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Clinical Trial Results:
A Two-Part Study of ZX008 in Children and Adults with Lennox-Gastaut Syndrome (LGS); Part 1: A Randomized, Double-blind, Placebo-controlled Trial of Two Fixed Doses of ZX008 (Fenfluramine Hydrochloride) Oral Solution as Adjunctive Therapy for Seizures in Children and Adults with LGS, Followed by Part 2: An Open-label Extension to Assess Long-Term Safety of ZX008 in Children and Adults with LGS

Summary
EudraCT number	2017-002628-26
Trial protocol	BE DE ES AT DK GB IT SE NL FR PL
Global end of trial date	23 May 2024

Results information
Results version number	v1(current)
This version publication date	05 Jan 2025
First version publication date	05 Jan 2025
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

ZX008-1601

ISRCTN number

US NCT number

NCT03355209

WHO universal trial number (UTN)

Sponsor organisation name

Zogenix International Limited A wholly owned subsidiary of UCB Biosciences, Inc.

Sponsor organisation address

4000 Paramount Pkwy, Suite 200, Morrisville, United States, NC 27560

Public contact

Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com

Scientific contact

Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

25 Jun 2024

Is this the analysis of the primary completion data?

Yes

Primary completion date

23 May 2024

Global end of trial reached?

Yes

Global end of trial date

23 May 2024

Was the trial ended prematurely?

Main objective of the trial

The primary objective of Part 1 is the primary objective of the entire study. The primary objective of Part 1 is: To evaluate the effect of ZX008 0.8 mg/kg/day versus placebo as adjunctive therapy for the treatment of uncontrolled seizures in children and adults with Lennox-Gastaut syndrome (LGS) based on the change in frequency of seizures that result in drops between baseline and the combined Titration and Maintenance Periods (T+M) The primary objective of Part 2 is to assess the long-term safety and tolerability of ZX008 in children and adults with LGS with regard to AEs, laboratory parameters, physical examination, neurological examination, Tanner Staging, cognition (BRIEF), vital signs (blood pressure, heart rate (HR), temperature, and respiratory rate), electrocardiograms (ECG), echocardiograms (ECHO), body weight, and body mass index (BMI).

Protection of trial subjects

During the conduct of the study all participants were closely monitored

Background therapy

Background therapy as permitted in the protocol

Evidence for comparator

Not applicable

Actual start date of recruitment

27 Nov 2017

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

72 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Mexico: 3

Country: Number of subjects enrolled

Spain: 25

Country: Number of subjects enrolled

Italy: 19

Country: Number of subjects enrolled

Poland: 18

Country: Number of subjects enrolled

France: 17

Country: Number of subjects enrolled

Germany: 17

Country: Number of subjects enrolled

Belgium: 12

Country: Number of subjects enrolled

Netherlands: 9

Country: Number of subjects enrolled

Denmark: 3

Country: Number of subjects enrolled

Sweden: 2

Country: Number of subjects enrolled

Australia: 9

Country: Number of subjects enrolled

Japan: 33

Country: Number of subjects enrolled

Canada: 7

Country: Number of subjects enrolled

United States: 122

Worldwide total number of subjects

296

EEA total number of subjects

122

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

117

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study started to enroll participants in November 2017 and concluded in May 2024. Cohort A included participants enrolled at sites in North America, Europe, and Australia. Cohort B included participants enrolled at sites in Japan only.

Screening details

The Participant Flow refers to the All Enrolled Participants Set for Part 1 and OLE Safety Population for Part 2 of the study. As planned, Part 2 summaries were presented by the participant's Part 1 treatment groups (placebo, ZX008 0.2 mg/kg/day, ZX008 0.8 mg/kg/day).

Period 1 title

Part 1: Double-Blind Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

Cohort A: Placebo

Arm description

Part 1: Participants received matching placebo as an oral solution, twice a day (bid) over 2 weeks of Titration Period and an additional 12 weeks of Maintenance Period. Participants who completed the Maintenance Period and did not continue in Part 2, and participants who discontinued from Part 1 early, were tapered off study medication over 8 days. In Part 2 (OLE Period): Participants initially received ZX008 0.2 mg/kg/day for 1 month. After 1 month, the Investigator could adjust the dose if needed. Participants received ZX008 for up to 12 months in OLE Period.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Participants received matching placebo at pre-specified time-points.

Cohort A: ZX008 0.2 mg/kg/day

Arm description

Part 1: Participants received ZX008 0.2 milligram per kilogram per day (mg/kg/day) during the 2-week Titration. Following titration, participants received ZX008 0.2 mg/kg/day as an oral solution, bid for an additional 12 weeks during Maintenance Period. Participants who completed the Maintenance Period and did not continue in Part 2, and participants who discontinued from Part 1 early, were tapered off study medication over 8 days. In Part 2 (OLE Period): Participants initially received ZX008 0.2 mg/kg/day for 1 month. After 1 month at a dose of ZX008 0.2 mg/kg/day, the Investigator could adjust the dose if needed. Participants received ZX008 for up to 12 months in OLE Period.

Arm type

Experimental

Investigational medicinal product name

Fenfluramine hydrochloride

Investigational medicinal product code

ZX008

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Participants received ZX008 at pre-specified time-points.

Cohort A: ZX008 0.8 mg/kg/day

Arm description

Part 1: Participants were titrated to their blinded randomized dose of ZX008 over the 2-week Titration from 0.2 mg/kg/day to ZX008 0.8 mg/kg/day (or a maximum dose of 30 mg/day or 20 mg/day for participants taking concomitant stiripentol [STP]). Following titration, participants continued to receive the randomized dose of ZX008 as an oral solution, bid for an additional 12 weeks during Maintenance Period. Participants who completed the Maintenance Period and did not continue in Part 2, and participants who discontinued from Part 1 early, were tapered off study medication over 8 days. In Part 2 (OLE Period): Participants initially received ZX008 0.2 mg/kg/day for 1 month. After 1 month at a dose of ZX008 0.2 mg/kg/day, the Investigator could adjust the dose if needed. Participants received ZX008 for up to 12 months in OLE Period.

Arm type

Experimental

Investigational medicinal product name

Fenfluramine hydrochloride

Investigational medicinal product code

ZX008

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Participants received ZX008 at pre-specified time-points.

Cohort B: Placebo

Arm description

Part 1: Participants received matching placebo as an oral solution, bid over 2 weeks of Titration Period and an additional 12 weeks of Maintenance Period. Participants who completed the Maintenance Period and did not continue in Part 2, and participants who discontinued from Part 1 early, were tapered off study medication over 8 days. In Part 2 (OLE Period): Participants initially received ZX008 0.2 mg/kg/day for 1 month. After 1 month at a dose of ZX008 0.2 mg/kg/day, the Investigator could adjust the dose if needed. Participants received ZX008 for up to 12 months in OLE Period. Participants who completed 12 months OLE Period had option to receive ZX008 for up to 72 months, or until ZX008 is approved in the participant's country.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Participants received matching placebo at pre-specified time-points.

Cohort B: ZX008 0.2 mg/kg/day

Arm description

Part 1: Participants received ZX008 0.2 mg/kg/day during the 2-week Titration. Following titration, participants received ZX008 0.2 mg/kg/day as an oral solution, bid for an additional 12 weeks during Maintenance Period. Participants who completed the Maintenance Period and did not continue in Part 2, and participants who discontinued from Part 1 early, were tapered off study medication over 8 days. In Part 2 (OLE Period): Participants initially received ZX008 0.2 mg/kg/day for 1 month. After 1 month at a dose of ZX008 0.2 mg/kg/day, the Investigator could adjust the dose if needed. Participants received ZX008 for up to 12 months in OLE Period. Participants who completed 12 months OLE Period had option to receive ZX008 for up to 72 months, or until ZX008 is approved in the participant's country.

Arm type

Experimental

Investigational medicinal product name

Fenfluramine hydrochloride

Investigational medicinal product code

ZX008

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Participants received ZX008 at pre-specified time-points.

Cohort B: ZX008 0.8 mg/kg/day

Arm description

Part 1: Participants were titrated to their blinded randomized dose of ZX008 over the 2-week Titration from 0.2 mg/kg/day to ZX008 0.8 mg/kg/day (or a maximum dose of 30 mg/day or 20 mg/day for participants taking concomitant STP). Following titration, participants continued to receive the randomized dose of ZX008 as an oral solution, bid for an additional 12 weeks during Maintenance Period. Participants who completed the Maintenance Period and did not continue in Part 2, and participants who discontinued from Part 1 early, were tapered off study medication over 8 days. In Part 2 (OLE Period): Participants initially received ZX008 0.2 mg/kg/day for 1 month. After 1 month at a dose of ZX008 0.2 mg/kg/day, the Investigator could adjust the dose if needed. Participants received ZX008 for up to 12 months in OLE Period. Participants who completed 12 months OLE Period had option to receive ZX008 for up to 72 months, or until ZX008 is approved in the participant's country.

Arm type

Experimental

Investigational medicinal product name

Fenfluramine hydrochloride

Investigational medicinal product code

ZX008

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Participants received ZX008 at pre-specified time-points.

Number of subjects in period 1	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Started	87	89	87	11	11	11
Completed	86	83	81	11	10	11
Not completed	1	6	6	0	1	0
Adverse event, serious fatal	-	-	1	-	-	-
Consent withdrawn by subject	1	1	1	-	-	-
Physician decision	-	1	-	-	-	-
Adverse event, non-fatal	-	4	4	-	1	-

Period 2 title

Part 2:Open-Label Extension (OLE) Period

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort A: Placebo

Arm description

Arm type

Placebo

Investigational medicinal product name

Fenfluramine hydrochloride

Investigational medicinal product code

ZX008

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Participants received ZX008 at pre-specified time-points.

Cohort A: ZX008 0.2 mg/kg/day

Arm description

Arm type

Experimental

Investigational medicinal product name

Fenfluramine hydrochloride

Investigational medicinal product code

ZX008

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Participants received ZX008 at pre-specified time-points.

Cohort A: ZX008 0.8 mg/kg/day

Arm description

Arm type

Experimental

Investigational medicinal product name

Fenfluramine hydrochloride

Investigational medicinal product code

ZX008

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Participants received ZX008 at pre-specified time-points.

Cohort B: Placebo

Arm description

Arm type

Placebo

Investigational medicinal product name

Fenfluramine hydrochloride

Investigational medicinal product code

ZX008

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Participants received ZX008 at pre-specified time-points.

