching placebo administered twice a day (BID) in equally divided doses.

Units	Counts
Participants	OG000

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Abdominal pain	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected43 at risk EG0011 affected44 at risk
Pyrexia	General disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected43 at risk EG0011 affected44 at risk
Gastroenteritis viral	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0000 affected43 at risk EG0011 affected44 at risk
Lower respiratory tract infection	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0000 affected43 at risk EG0011 affected44 at risk
Pneumonia	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0000 affected43 at risk EG0011 affected44 at risk
Osteochondritis	Musculoskeletal and connective tissue disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected43 at risk EG0010 affected44 at risk
Generalised tonic-clonic seizure	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected43 at risk EG0011 affected44 at risk
Lethargy	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected43 at risk EG0010 affected44 at risk
Seizure	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0001 affected43 at risk EG0014 affected44 at risk
Seizure cluster	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected43 at risk EG0011 affected44 at risk
Status epilepticus	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0003 affected43 at risk EG0010 affected44 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Diarrhea	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG00010 affected43 at risk EG0013 affected44 at risk
Fatigue	General disorders	MedDRA (19.0)	Systematic Assessment	EG00011 affected43 at risk EG0012 affected44 at risk
Pyrexia	General disorders	MedDRA (19.0)	Systematic Assessment	EG00011 affected43 at risk EG0014 affected44 at risk
Bronchitis	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0005 affected43 at risk EG0012 affected44 at risk
Blood glucose decreased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0006 affected43 at risk EG0012 affected44 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA (19.0)	Systematic Assessment	EG00019 affected43 at risk EG0015 affected44 at risk
Lethargy	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0006 affected43 at risk EG0012 affected44 at risk
Seizure	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0002 affected43 at risk EG0017 affected44 at risk
Constipation	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0004 affected43 at risk EG0011 affected44 at risk
Vomiting	Gastrointestinal disorders	MedDRA (19.0)	Systematic Assessment	EG0002 affected43 at risk EG0013 affected44 at risk
Asthenia	General disorders	MedDRA (19.0)	Systematic Assessment	EG0003 affected43 at risk EG0012 affected44 at risk
Ear Infection	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0004 affected43 at risk EG0012 affected44 at risk
Nasopharyngitis	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0007 affected43 at risk EG00115 affected44 at risk
Rhinitis	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0003 affected43 at risk EG0011 affected44 at risk
Sinusitis	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0001 affected43 at risk EG0013 affected44 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA (19.0)	Systematic Assessment	EG0004 affected43 at risk EG0013 affected44 at risk
Blood pressure diastolic increased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0000 affected43 at risk EG0013 affected44 at risk
Blood pressure increased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0000 affected43 at risk EG0013 affected44 at risk
Echocardiogram abnormal	Investigations	MedDRA (19.0)	Systematic Assessment	EG0004 affected43 at risk EG0010 affected44 at risk
Weight decreased	Investigations	MedDRA (19.0)	Systematic Assessment	EG0004 affected43 at risk EG0011 affected44 at risk
Generalized tonic-clonic seizure	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0000 affected43 at risk EG0013 affected44 at risk
Somnolence	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0003 affected43 at risk EG0013 affected44 at risk
Status epilepticus	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0005 affected43 at risk EG0010 affected44 at risk
Tremor	Nervous system disorders	MedDRA (19.0)	Systematic Assessment	EG0005 affected43 at risk EG0010 affected44 at risk
Abnormal behavior	Psychiatric disorders	MedDRA (19.0)	Systematic Assessment	EG0004 affected43 at risk EG0011 affected44 at risk
Irritability	Psychiatric disorders	MedDRA (19.0)	Systematic Assessment	EG0004 affected43 at risk EG0012 affected44 at risk

ID	Term
D004831	Epilepsies, Myoclonic
D012640	Seizures
D004827	Epilepsy
D001927	Brain Diseases

ID	Term
D004829	Epilepsy, Generalized
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases
D000073376	Epileptic Syndromes
D009461	Neurologic Manifestations
D012816	Signs and Symptoms
D013568	Pathological Conditions, Signs and Symptoms

ID	Term
D010627	Phenethylamines
D005021	Ethylamines
D000588	Amines
D009930	Organic Chemicals

ID	Title	Description
BG000	Cohort 2: ZX008 0.5 mg/kg/Day	ZX008 0.5 mg/kg/day (maximum 20 mg/day) dose administered twice a day (BID) in equally divided doses.
BG001	Cohort 2: Matching Placebo	Matching placebo administered twice a day (BID) in equally divided doses.
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Cohort 2: ZX008 0.5 mg/kg/Day	ZX008 0.5 mg/kg/day (maximum 20 mg/day) dose administered twice a day (BID) in equally divided doses.	0	43	6	43	42	43
EG001	Cohort 2: Matching Placebo	Matching placebo administered twice a day (BID) in equally divided doses.	0	44	7	44	42	44