Cohort B: ZX008 0.2 mg/kg/day

Arm description

Arm type

Experimental

Investigational medicinal product name

Fenfluramine hydrochloride

Investigational medicinal product code

ZX008

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Participants received ZX008 at pre-specified time-points.

Cohort B: ZX008 0.8 mg/kg/day

Arm description

Part 1: Participants were titrated to their blinded randomized dose of ZX008 over the 2-week Titration from 0.2 mg/kg/day to ZX008 0.8 mg/kg/day (or a maximum dose of 30 mg/day or 20 mg/day for participants taking concomitant STP). Following titration, participants continued to receive the randomized dose of ZX008 as an oral solution, bid for an additional 12 weeks during Maintenance Period. Participants who completed the Maintenance Period and did not continue in Part 2, and participants who discontinued from Part 1 early, were tapered off study medication over 8 days. In Part 2 (OLE Period): Participants initially received ZX008 0.2 mg/kg/day for 1 month. After 1 month at a dose of ZX008 0.2 mg/kg/day, the Investigator could adjust the dose if needed. Participants received ZX008 for up to 12 months in OLE Period. Participants who completed 12 months OLE Period had option to receive ZX008 for up to 72 months, or until ZX008 is approved in the participant's country.

Arm type

Experimental

Investigational medicinal product name

Fenfluramine hydrochloride

Investigational medicinal product code

ZX008

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Participants received ZX008 at pre-specified time-points.

Number of subjects in period 2 ^[1]	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Started	86	83	78	11	10	11
Completed	61	51	46	5	1	5
Not completed	25	32	32	6	9	6
Adverse event, serious fatal	-	1	-	-	-	-
Consent withdrawn by subject	6	5	4	-	2	-
Physician decision	-	-	-	1	-	1
Rollover into ZX008-1900	1	-	2	-	-	-
Switching to commercial ZX008	-	-	-	5	6	3
Adverse event, non-fatal	5	5	3	-	1	1
Lack of efficacy	13	21	23	-	-	1

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: 3 participants completed Part 1 but did not receive Part 2 study treatment. Reason for withdrawal after completing Part 1 but not Entering Part 2 was AE/AE/Withdrawal by Subject.

Baseline characteristics

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Reporting group title

Cohort A: Placebo

Reporting group description

Reporting group title

Cohort A: ZX008 0.2 mg/kg/day

Reporting group description

Reporting group title

Cohort A: ZX008 0.8 mg/kg/day

Reporting group description

Reporting group title

Cohort B: Placebo

Reporting group description

Reporting group title

Cohort B: ZX008 0.2 mg/kg/day

Reporting group description

Reporting group title

Cohort B: ZX008 0.8 mg/kg/day

Reporting group description

Part 1: Participants were titrated to their blinded randomized dose of ZX008 over the 2-week Titration from 0.2 mg/kg/day to ZX008 0.8 mg/kg/day (or a maximum dose of 30 mg/day or 20 mg/day for participants taking concomitant STP). Following titration, participants continued to receive the randomized dose of ZX008 as an oral solution, bid for an additional 12 weeks during Maintenance Period. Participants who completed the Maintenance Period and did not continue in Part 2, and participants who discontinued from Part 1 early, were tapered off study medication over 8 days. In Part 2 (OLE Period): Participants initially received ZX008 0.2 mg/kg/day for 1 month. After 1 month at a dose of ZX008 0.2 mg/kg/day, the Investigator could adjust the dose if needed. Participants received ZX008 for up to 12 months in OLE Period. Participants who completed 12 months OLE Period had option to receive ZX008 for up to 72 months, or until ZX008 is approved in the participant's country.

Reporting group values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day	Total
Number of subjects	87	89	87	11	11	11	296
Age Categorical
Units: participants
2 - < 12 years	32	41	37	2	3	2	117
12 - < 18 years	29	23	25	5	2	3	87
18 - 35 years	26	25	25	4	6	6	92
Age Continuous
Units: years
arithmetic mean (standard deviation)	14.4 ( 7.71 )	13.4 ( 7.79 )	13.4 ( 7.28 )	18.5 ( 7.78 )	20.1 ( 7.79 )	18.5 ( 7.94 )	-
Sex: Female, Male
Units: participants
Female	41	43	33	5	2	2	126
Male	46	46	54	6	9	9	170

End points

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Reporting group title

Cohort A: Placebo

Reporting group description

Reporting group title

Cohort A: ZX008 0.2 mg/kg/day

Reporting group description

Reporting group title

Cohort A: ZX008 0.8 mg/kg/day

Reporting group description

Reporting group title

Cohort B: Placebo

Reporting group description

Reporting group title

Cohort B: ZX008 0.2 mg/kg/day

Reporting group description

Reporting group title

Cohort B: ZX008 0.8 mg/kg/day

Reporting group description

Part 1: Participants were titrated to their blinded randomized dose of ZX008 over the 2-week Titration from 0.2 mg/kg/day to ZX008 0.8 mg/kg/day (or a maximum dose of 30 mg/day or 20 mg/day for participants taking concomitant STP). Following titration, participants continued to receive the randomized dose of ZX008 as an oral solution, bid for an additional 12 weeks during Maintenance Period. Participants who completed the Maintenance Period and did not continue in Part 2, and participants who discontinued from Part 1 early, were tapered off study medication over 8 days. In Part 2 (OLE Period): Participants initially received ZX008 0.2 mg/kg/day for 1 month. After 1 month at a dose of ZX008 0.2 mg/kg/day, the Investigator could adjust the dose if needed. Participants received ZX008 for up to 12 months in OLE Period. Participants who completed 12 months OLE Period had option to receive ZX008 for up to 72 months, or until ZX008 is approved in the participant's country.

Reporting group title

Cohort A: Placebo

Reporting group description

Reporting group title

Cohort A: ZX008 0.2 mg/kg/day

Reporting group description

Reporting group title

Cohort A: ZX008 0.8 mg/kg/day

Reporting group description

Reporting group title

Cohort B: Placebo

Reporting group description

Reporting group title

Cohort B: ZX008 0.2 mg/kg/day

Reporting group description

Reporting group title

Cohort B: ZX008 0.8 mg/kg/day

Reporting group description

Part 1: Participants were titrated to their blinded randomized dose of ZX008 over the 2-week Titration from 0.2 mg/kg/day to ZX008 0.8 mg/kg/day (or a maximum dose of 30 mg/day or 20 mg/day for participants taking concomitant STP). Following titration, participants continued to receive the randomized dose of ZX008 as an oral solution, bid for an additional 12 weeks during Maintenance Period. Participants who completed the Maintenance Period and did not continue in Part 2, and participants who discontinued from Part 1 early, were tapered off study medication over 8 days. In Part 2 (OLE Period): Participants initially received ZX008 0.2 mg/kg/day for 1 month. After 1 month at a dose of ZX008 0.2 mg/kg/day, the Investigator could adjust the dose if needed. Participants received ZX008 for up to 12 months in OLE Period. Participants who completed 12 months OLE Period had option to receive ZX008 for up to 72 months, or until ZX008 is approved in the participant's country.

Subject analysis set title

Part 2: Cohort A- Overall

Subject analysis set type

Safety analysis

Subject analysis set description

All Cohort A participants who continued in Part 2 received ZX008 0.2 milligram per kilogram per day (mg/kg/day) as an oral solution, twice a day (bid), for 1 month. After 1 month at a dose of ZX008 0.2 mg/kg/day, the Investigator could adjust the dose if needed. Dose changes were made in maximum increments of 0.2 mg/kg/day, to a maximum of 0.8 mg/kg/day (or 0.5 mg/kg/day for participants taking concomitant STP) but not to exceed a total dose of 30 mg/day (or 20 mg/kg/day for subjects taking concomitant STP). Participants received ZX008 for up to 12 months in OLE Period.

Subject analysis set title

Part 2: Cohort B- Overall

Subject analysis set type

Safety analysis

Subject analysis set description

All Cohort B participants who continued in Part 2 received ZX008 0.2 mg/kg/day as an oral solution, twice a day (bid), for 1 month. After 1 month at a dose of ZX008 0.2 mg/kg/day, the Investigator could adjust the dose if needed. Dose changes were made in maximum increments of 0.2 mg/kg/day, to a maximum of 0.8 mg/kg/day (or 0.5 mg/kg/day for participants taking concomitant STP) but not to exceed a total dose of 30 mg/day (or 20 mg/kg/day for subjects taking concomitant STP). Participants received ZX008 for up to 12 months in OLE Period. Participants who completed 12 months OLE Period had option to receive ZX008 for up to 72 months, or until ZX008 is approved in the participant's country.

Subject analysis set title

Part 2: Cohort A- Overall

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

Part 2: Cohort B- Overall

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

Part 2: Cohort A- Overall

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

Part 2: Cohort A- Overall

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Subject analysis set title

Part 2: Cohort B- Overall

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Primary: Part 1: Percent change from Baseline in the frequency of seizures that result in drops (ESC-confirmed) in the combined Titration and Maintenance Period (T+M) in the ZX008 0.8 mg/kg/day group compared to the placebo group

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End point title

Part 1: Percent change from Baseline in the frequency of seizures that result in drops (ESC-confirmed) in the combined Titration and Maintenance Period (T+M) in the ZX008 0.8 mg/kg/day group compared to the placebo group ^[1]

End point description

Percent change in frequency of seizures that result in drops (DSF: drop seizure frequency) per 28 days between the combined Titration and Maintenance (T+M) and Baseline. The percent change from Baseline DSF was calculated as the change in DSF between T+M and Baseline / DSF during Baseline* 100. The seizure types included in the count were: atonic, tonic, tonic/atonic, generalized tonic-clonic, and secondarily generalized tonic-clonic seizures resulting in drops. The Modified Intent-to-Treat (mITT) Population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.

End point type

Primary

End point timeframe

From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The 'Cohort A: ZX008 0.2 mg/kg/day' and 'Cohort B: ZX008 0.2 mg/kg/day' arms which was part of baseline period were not required for the primary endpoint assessment. Therefore, no data was reported for this arm.

End point values	Cohort A: Placebo	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.8 mg/kg/day
Number of subjects analysed	87	87	11	11
Units: percent change
median (full range (min-max))	-7.59 (-100.0 to 557.1)	-26.49 (-95.2 to 402.1)	-17.89 (-97.3 to 61.8)	-34.52 (-69.4 to 45.5)

Statistical Analysis 1

Comparison groups

Cohort A: Placebo v Cohort A: ZX008 0.8 mg/kg/day

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

= 0.0008

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median Difference (A-P)

Point estimate

-19.88

Confidence interval

level

95%

sides

2-sided

lower limit

-31.02

upper limit

-8.74

Notes
[2] - Median Difference was calculated using Hodges-Lehmann (HL) method.

Primary: Part 2: Percentage of participants with treatment-emergent adverse events (TEAEs)

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End point title

Part 2: Percentage of participants with treatment-emergent adverse events (TEAEs) ^[3]

End point description

An Adverse event (AE) was defined as any unfavourable and unintended sign, symptom, or disease temporally associated with the use of investigational product, or whether considered related to the investigational product. A TEAE in Part 2 was defined as any AE with an onset on or after the first dose in Part 2. AEs with onset in Part 1 that are ongoing in Part 2 were not included in the count of AEs in Part 2. The OLE Safety Population included all participants who received at least 1 dose of ZX008 during the OLE.

End point type

Primary

End point timeframe

From Part 2 Baseline until end of the OLE Period (up to 72 months)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.

End point values	Part 2: Cohort A- Overall	Part 2: Cohort B- Overall
Number of subjects analysed	247	32
Units: percentage of participants
number (not applicable)	83.0	96.9

No statistical analyses for this end point

Primary: Part 2: Percentage of participants with Serious TEAEs

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End point title

Part 2: Percentage of participants with Serious TEAEs ^[4]

End point description

A serious adverse event (SAE) was defined as any untoward medical occurrence that at any dose: Results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, or is medically significant. The OLE Safety Population included all participants who received at least 1 dose of ZX008 during the OLE.

End point type

Primary

End point timeframe

From Part 2 Baseline until end of the OLE Period (up to 72 months)

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.

End point values	Part 2: Cohort A- Overall	Part 2: Cohort B- Overall
Number of subjects analysed	247	32
Units: percentage of participants
number (not applicable)	16.6	18.8

No statistical analyses for this end point

Secondary: Part 1: Percent change from Baseline in the frequency of seizures that result in drops (ESC-confirmed) in T+M in the ZX008 0.2 mg/kg/day group compared to the placebo group

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End point title

Part 1: Percent change from Baseline in the frequency of seizures that result in drops (ESC-confirmed) in T+M in the ZX008 0.2 mg/kg/day group compared to the placebo group ^[5]

End point description

Percent change in frequency of seizures that result in drops (DSF: drop seizure frequency) per 28 days between the combined Titration and Maintenance (T+M) and Baseline. The percent change from Baseline DSF was calculated as the change in DSF between T+M and Baseline / DSF during Baseline* 100. The seizure types included in the count were: atonic, tonic, tonic/atonic, generalized tonic-clonic, and secondarily generalized tonic-clonic seizures resulting in drops. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.

End point type

Secondary

End point timeframe

From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The data for the 'Cohort A: ZX008 0.8 mg/kg/day' and 'Cohort B: ZX008 0.8 mg/kg/day' arms was reported in primary endpoint therefore, these arms which was part of baseline period were not required for the secondary endpoint assessment. Hence, no data was reported for these arms.

End point values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day
Number of subjects analysed	87	89	11	11
Units: percent change
median (full range (min-max))	-7.59 (-100.0 to 557.1)	-14.16 (-100.0 to 3307.3)	-17.89 (-97.3 to 61.8)	-14.12 (-95.6 to 66.4)

Statistical Analysis 1

Comparison groups

Cohort A: Placebo v Cohort A: ZX008 0.2 mg/kg/day

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

P-value

= 0.146

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median Difference (A-P)

Point estimate

-10.5

Confidence interval

level

95%

sides

2-sided

lower limit

-24.99

upper limit

3.99

Notes
[6] - Median Difference was calculated using HL method.

Secondary: Part 1: Percentage of participants who achieve a >=50% reduction from Baseline in the frequency of seizures that result in drops comparing the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

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End point title

Part 1: Percentage of participants who achieve a >=50% reduction from Baseline in the frequency of seizures that result in drops comparing the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

End point description

The seizure types included in the count were: atonic, tonic, tonic/atonic, generalized tonic-clonic, and secondarily generalized tonic-clonic seizures resulting in drops. Participants who achieved a >=50% reduction from Baseline in the DSF, ie, a decrease in DSF of at least 50 percentage points per 28 days during Titration and Maintenance Period. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.

End point type

Secondary

End point timeframe

From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]

End point values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Number of subjects analysed	87	89	87	11	11	11
Units: percentage of participants
number (not applicable)	10.3	28.1	25.3	9.1	36.4	36.4

Statistical Analysis 2

Comparison groups

Cohort A: Placebo v Cohort A: ZX008 0.8 mg/kg/day

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.015

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

2.87

Confidence interval

level

95%

sides

2-sided

lower limit

1.23

upper limit

6.7

Statistical Analysis 1

Comparison groups

Cohort A: Placebo v Cohort A: ZX008 0.2 mg/kg/day

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0051

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

3.3

Confidence interval

level

95%

sides

2-sided

lower limit

1.43

upper limit

7.59

Secondary: Part 1: Percentage of participants who achieve improvement (minimally, much or very much improved) in the CGI-I scale as assessed by Principal Investigator comparing ZX008 0.8 and 0.2 mg/kg/day groups independently versus placebo

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End point title

Part 1: Percentage of participants who achieve improvement (minimally, much or very much improved) in the CGI-I scale as assessed by Principal Investigator comparing ZX008 0.8 and 0.2 mg/kg/day groups independently versus placebo

End point description

Clinical Global Impression – Improvement (CGI-I) scale measures improvement in the participant's condition from Baseline. The severity of a participant's condition was 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 and 7-very much worse. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available. Here, number of participants analyzed included those participants who were evaluable for the assessment.

End point type

Secondary

End point timeframe

At Day 99 (Visit 12)

End point values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Number of subjects analysed	80	85	80	11	11	11
Units: percentage of participants
number (not applicable)	33.8	44.7	48.8	9.1	45.5	72.7

Statistical Analysis 2

Statistical analysis description

Visit 12

Comparison groups

Cohort A: Placebo v Cohort A: ZX008 0.8 mg/kg/day

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0567

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.86

Confidence interval

level

95%

sides

2-sided

lower limit

0.98

upper limit

3.52

Statistical Analysis 1

Statistical analysis description

Visit 12

Comparison groups

Cohort A: Placebo v Cohort A: ZX008 0.2 mg/kg/day

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1565

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.58

Confidence interval

level

95%

sides

2-sided

lower limit

0.84

upper limit

2.97

Secondary: Part 1: Percent change from Baseline in frequency of all seizures that typically result in drops in T+M, whether ESC-confirmed as drop or not in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

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End point title

Part 1: Percent change from Baseline in frequency of all seizures that typically result in drops in T+M, whether ESC-confirmed as drop or not in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

End point description

Seizures that typically result in drops included all: generalized tonic-clonic seizures [GTC], secondarily generalized tonic-clonic [SGTC], tonic seizures [TS], atonic seizures [AS], and tonic/atonic seizures [TA], whether confirmed by the ESC or not. Seizures that result in a drop were defined as seizures involving the entire body, trunk, or head that led to a fall, injury, slumping in a chair, or the participant's head hitting a surface or that could have led to a fall or injury, depending on the patient’s position at the time of the seizure. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.

End point type

Secondary

End point timeframe

From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]

End point values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Number of subjects analysed	87	89	87	11	11	11
Units: percent change
median (full range (min-max))	-8.43 (-100.0 to 557.1)	-11.75 (-100.0 to 3307.3)	-26.28 (-95.2 to 402.1)	-17.89 (-97.3 to 61.8)	-14.12 (-95.6 to 66.4)	-34.04 (-69.4 to 45.5)

No statistical analyses for this end point

Secondary: Part 1: Percent change from Baseline in the frequency of all countable motor seizures in T+M in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

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End point title

Part 1: Percent change from Baseline in the frequency of all countable motor seizures in T+M in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

End point description

Countable motor seizures included: GTC, SGTC, TS, AS, TA, clonic seizures [CS], hemiclonic seizures [HS], and focal seizures [FS] with clearly observable signs. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.

End point type

Secondary

End point timeframe

From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]

End point values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Number of subjects analysed	87	89	87	11	11	11
Units: percent change
median (full range (min-max))	-8.43 (-80.8 to 497.8)	-11.75 (-100.0 to 3307.3)	-26.28 (-91.9 to 402.1)	-17.89 (-97.3 to 61.8)	-14.12 (-95.6 to 174.1)	-34.04 (-69.4 to 45.5)

No statistical analyses for this end point

Secondary: Part 1: Change from Baseline in the frequency of all countable non-motor seizures in T+M in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

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End point title

Part 1: Change from Baseline in the frequency of all countable non-motor seizures in T+M in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

End point description

Countable non-motor seizures included: focal seizures [FS] without clear observable signs, myoclonic seizures [MS], absence/atypical absence, infantile spasms, epileptic spasms, and other seizures. For each participant, the seizure frequency per 28 days was calculated as the number of seizures recorded during the period, divided by the number of days in the period and multiplied by 28. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.

End point type

Secondary

End point timeframe

From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]

End point values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Number of subjects analysed	87	89	87	11	11	11
Units: seizure frequency per 28 days
median (full range (min-max))	0.00 (-338.3 to 364.3)	0.00 (-418.7 to 675.8)	0.00 (-364.0 to 2952.7)	-7.16 (-30.3 to 13.1)	0.00 (-32.3 to 104.8)	0.00 (-61.6 to 209.5)

No statistical analyses for this end point

Secondary: Part 1: Percent change from Baseline in the frequency of all countable seizures (motor and non-motor) in T+M in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

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End point title

Part 1: Percent change from Baseline in the frequency of all countable seizures (motor and non-motor) in T+M in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

End point description

Countable motor seizures included: GTC, SGTC, TS, AS, TA, CS, HS, and FS with clearly observable signs. Countable non-motor seizures included: FS without clear observable signs, MS, absence/atypical absence, infantile spasms, epileptic spasms, and other seizures. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.

End point type

Secondary

End point timeframe

From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]

End point values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Number of subjects analysed	87	89	87	11	11	11
Units: percent change
median (full range (min-max))	-9.40 (-85.4 to 497.8)	-23.55 (-100.0 to 882.1)	-21.70 (-91.9 to 224.9)	-17.69 (-97.2 to 61.8)	-20.41 (-87.1 to 826.2)	-13.85 (-64.9 to 63.8)

No statistical analyses for this end point

Secondary: Part 1: Percent change from Baseline in the frequency of seizures that typically result in drops in the Maintenance Period in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

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End point title

Part 1: Percent change from Baseline in the frequency of seizures that typically result in drops in the Maintenance Period in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

End point description

Seizures that typically result in drops included all: GTC, SGTC, TS, AS, and TA, whether confirmed by the ESC or not. The mITT Population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available. Here, number of participants analyzed included those participants who were evaluable for the assessment.

End point type

Secondary

End point timeframe

During Maintenance Period (12 weeks), compared to Baseline

End point values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Number of subjects analysed	87	88	86	11	11	11
Units: percent change
median (full range (min-max))	-9.37 (-100.0 to 516.7)	-17.30 (-100.0 to 964.0)	-26.30 (-100.0 to 643.3)	-18.18 (-99.4 to 66.7)	-12.88 (-100.0 to 239.4)	-46.88 (-77.8 to 52.2)

No statistical analyses for this end point

Secondary: Part 1: Percent change from Baseline in the frequency of seizures that result in drops (ESC confirmed) between Baseline and the Maintenance Period

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End point title

Part 1: Percent change from Baseline in the frequency of seizures that result in drops (ESC confirmed) between Baseline and the Maintenance Period

End point description

The frequency of drop seizures during a given interval was derived from the number and type of events recorded in participant electronic diaries. The seizure types included in the count were: atonic, tonic, tonic/atonic, generalized tonic-clonic, and secondarily generalized tonic-clonic seizures resulting in drops. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available. Here, number of participants analyzed included those participants who were evaluable for the assessment.

End point type

Secondary

End point timeframe

During Maintenance Period (12 weeks), compared to Baseline

End point values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Number of subjects analysed	87	88	86	11	11	11
Units: percent change
median (full range (min-max))	-7.28 (-100.0 to 516.7)	-18.63 (-100.0 to 964.0)	-27.16 (-100.0 to 643.3)	-18.18 (-99.4 to 66.7)	-12.88 (-100.0 to 239.4)	-45.07 (-77.8 to 52.2)

No statistical analyses for this end point

Secondary: Part 1: Percent change from Baseline in the frequency of all countable motor seizures in the Maintenance Period in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

Top of page

End point title

Part 1: Percent change from Baseline in the frequency of all countable motor seizures in the Maintenance Period in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

End point description

Countable motor seizures included: GTC, SGTC,TS, AS, TA, CS, HS, and FS with clearly observable signs. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available. Here, number of participants analyzed included those participants who were evaluable for the assessment.

End point type

Secondary

End point timeframe

During Maintenance Period (12 weeks), compared to Baseline

End point values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Number of subjects analysed	87	88	86	11	11	11
Units: percent change
median (full range (min-max))	-10.21 (-81.1 to 439.8)	-17.30 (-100.0 to 964.0)	-28.33 (-100.0 to 643.3)	-18.18 (-99.4 to 66.7)	-12.88 (-100.0 to 472.7)	-46.88 (-77.8 to 52.2)

No statistical analyses for this end point

Secondary: Part 1: Change from Baseline in the frequency of all countable non-motor seizures in the Maintenance Period in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

Top of page

End point title

Part 1: Change from Baseline in the frequency of all countable non-motor seizures in the Maintenance Period in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

End point description

End point type

Secondary

End point timeframe

During Maintenance Period (12 weeks), compared to Baseline

End point values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Number of subjects analysed	87	88	86	11	11	11
Units: seizure frequency per 28 days
median (full range (min-max))	-0.04 (-340.6 to 362.3)	-0.13 (-442.3 to 588.1)	0.00 (-368.3 to 3219.3)	-4.00 (-30.7 to 15.3)	0.00 (-37.2 to 192.0)	0.00 (-86.8 to 250.7)

No statistical analyses for this end point

Secondary: Part 1: Percent change from Baseline in the frequency of all countable seizures (motor and non-motor) in the Maintenance Period in ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

Top of page

End point title

Part 1: Percent change from Baseline in the frequency of all countable seizures (motor and non-motor) in the Maintenance Period in ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

End point description

End point type

Secondary

End point timeframe

During Maintenance Period (12 weeks), compared to Baseline

End point values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Number of subjects analysed	87	88	86	11	11	11
Units: percent change
median (full range (min-max))	-9.49 (-85.7 to 439.8)	-27.63 (-100.0 to 211.1)	-23.34 (-100.0 to 254.5)	-18.18 (-99.5 to 66.7)	-20.33 (-95.7 to 1626.7)	-17.68 (-72.3 to 80.5)

No statistical analyses for this end point

Secondary: Part 1: Percent change from Baseline in frequency of countable seizures that do not result in drops (ESC Confirmed)

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End point title

Part 1: Percent change from Baseline in frequency of countable seizures that do not result in drops (ESC Confirmed)

End point description

Non-drop seizures were defined as any countable seizure types that did not meet the criteria of drop seizures, ie, are classified as CS, HC, FS with or without observable signs, MS, absence/atypical absence, infantile spasms, epileptic spasms, or other; or are seizures of the following classifications that were approved for each subject as non-drop seizure types by the ESC: GTC, SGTC, TS, AS, or TA. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available. Here, number of participants analyzed included those participants who were evaluable for the assessment.

End point type

Secondary

End point timeframe

From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]

End point values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Number of subjects analysed	70	73	64	8	7	9
Units: percent change
median (full range (min-max))	-26.92 (-100.0 to 5070.3)	-31.32 (-100.0 to 571.8)	-22.68 (-100.0 to 481.3)	-23.38 (-96.9 to 657.1)	0.27 (-32.3 to 2915.4)	-22.99 (-85.7 to 138.8)

No statistical analyses for this end point

Secondary: Part 1: Percentage of participants who achieved a worsening from Baseline (ie <=0% reduction), or >0, >=25%, >=50%, >=75%, 100% reduction, and “near seizure freedom” between Baseline and T+M, and Baseline and M, in seizures that result in drops

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End point title

Part 1: Percentage of participants who achieved a worsening from Baseline (ie <=0% reduction), or >0, >=25%, >=50%, >=75%, 100% reduction, and “near seizure freedom” between Baseline and T+M, and Baseline and M, in seizures that result in drops

End point description

The seizure types included in the count were: atonic, tonic, tonic/atonic, generalized tonic-clonic, and secondarily generalized tonic-clonic seizures resulting in drops. The participants who experienced a worsening or no change from Baseline (ie <= 0% reduction); >0%, >=25%, >=50%, >=75%, and 100% reduction (a 100% reduction was equivalent to achieving seizure freedom during T+M); and “near seizure freedom,” (defined as 0 or 1 seizure leading to a drop) during combined T+M Period and Maintenance Period were reported. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available. Here, 'n' included those participants who were evaluable at specified time point.

End point type

Secondary

End point timeframe

From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]; During Maintenance Period (12 weeks), compared to Baseline

End point values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Number of subjects analysed	87	89	87	11	11	11
Units: percentage of participants
number (not applicable)
Worsening or No Change (T+M) (n=87,89,87,11,11,11)	37.9	34.8	21.8	36.4	27.3	9.1
> 0% reduction (T+M) (n=87,89,87,11,11,11)	62.1	65.2	78.2	63.6	72.7	90.9
>= 25% reduction (T+M) (n=87,89,87,11,11,11)	31.0	47.2	51.7	36.4	36.4	63.6
>= 50% reduction (T+M) (n=87,89,87,11,11,11)	10.3	28.1	25.3	9.1	36.4	36.4
>= 75% reduction (T+M) (n=87,89,87,11,11,11)	4.6	10.1	8.0	9.1	9.1	0
100% reduction (T+M) (n=87,89,87,11,11,11)	1.1	1.1	0	0	0	0
Near Seizure free (T+M) (n=87,89,87,11,11,11)	1.1	2.2	1.1	0	0	0
Worsening or No Change (M) (n=87, 88,86,11,11,11)	40.2	35.2	20.9	36.4	27.3	9.1
> 0% reduction (M) (n=87, 88,86,11,11,11)	59.8	64.8	79.1	63.6	72.7	90.9
>= 25% reduction (M) (n=87, 88,86,11,11,11)	33.3	46.6	53.5	36.4	36.4	72.7
>= 50% reduction (M) (n=87, 88,86,11,11,11)	12.6	31.8	31.4	9.1	36.4	36.4
>= 75% reduction (M) (n=87, 88,86,11,11,11)	3.4	11.4	14.0	9.1	9.1	9.1
100% reduction (M) (n=87, 88,86,11,11,11)	1.1	3.4	2.3	0	9.1	0
Near Seizure free (M) (n=87, 88,86,11,11,11)	1.1	4.5	2.3	9.1	9.1	0

No statistical analyses for this end point

Secondary: Part 1: Percentage of participants who achieved a worsening from Baseline, or >0%, >=25%, >=50%, >=75%, 100% reduction, and “near seizure freedom” between Baseline and T+M, and Baseline and M, in seizures that typically results in drops

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End point title

Part 1: Percentage of participants who achieved a worsening from Baseline, or >0%, >=25%, >=50%, >=75%, 100% reduction, and “near seizure freedom” between Baseline and T+M, and Baseline and M, in seizures that typically results in drops

End point description

Seizures that typically result in drops included all: GTC, SGTC, TS, AS, and TA, whether confirmed by the ESC or not. The participants who experienced a worsening no change from Baseline (ie <= 0% reduction); >0%, >=25%, >=50%, >=75%, and 100% reduction (a 100% reduction was equivalent to achieving seizure freedom during T+M); and “near seizure freedom,” (defined as 0 or 1 seizure leading to a drop) during combined T+M Period and Maintenance Period were reported. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available. Here, 'n' included those participants who were evaluable at specified time point.

End point type

Secondary

End point timeframe

From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]; During Maintenance Period (12 weeks), compared to Baseline

End point values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Number of subjects analysed	87	89	87	11	11	11
Units: percentage of participants
number (not applicable)
Worsening or No Change (T+M) (n=87,89,87,11,11,11)	35.6	36.0	20.7	36.4	27.3	9.1
> 0% reduction (T+M) (n=87,89,87,11,11,11)	64.4	64.0	79.3	63.6	72.7	90.9
>= 25% reduction (T+M) (n=87,89,87,11,11,11)	31.0	46.1	50.6	36.4	36.4	63.6
>= 50% reduction (T+M) (n=87,89,87,11,11,11)	9.2	27.0	26.4	9.1	36.4	36.4
>= 75% reduction (T+M) (n=87,89,87,11,11,11)	3.4	9.0	8.0	9.1	9.1	0
100% reduction (T+M) (n=87,89,87,11,11,11)	1.1	1.1	0	0	0	0
Near Seizure free (T+M) (n=87,89,87,11,11,11)	1.1	1.1	1.1	0	0	0
Worsening or No Change (M) (n=87,88,86,11,11,11)	37.9	37.5	19.8	36.4	27.3	9.1
> 0% reduction (M) (n=87,88,86,11,11,11)	62.1	62.5	80.2	63.6	72.7	90.9
>= 25% reduction (M) (n=87,88,86,11,11,11)	33.3	45.5	52.3	36.4	36.4	72.7
>= 50% reduction (M) (n=87,88,86,11,11,11)	10.3	30.7	31.4	9.1	36.4	36.4
>= 75% reduction (M) (n=87,88,86,11,11,11)	2.3	10.2	12.8	9.1	9.1	9.1
100% reduction (M) (n=87,88,86,11,11,11)	1.1	2.3	2.3	0	9.1	0
Near Seizure free (M) (n=87,88,86,11,11,11)	1.1	2.3	2.3	9.1	9.1	0

No statistical analyses for this end point

Secondary: Part 1: Percentage of participants who achieved a worsening from Baseline, or >0%, >=25%, >=50%, >=75%, 100% reduction, and “near seizure freedom” between Baseline and T+M, and Baseline and M, in all countable motor seizures

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End point title

End point description

Countable motor seizures included: GTC, SGTC, TS, AS, TA, CS, HS, and FS with clearly observable signs. The participants who experienced a worsening or no change from Baseline (ie <= 0% reduction); >0%, >=25%, >=50%, >=75%, and 100% reduction (a 100% reduction was equivalent to achieving seizure freedom during T+M); and “near seizure freedom,” (defined as 0 or 1 seizure leading to a drop) during combined T+M Period and Maintenance Period were reported. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available. Here, 'n' included those participants who were evaluable at specified time point.

End point type

Secondary

End point timeframe

From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]; During Maintenance Period (12 weeks), compared to Baseline

End point values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Number of subjects analysed	87	89	87	11	11	11
Units: percentage of participants
number (not applicable)
Worsening or No Change (T+M) (n=87,89,87,11,11,11)	34.5	38.2	20.7	36.4	27.3	9.1
> 0% reduction (T+M) (n=87,89,87,11,11,11)	65.5	61.8	79.3	63.6	72.7	90.9
>= 25% reduction (T+M) (n=87,89,87,11,11,11)	33.3	44.9	50.6	36.4	36.4	63.6
>= 50% reduction (T+M) (n=87,89,87,11,11,11)	9.2	24.7	25.3	9.1	36.4	36.4
>= 75% reduction (T+M) (n=87,89,87,11,11,11)	2.3	9.0	6.9	9.1	9.1	0
100% reduction (T+M) (n=87,89,87,11,11,11)	0	1.1	0	0	0	0
Near Seizure free (T+M) (n=87,89,87,11,11,11)	0	1.1	0	0	0	0
Worsening or No Change (M) (n=87,88,86,11,11,11)	36.8	38.6	18.6	36.4	27.3	9.1
> 0% reduction (M) (n=87,88,86,11,11,11)	63.2	61.4	81.4	63.6	72.7	90.9
>= 25% reduction (M) (n=87,88,86,11,11,11)	34.5	45.5	53.5	36.4	36.4	72.7
>= 50% reduction (M) (n=87,88,86,11,11,11)	10.3	28.4	26.7	9.1	36.4	36.4
>= 75% reduction (M) (n=87,88,86,11,11,11)	1.1	11.4	10.5	9.1	9.1	9.1
100% reduction (M) (n=87,88,86,11,11,11)	0	2.3	1.2	0	9.1	0
Near Seizure free (M) (n=87,88,86,11,11,11)	0	2.3	1.2	9.1	9.1	0

No statistical analyses for this end point

Secondary: Part 1: Percentage of participants who achieved a worsening from Baseline, or >0%, >=25%, >=50%, >=75%, 100% reduction, and “near seizure freedom” between Baseline and T+M, and Baseline and M, in countable motor seizures that do not result in drops

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End point title

End point description

Countable motor seizures included: GTC, SGTC; TS, AS, TA, CS, HS, FS with clearly observable signs. The participants who experienced a worsening or no change from Baseline (ie <= 0% reduction); >0%, >=25%, >=50%, >=75%, and 100% reduction (a 100% reduction was equivalent to achieving seizure freedom during T+M); and “near seizure freedom,” (defined as 0 or 1 seizure leading to a drop) during combined T+M Period and Maintenance Period were reported. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available. Here, number of participants analyzed included those participants who were evaluable for the assessment. 'n' included those participants who were evaluable at specified time point.

End point type

Secondary

End point timeframe

From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]; During Maintenance Period (12 weeks), compared to Baseline

End point values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Number of subjects analysed	70	73	64	8	7	9
Units: percentage of participants
number (not applicable)
Worsening or No Change (T+M) (n=70,73,64,8,7,9)	35.7	34.2	34.4	25.0	57.1	44.4
> 0% reduction (T+M) (n=70,73,64,8,7,9)	64.3	65.8	65.6	75.0	42.9	55.6
>= 25% reduction (T+M) (n=70,73,64,8,7,9)	51.4	53.4	46.9	50.0	14.3	44.4
>= 50% reduction (T+M) (n=70,73,64,8,7,9)	30.0	43.8	32.8	25.0	0	22.2
>= 75% reduction (T+M) (n=70,73,64,8,7,9)	12.9	26.0	12.5	12.5	0	11.1
100% reduction (T+M) (n=70,73,64,8,7,9)	2.9	5.5	4.7	0	0	0
Near Seizure free (T+M) (n=70,73,64,8,7,9)	2.9	9.6	7.8	0	0	0
Worsening or No Change (M) (n=70,72,63,8,7,9)	31.4	33.3	34.9	25.0	57.1	44.4
> 0% reduction (M) (n=70,72,63,8,7,9)	68.6	66.7	65.1	75.0	42.9	55.6
>= 25% reduction (M) (n=70,72,63,8,7,9)	54.3	56.9	49.2	50.0	14.3	44.4
>= 50% reduction (M) (n=70,72,63,8,7,9)	31.4	44.4	33.3	25.0	0	22.2
>= 75% reduction (M) (n=70,72,63,8,7,9)	17.1	29.2	17.5	12.5	0	11.1
100% reduction (M) (n=70,72,63,8,7,9)	5.7	9.7	6.3	12.5	0	0
Near Seizure free (M) (n=70,72,63,8,7,9)	7.1	13.9	9.5	12.5	0	0

No statistical analyses for this end point

Secondary: Part 1: Percentage of participants who achieved a worsening from Baseline (ie <= 0% reduction), or >0%, >=25%, >=50%, >=75%, 100% reduction, and “near seizure freedom” between Baseline and T+M, and Baseline and M, in all countable seizures

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End point title

Part 1: Percentage of participants who achieved a worsening from Baseline (ie <= 0% reduction), or >0%, >=25%, >=50%, >=75%, 100% reduction, and “near seizure freedom” between Baseline and T+M, and Baseline and M, in all countable seizures

End point description

Countable motor seizures included: GTC, SGTC; TS, AS, TA, CS, HS, and FS with clearly observable signs. Countable non-motor seizures included: FS without clear observable signs, MS, absence/atypical absence, infantile spasms, epileptic spasms, and other seizures. The participants who experienced a worsening or no change from Baseline (ie <= 0% reduction); >0%, >=25%, >=50%, >=75%, and 100% reduction (a 100% reduction was equivalent to achieving seizure freedom during T+M); and “near seizure freedom,” (defined as 0 or 1 seizure leading to a drop) during combined T+M Period and Maintenance Period were reported. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available. Here, 'n' included those participants who were evaluable at specified time point.

End point type

Secondary

End point timeframe

From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]; During Maintenance Period (12 weeks), compared to Baseline

End point values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Number of subjects analysed	87	89	87	11	11	11
Units: percentage of participants
number (not applicable)
Worsening or No Change (T+M) (n=87,89,87,11,11,11)	36.8	32.6	28.7	27.3	27.3	36.4
> 0% reduction (T+M) (n=87,89,87,11,11,11)	63.2	67.4	71.3	72.7	72.7	63.6
>= 25% reduction (T+M) (n=87,89,87,11,11,11)	35.6	48.3	46.0	27.3	27.3	45.5
>= 50% reduction (T+M) (n=87,89,87,11,11,11)	11.5	22.5	20.7	9.1	27.3	27.3
>= 75% reduction (T+M) (n=87,89,87,11,11,11)	3.4	6.7	4.6	9.1	9.1	0
100% reduction (T+M) (n=87,89,87,11,11,11)	0	1.1	0	0	0	0
Near Seizure free (T+M) (n=87,89,87,11,11,11)	0	1.1	0	0	0	0
Worsening or No Change (M) (n=87,88,86,11,11,11)	34.5	33.0	27.9	27.3	27.3	27.3
> 0% reduction (M) (n=87,88,86,11,11,11)	65.5	67.0	72.1	72.7	72.7	72.7
>= 25% reduction (M) (n=87,88,86,11,11,11)	34.5	51.1	47.7	27.3	27.3	45.5
>= 50% reduction (M) (n=87,88,86,11,11,11)	13.8	28.4	24.4	9.1	27.3	27.3
>= 75% reduction (M) (n=87,88,86,11,11,11)	3.4	9.1	7.0	9.1	9.1	0
100% reduction (M) (n=87,88,86,11,11,11)	0	1.1	1.2	0	0	0
Near Seizure free (M) (n=87,88,86,11,11,11)	0	1.1	1.2	9.1	0	0

No statistical analyses for this end point

Secondary: Part 1: Percentage of participants who achieved a worsening from Baseline, or >0%, >=25%, >=50%, >=75%, 100% reduction, and “near seizure freedom” between Baseline and T+M, and Baseline and M, in all countable non-motor seizures

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End point title

End point description

Countable non-motor seizures include: FS without clear observable signs, MS, absence/atypical absence, infantile spasms, epileptic spasms, and other seizures. The participants who experienced a worsening or no change from Baseline (ie <= 0% reduction); >0%, >=25%, >=50%, >=75%, and 100% reduction (a 100% reduction was equivalent to achieving seizure freedom during T+M); and “near seizure freedom,” (defined as 0 or 1 seizure leading to a drop) during combined T+M Period and Maintenance Period were reported. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available. Here, number of participants analyzed included those participants who were evaluable for the assessment. 'n' included those participants who were evaluable at specified time point.

End point type

Secondary

End point timeframe

From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]; During Maintenance Period (12 weeks), compared to Baseline

End point values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Number of subjects analysed	63	64	57	8	7	8
Units: percentage of participants
number (not applicable)
Worsening or No Change (T+M) (n=63,64,57,8,7,8)	33.3	34.4	36.8	25.0	57.1	37.5
> 0% reduction (T+M) (n=63,64,57,8,7,8)	66.7	65.6	63.2	75.0	42.9	62.5
>= 25% reduction (T+M) (n=63,64,57,8,7,8)	52.4	56.3	43.9	50.0	14.3	37.5
>= 50% reduction (T+M) (n=63,64,57,8,7,8)	30.2	48.4	35.1	25.0	0	25.0
>= 75% reduction (T+M) (n=63,64,57,8,7,8)	14.3	32.8	12.3	12.5	0	0
100% reduction (T+M) (n=63,64,57,8,7,8)	3.2	6.3	3.5	0	0	0
Near Seizure free (T+M) (n=63,64,57,8,7,8)	3.2	14.1	5.3	0	0	0
Worsening or No Change (M) (n=63,63,56,8,7,8)	30.2	30.2	33.9	12.5	57.1	37.5
> 0% reduction (M) (n=63,63,56,8,7,8)	69.8	69.8	66.1	87.5	42.9	62.5
>= 25% reduction (M) (n=63,63,56,8,7,8)	54.0	60.3	48.2	50.0	14.3	37.5
>= 50% reduction (M) (n=63,63,56,8,7,8)	34.9	49.2	33.9	25.0	0	37.5
>= 75% reduction (M) (n=63,63,56,8,7,8)	17.5	31.7	17.9	12.5	0	0
100% reduction (M) (n=63,63,56,8,7,8)	6.3	9.5	8.9	12.5	0	0
Near Seizure free (M) (n=63,63,56,8,7,8)	7.9	15.9	10.7	12.5	0	0

No statistical analyses for this end point

Secondary: Part 1: Change from Baseline in number of seizure-free days during T+M and M Period

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End point title

Part 1: Change from Baseline in number of seizure-free days during T+M and M Period

End point description

A day with no seizures leading to a drop was defined as a day for which electronic (e) diary data were available and no drop seizures were reported. The total number of drop seizure–free days was calculated per 28 days for Baseline and for T+M. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available. Here, 'n' included those participants who were evaluable for specified category.

End point type

Secondary

End point timeframe

From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]; During Maintenance Period (12 weeks), compared to Baseline

End point values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Number of subjects analysed	87	89	87	11	11	11
Units: seizure free days per 28 days
median (full range (min-max))
T+M Period (n=87,89,87,11,11,11)	0.27 (-5.0 to 16.0)	0.00 (-9.0 to 16.8)	0.29 (-6.1 to 20.0)	0.00 (-2.2 to 23.6)	0.38 (-2.3 to 22.0)	6.65 (-2.4 to 8.5)
M Period (n=87,88,86,11,11,11)	0.31 (-5.4 to 15.7)	0.00 (-4.1 to 18.2)	0.16 (-7.4 to 21.7)	-0.65 (-2.7 to 24.7)	0.33 (-7.3 to 26.0)	7.72 (-2.3 to 10.3)

No statistical analyses for this end point

Secondary: Part 1: Duration of longest interval (days) between seizures that result in drops comparing the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

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End point title

Part 1: Duration of longest interval (days) between seizures that result in drops comparing the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

End point description

The longest interval between seizures leading to drops were obtained from the eDiary entries in Titration and Maintenance Period. The interval was derived as the maximum value of the number of days between consecutive drop seizures. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.

End point type

Secondary

End point timeframe

From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]

End point values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Number of subjects analysed	87	89	87	11	11	11
Units: days
median (full range (min-max))	5.00 (1.0 to 39.0)	4.00 (1.0 to 97.0)	5.00 (1.0 to 89.0)	4.00 (1.0 to 91.0)	4.00 (1.0 to 32.0)	6.00 (2.0 to 16.0)

No statistical analyses for this end point

Secondary: Part 1: Clinical Global Impression – Improvement as assessed by the Parent/Caregiver

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End point title

Part 1: Clinical Global Impression – Improvement as assessed by the Parent/Caregiver

End point description

CGI-I scale measures improvement in the participant's condition from Baseline. The severity of a participant's condition was 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 and 7-very much worse. The mITT population included all randomized participants who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available. Here, number of participants analyzed included those participants who were evaluable for the assessment. 'n' included those participants who were evaluable at specified time point.

End point type

Secondary

End point timeframe

At Days (D) 15, 43, 71, and 99

End point values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Number of subjects analysed	85	85	81	11	11	11
Units: percentage of participants
number (not applicable)
1=Very much improved (D15) (n=85,85,81,11,10,11)	2.4	5.9	9.9	9.1	10.0	9.1
2=Much improved (D15) (n=85,85,81,11,10,11)	4.7	15.3	21.0	18.2	10.0	18.2
3=Minimally improved (D15) (n=85,85,81,11,10,11)	31.8	27.1	39.5	9.1	30.0	27.3
4=No Change (D15) (n=85,85,81,11,10,11)	51.8	42.4	18.5	63.6	30.0	27.3
5=Minimally worse (D15) (n=85,85,81,11,10,11)	4.7	5.9	7.4	0	20.0	18.2
6=Much worse (D15) (n=85,85,81,11,10,11)	4.7	3.5	2.5	0	0	0
7=Very much worse (D15) (n=85,85,81,11,10,11)	0	0	1.2	0	0	0
1=Very much improved (D43) (n=85,82,80,11,9,10)	1.2	7.3	13.8	9.1	0	10.0
2=Much improved (D43) (n=85,82,80,11,9,10)	9.4	19.5	25.0	0	22.2	40.0
3=Minimally improved (D43) (n=85,82,80,11,9,10)	20.0	18.3	33.8	18.2	44.4	30.0
4=No Change (D43) (n=85,82,80,11,9,10)	60.0	39.0	17.5	63.6	33.3	0
5=Minimally worse (D43) (n=85,82,80,11,9,10)	5.9	11.0	5.0	9.1	0	20.0
6=Much worse (D43) (n=85,82,80,11,9,10)	2.4	4.9	5.0	0	0	0
7=Very much worse (D43) (n=85,82,80,11,9,10)	1.2	0	0	0	0	0
1=Very much improved (D71) (n=82,75,75,11,9,9)	2.4	4.0	10.7	9.1	0	0
2=Much improved (D71) (n=82,75,75,11,9,9)	6.1	20.0	28.0	0	22.2	11.1
3=Minimally improved (D71) (n=82,75,75,11,9,9)	24.4	16.0	33.3	18.2	22.2	55.6
4=No Change (D71) (n=82,75,75,11,9,9)	53.7	48.0	24.0	63.6	55.6	22.2
5=Minimally worse (D71) (n=82,75,75,11,9,9)	7.3	8.0	1.3	9.1	0	11.1
6=Much worse (D71) (n=82,75,75,11,9,9)	6.1	4.0	2.7	0	0	0
7=Very much worse (D71) (n=82,75,75,11,9,9)	0	0	0	0	0	0
1=Very much improved (D99) (n=81,85,80,11,11,11)	1.2	8.2	10.0	9.1	0	18.2
2=Much improved (D99) (n=81,85,80,11,11,11)	3.7	18.8	23.8	0	18.2	18.2
3=Minimally improved (D99) (n=81,85,80,11,11,11)	32.1	16.5	27.5	18.2	27.3	36.4
4=No Change (D99) (n=81,85,80,11,11,11)	53.1	37.6	27.5	63.6	45.5	27.3
5=Minimally worse (D99) (n=81,85,80,11,11,11)	7.4	8.2	5.0	0	9.1	0
6=Much worse (D99) (n=81,85,80,11,11,11)	2.5	7.1	5.0	9.1	0	0
7=Very much worse (D99) (n=81,85,80,11,11,11)	0	3.5	1.3	0	0	0

No statistical analyses for this end point

Secondary: Part 1: Percentage of participants with TEAEs

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End point title

Part 1: Percentage of participants with TEAEs

End point description

Adverse events were defined as any unfavorable and unintended sign (including an abnormal, clinically significant laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product. A TEAE in Part 1 was defined as any AE that, based on start date information, occurred after the first dose of study drug in Part 1, but not on or after the first dose of study drug in Part 2. The Safety Population included all randomized participants who received at least 1 dose of study drug.

End point type

Secondary

End point timeframe

Baseline up to 14 weeks + Taper/Transition (2 weeks)

End point values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Number of subjects analysed	87	89	87	11	11	11
Units: percentage of participants
number (not applicable)	80.5	78.7	89.7	72.7	90.9	63.6

No statistical analyses for this end point

Secondary: Part 1: Percentage of participants with Serious TEAEs

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End point title

Part 1: Percentage of participants with Serious TEAEs

End point description

A serious adverse event (SAE) was defined as any untoward medical occurrence that at any dose: Results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, or is medically significant. The Safety Population included all randomized participants who received at least 1 dose of study drug.

End point type

Secondary

End point timeframe

Baseline up to 14 weeks + Taper/Transition (2 weeks)

End point values	Cohort A: Placebo	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day	Cohort B: Placebo	Cohort B: ZX008 0.2 mg/kg/day	Cohort B: ZX008 0.8 mg/kg/day
Number of subjects analysed	87	89	87	11	11	11
Units: percentage of participants
number (not applicable)	4.6	4.5	11.5	9.1	9.1	0

No statistical analyses for this end point

Secondary: Part 1: Minimum observed plasma concentration of fenfluramine and norfenfluramine at steady state determined directly from the concentration-time profile [Cmin] at steady state

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End point title

Part 1: Minimum observed plasma concentration of fenfluramine and norfenfluramine at steady state determined directly from the concentration-time profile [Cmin] at steady state ^[7]

End point description

Cmin is the minimum plasma concentration determined directly from the concentration-time profile. The PK analysis set included those participants who received at least one dose of ZX008 and at least one plasma concentration measurement in Study ZX008-1601.

End point type

Secondary

End point timeframe

At Visit 8 (Day 43) of the Maintenance Period: pre-dose, 1, 2, and 4-6 hours post-dose

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: PK endpoints were planned to be reported for ZX008 arms only.

End point values	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day
Number of subjects analysed	84	80
Units: ng/mL
geometric mean (geometric coefficient of variation)
Fenfluramine	8.19 ( 75.6 )	31.8 ( 60.8 )
Norfenfluramine	8.23 ( 61.3 )	26.2 ( 58.9 )

No statistical analyses for this end point

Secondary: Part 1: Maximum observed Plasma concentration of fenfluramine and norfenfluramine determined directly from the concentration time profile [Cmax] at steady state

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End point title

Part 1: Maximum observed Plasma concentration of fenfluramine and norfenfluramine determined directly from the concentration time profile [Cmax] at steady state ^[8]

End point description

Cmax is the maximum plasma concentration determined directly from the concentration time profile. The PK analysis set included those participants who received at least one dose of ZX008 and at least one plasma concentration measurement in Study ZX008-1601.

End point type

Secondary

End point timeframe

At Visit 8 (Day 43) of the Maintenance Period: pre-dose, 1, 2, and 4-6 hours post-dose

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: PK endpoints were planned to be reported for ZX008 arms only.

End point values	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day
Number of subjects analysed	84	80
Units: nanograms per milliliter (ng/mL)
geometric mean (geometric coefficient of variation)
Fenfluramine	11.9 ( 56.1 )	44.8 ( 47.0 )
Norfenfluramine	9.04 ( 53.4 )	28.9 ( 52.9 )

No statistical analyses for this end point

Secondary: Part 1: Area under the concentration-time curve of of fenfluramine and norfenfluramine from time zero to time 24 hours [AUC0-24hours] at steady state

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End point title

Part 1: Area under the concentration-time curve of of fenfluramine and norfenfluramine from time zero to time 24 hours [AUC0-24hours] at steady state ^[9]

End point description

AUC0-24 is the area under the concentration-time curve from time 0 to 24 hours. The PK analysis set included those participants who received at least one dose of ZX008 and at least one plasma concentration measurement in Study ZX008-1601.

End point type

Secondary

End point timeframe

At Visit 8 (Day 43) of the Maintenance Period: pre-dose, 1, 2, and 4-6 hours post-dose

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: PK endpoints were planned to be reported for ZX008 arms only.

End point values	Cohort A: ZX008 0.2 mg/kg/day	Cohort A: ZX008 0.8 mg/kg/day
Number of subjects analysed	84	80
Units: nanogramshour per milliliter (ngh/mL)
geometric mean (geometric coefficient of variation)
Fenfluramine	246 ( 63.0 )	933 ( 52.1 )
Norfenfluramine	209 ( 56.3 )	667 ( 55.1 )

No statistical analyses for this end point

Secondary: Part 2: Percent change from Baseline in the frequency of seizures that result in drops (ESC Confirmed) in OLE Period

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End point title

Part 2: Percent change from Baseline in the frequency of seizures that result in drops (ESC Confirmed) in OLE Period

End point description

The frequency of drop seizures during a given interval was derived from the number and type of events recorded in subject electronic diaries. The seizure types included in the count were: atonic, tonic, tonic/atonic, generalized tonic-clonic, and secondarily generalized tonic-clonic seizures resulting in drops. The Open-Label Extension Modified Intent-To-Treat (mITT) Population included all participants who received at least 1 dose of ZX008 and had a valid estimate of the frequency of seizures that resulted in drops from Part 1 and at least 1 month (30 days) of valid seizure data during the OLE.

End point type

Secondary

End point timeframe

From OLE Month 1 to Month12, compared to Baseline (Part 1)

End point values	Part 2: Cohort B- Overall	Part 2: Cohort A- Overall
Number of subjects analysed	32	241
Units: percent change
median (full range (min-max))	-43.42 (-99.0 to 64.2)	-29.53 (-100.0 to 2625.3)

No statistical analyses for this end point

Secondary: Part 2: Percent change from Baseline in the frequency all seizures that typically result in drops between Baseline and the OLE Period whether ESC confirmed as drop or not

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End point title

Part 2: Percent change from Baseline in the frequency all seizures that typically result in drops between Baseline and the OLE Period whether ESC confirmed as drop or not

End point description

Seizures that typically result in drops included all: generalized tonic-clonic seizures [GTC], secondarily generalized tonic-clonic [SGTC], tonic seizures [TS], atonic seizures [AS], and tonic/atonic seizures [TA], whether confirmed by the ESC or not. Seizures that result in a drop were defined as seizures involving the entire body, trunk, or head that led to a fall, injury, slumping in a chair, or the participant's head hitting a surface or that could have led to a fall or injury, depending on the patient’s position at the time of the seizure. The OLE mITT population included all participants who received at least 1 dose of ZX008 and had a valid estimate of the frequency of seizures that resulted in drops from Part 1 and at least 1 month (30 days) of valid seizure data during the OLE.

End point type

Secondary

End point timeframe

From OLE Month 1 to Month12, compared to Baseline (Part 1)

End point values	Part 2: Cohort B- Overall	Part 2: Cohort A- Overall
Number of subjects analysed	32	241
Units: percent change
median (full range (min-max))	-43.78 (-99.0 to 64.2)	-27.94 (-100.0 to 2625.3)

No statistical analyses for this end point

Secondary: Part 2: Percent change from Baseline in the frequency of all countable motor seizures in OLE Period

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End point title

Part 2: Percent change from Baseline in the frequency of all countable motor seizures in OLE Period

End point description

Countable motor seizures included: GTC, SGTC, TS, AS, TA, clonic seizures [CS], hemiclonic seizures [HS], and focal seizures [FS] with clearly observable signs. The OLE mITT population included all participants who received at least 1 dose of ZX008 and had a valid estimate of the frequency of seizures that resulted in drops from Part 1 and at least 1 month (30 days) of valid seizure data during the OLE.

End point type

Secondary

End point timeframe

From OLE Month 1 to Month12, compared to Baseline (Part 1)

End point values	Part 2: Cohort B- Overall	Part 2: Cohort A- Overall
Number of subjects analysed	32	241
Units: percent change
median (full range (min-max))	-41.94 (-99.0 to 64.2)	-28.18 (-100.0 to 2625.3)

No statistical analyses for this end point

Secondary: Part 2: Percentage of participants who achieved a worsening from Baseline, or > 0%, >=25%, >= 50%, >= 75%, 100% reduction, and “near seizure freedom” from Baseline in frequency of seizures that result in drops (ESC confirmed)

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End point title

Part 2: Percentage of participants who achieved a worsening from Baseline, or > 0%, >=25%, >= 50%, >= 75%, 100% reduction, and “near seizure freedom” from Baseline in frequency of seizures that result in drops (ESC confirmed)

End point description

The seizure types included in the count were: atonic, tonic, tonic/atonic, generalized tonic-clonic, and secondarily gneralized tonic-clonic seizures resulting in drops. The participants who experienced a worsening or no change from Baseline (ie <= 0% reduction); >0%, >=25%, >=50%, >=75%, and 100% reduction (a 100% reduction was equivalent to achieving seizure freedom during OLE Period); and “near seizure freedom,” (defined as 0 or 1 seizure leading to a drop) during OLE Period was reported. The OLE mITT population included all participants who received at least 1 dose of ZX008 and had a valid estimate of the frequency of seizures that resulted in drops from Part 1 and at least 1 month (30 days) of valid seizure data during the OLE.

End point type

Secondary

End point timeframe

From OLE Month 1 to Month12, compared to Baseline (Part 1)

End point values	Part 2: Cohort B- Overall	Part 2: Cohort A- Overall
Number of subjects analysed	32	241
Units: percentage of participants
number (not applicable)
Worsening or No Change	18.8	31.5
> 0%	81.3	68.5
>= 25%	62.5	55.6
>= 50%	43.8	32.8
>= 75%	21.9	12.4
100%	0	1.2
Near Seizure free	0	1.7

No statistical analyses for this end point

Secondary: Part 2: Change from Baseline in the frequency of all countable non-motor seizures in OLE Period

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End point title

Part 2: Change from Baseline in the frequency of all countable non-motor seizures in OLE Period

End point description

Countable non-motor seizures included: focal seizures [FS] without clear observable signs, myoclonic seizures [MS], absence/atypical absence, infantile spasms, epileptic spasms, and other seizures. For each participant, the seizure frequency per 28 days was calculated as the number of seizures recorded during the period, divided by the number of days in the period and multiplied by 28. The OLE mITT population included all participants who received at least 1 dose of ZX008 and had a valid estimate of the frequency of seizures that resulted in drops from Part 1 and at least 1 month (30 days) of valid seizure data during the OLE.

End point type

Secondary

End point timeframe

From OLE Month 1 to Month12, compared to Baseline (Part 1)

End point values	Part 2: Cohort B- Overall	Part 2: Cohort A- Overall
Number of subjects analysed	32	241
Units: seizure frequency per 28 days
median (full range (min-max))	0.00 (-89.4 to 258.9)	0.00 (-4257.2 to 1774.3)

No statistical analyses for this end point

Secondary: Part 2: Percent change from Baseline in the frequency of all countable seizures (ESC confirmed or not) in OLE Period

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End point title

Part 2: Percent change from Baseline in the frequency of all countable seizures (ESC confirmed or not) in OLE Period

End point description

Countable motor seizures included: GTC, SGTC, TS, AS, TA, CS, HS, and FS with clearly observable signs. Countable non-motor seizures included: FS without clear observable signs, MS, absence/atypical absence, infantile spasms, epileptic spasms, and other seizures. The OLE mITT population included all participants who received at least 1 dose of ZX008 and had a valid estimate of the frequency of seizures that resulted in drops from Part 1 and at least 1 month (30 days) of valid seizure data during the OLE.

End point type

Secondary

End point timeframe

From OLE Month 1 to Month12, compared to Baseline (Part 1)

End point values	Part 2: Cohort B- Overall	Part 2: Cohort A- Overall
Number of subjects analysed	32	241
Units: percent change
median (full range (min-max))	-28.00 (-99.1 to 83.3)	-28.83 (-100.0 to 606.1)

No statistical analyses for this end point

Secondary: Part 2: Change from Baseline in the frequency of all countable seizures that did not result in drops (ESC confirmed) in OLE Period

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End point title

Part 2: Change from Baseline in the frequency of all countable seizures that did not result in drops (ESC confirmed) in OLE Period

End point description

Non-drop seizures were defined as any countable seizure types that did not meet the criteria of drop seizures, ie, are classified as CS, HC, FS with or without observable signs, MS, absence/atypical absence, infantile spasms, epileptic spasms, or other; or are seizures of the following classifications that were approved for each participant as non-drop seizure types by the ESC: GTC, SGTC, TS, AS, or TA. For each participant, the seizure frequency per 28 days was calculated as the number of seizures recorded during the period, divided by the number of days in the period and multiplied by 28. The OLE mITT population included all participants who received at least 1 dose of ZX008 and had a valid estimate of the frequency of seizures that resulted in drops from Part 1 and at least 1 month (30 days) of valid seizure data during the OLE.

End point type

Secondary

End point timeframe

From OLE Month 1 to Month12, compared to Baseline (Part 1)

End point values	Part 2: Cohort B- Overall	Part 2: Cohort A- Overall
Number of subjects analysed	32	241
Units: seizure frequency per 28 days
median (full range (min-max))	0.00 (-89.4 to 258.9)	-0.99 (-4482.2 to 1774.3)

No statistical analyses for this end point

Secondary: Part 2: Percentage of participants who achieved a worsening from Baseline, or > 0%, >=25%, >= 50%, >= 75%, 100% reduction, and “near seizure freedom” from Baseline in frequency of seizures that typically result in drops

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End point title

End point description

Seizures that typically result in drops included all: GTC, SGTC, TS, AS, and TA, whether confirmed by the ESC or not. The participants who experienced a worsening or no change from Baseline (ie <= 0% reduction); >0%, >=25%, >=50%, >=75%, and 100% reduction (a 100% reduction was equivalent to achieving seizure freedom during OLE Period); and “near seizure freedom,” (defined as 0 or 1 seizure leading to a drop) during combined OLE Period were reported. The OLE mITT population included all participants who received at least 1 dose of ZX008 and had a valid estimate of the frequency of seizures that resulted in drops from Part 1 and at least 1 month (30 days) of valid seizure data during the OLE.

End point type

Secondary

End point timeframe

From OLE Month 1 to Month12, compared to Baseline (Part 1)

End point values	Part 2: Cohort B- Overall	Part 2: Cohort A- Overall
Number of subjects analysed	32	241
Units: percentage of participants
number (not applicable)
Worsening or No Change	21.9	32.0
> 0%	78.1	68.0
>= 25%	65.6	53.1
>= 50%	43.8	29.9
>= 75%	21.9	11.2
100%	0	0.8
Near Seizure free	0	1.2

No statistical analyses for this end point

Secondary: Part 2: Percentage of participants who achieved a worsening from Baseline, or > 0%, >=25%, >= 50%, >= 75%, 100% reduction, and “near seizure freedom” from Baseline in frequency of all countable motor seizures

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End point title

End point description

Countable motor seizures included: GTC, SGTC, TS, AS, TA, CS, HS, and FS with clearly observable signs. The participants who experienced a worsening or no change from Baseline (ie <= 0% reduction); >0%, >=25%, >=50%, >=75%, and 100% reduction (a 100% reduction was equivalent to achieving seizure freedom during OLE Period); and “near seizure freedom,” (defined as 0 or 1 seizure leading to a drop) during OLE Period was reported. The OLE mITT population included all participants who received at least 1 dose of ZX008 and had a valid estimate of the frequency of seizures that resulted in drops from Part 1 and at least 1 month (30 days) of valid seizure data during the OLE.

End point type

Secondary

End point timeframe

From OLE Month 1 to Month12, compared to Baseline (Part 1)

End point values	Part 2: Cohort B- Overall	Part 2: Cohort A- Overall
Number of subjects analysed	32	241
Units: percentage of participants
number (not applicable)
Worsening or No Change	21.9	29.5
> 0%	78.1	70.5
>= 25%	62.5	54.8
>= 50%	40.6	29.9
>= 75%	21.9	9.1
100%	0	0.4
Near Seizure free	0	0.8

No statistical analyses for this end point

Secondary: Part 2: Percentage of participants who achieved a worsening from Baseline, or > 0%, >=25%, >= 50%, >= 75%, 100% reduction, and “near seizure freedom” from Baseline in frequency of all countable non-motor seizures

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End point title

End point description

Countable non-motor seizures included: FS without clear observable signs, MS, absence/atypical absence, infantile spasms, epileptic spasms, and other seizures. The participants who experienced a worsening or change from Baseline (ie <= 0% reduction); >0%, >=25%, >=50%, >=75%, and 100% reduction (a 100% reduction was equivalent to achieving seizure freedom during OLE Period); and “near seizure freedom,” (defined as 0 or 1 seizure leading to a drop) during OLE Period was reported. The OLE mITT population included all participants who received at least 1 dose of ZX008 and had a valid estimate of the frequency of seizures that resulted in drops from Part 1 and at least 1 month (30 days) of valid seizure data during the OLE.

End point type

Secondary

End point timeframe

From OLE Month 1 to Month12, compared to Baseline (Part 1)

End point values	Part 2: Cohort B- Overall	Part 2: Cohort A- Overall
Number of subjects analysed	32	241
Units: percentage of participants
number (not applicable)
Worsening or No Change	37.5	24.1
> 0%	31.3	46.1
>= 25%	25.0	41.9
>= 50%	18.8	34.0
>= 75%	6.3	22.8
100%	3.1	4.6
Near Seizure free	6.3	7.5

No statistical analyses for this end point

Secondary: Part 2: Percentage of participants who achieved a worsening from Baseline, or > 0%, >=25%, >= 50%, >= 75%, 100% reduction, and “near seizure freedom” from Baseline in frequency of all countable seizures

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End point title

End point description

Countable motor seizures included: GTC, SGTC; TS, AS, TA, CS, HS, and FS with clearly observable signs. Countable non-motor seizures included: FS without clear observable signs, MS, absence/atypical absence, infantile spasms, epileptic spasms, and other seizures. The participants who experienced a worsening or change from Baseline (ie <= 0% reduction); >0%, >=25%, >=50%, >=75%, and 100% reduction (a 100% reduction was equivalent to achieving seizure freedom during OLE Period); and “near seizure freedom,” (defined as 0 or 1 seizure leading to a drop) during OLE Period were reported. The OLE mITT population included all participants who received at least 1 dose of ZX008 and had a valid estimate of the frequency of seizures that resulted in drops from Part 1 and at least 1 month (30 days) of valid seizure data during the OLE.

End point type

Secondary

End point timeframe

From OLE Month 1 to Month12, compared to Baseline (Part 1)

End point values	Part 2: Cohort B- Overall	Part 2: Cohort A- Overall
Number of subjects analysed	32	241
Units: percentage of participants
number (not applicable)
Worsening or No Change	37.5	30.3
> 0%	62.5	69.7
>= 25%	56.3	53.1
>= 50%	28.1	30.7
>= 75%	12.5	9.1
100%	0	0.4
Near Seizure free	0	0.4

No statistical analyses for this end point

Secondary: Part 2: Clinical Global Impression – Improvement as assessed by the Principal Investigator

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End point title

Part 2: Clinical Global Impression – Improvement as assessed by the Principal Investigator

End point description

CGI-I scale measures improvement in the participant's condition from Baseline. The severity of a participant's condition was 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 and 7-very much worse. The OLE mITT population included all participants who received at least 1 dose of ZX008 and had a valid estimate of the frequency of seizures that resulted in drops from Part 1 and at least 1 month (30 days) of valid seizure data during the OLE. Here, number of participants analyzed included those participants who were evaluable for the assessment. 'n' analyzed included those participants who were evaluable at specified time point.

End point type

Secondary

End point timeframe

At OLE Day 1, OLE Months (M) 1, 2, 3, 6, 9, 12, and Last Assessment (up to 72 months)

End point values	Part 2: Cohort B- Overall	Part 2: Cohort A- Overall
Number of subjects analysed	32	237
Units: percentage of participants
number (not applicable)
1=Very much improved (OLE D1) (n=236,32)	3.1	2.5
2=Much improved (OLE D1) (n=236,32)	18.8	15.3
3=Minimally improved (OLE D1) (n=236,32)	18.8	25.8
4=No Change (OLE D1) (n=236,32)	56.3	48.3
5=Minimally worse (OLE D1)(n=236,32)	3.1	7.2
6=Much worse (OLE D1) (n=236,32)	0	0.8
7=Very much worse (OLE D1) (n=236,32)	0	0
1=Very much improved (OLE M1) (n=225,32)	9.4	4.4
2=Much improved (OLE M1) (n=225,32)	21.9	20.0
3=Minimally improved (OLE M1) (n=225,32)	37.5	32.4
4=No Change (OLE M1) (n=225,32)	31.3	34.2
5=Minimally worse (OLE M1) (n=225,32)	0	7.6
6=Much worse (OLE M1) (n=225,32)	0	1.3
7=Very much worse (OLE M1) (n=225,32)	0	0
1=Very much improved (OLE M2) (n=220,31)	6.5	5.5
2=Much improved (OLE M2) (n=220,31)	19.4	24.5
3=Minimally improved (OLE M2) (n=220,31)	35.5	34.1
4=No Change (OLE M2) (n=220,31)	32.3	27.7
5=Minimally worse (OLE M2) (n=220,31)	6.5	5.0
6=Much worse (OLE M2) (n=220,31)	0	3.2
7=Very much worse (OLE M2) (n=220,31)	0	0
1=Very much improved (OLE M3) (n=207,29)	6.9	7.2
2=Much improved (OLE M3) (n=207,29)	17.2	25.1
3=Minimally improved (OLE M3) (n=207,29)	55.2	36.2
4=No Change (OLE M3) (n=207,29)	20.7	21.7
5=Minimally worse (OLE M3) (n=207,29)	0	7.2
6=Much worse (OLE M3) (n=207,29)	0	2.4
7=Very much worse (OLE M3) (n=207,29)	0	0
1=Very much improved (OLE M6) (n=184,29)	3.4	8.2
2=Much improved (OLE M6) (n=184,29)	27.6	33.7
3=Minimally improved (OLE M6) (n=184,29)	34.5	31.0
4=No Change (OLE M6) (n=184,29)	27.6	20.1
5=Minimally worse (OLE M6) (n=184,29)	6.9	3.8
6=Much worse (OLE M6) (n=184,29)	0	3.3
7=Very much worse (OLE M6) (n=184,29)	0	0
1=Very much improved (OLE M9) (n=133,28)	3.6	9.0
2=Much improved (OLE M9) (n=133,28)	28.6	37.6
3=Minimally improved (OLE M9) (n=133,28)	28.6	27.1
4=No Change (OLE M9) (n=133,28)	35.7	18.8
5=Minimally worse (OLE M9) (n=133,28)	3.6	6.0
6=Much worse (OLE M9) (n=133,28)	0	1.5
7=Very much worse (OLE M9) (n=133,28)	0	0
1=Very much improved (OLE M12) (n=145,26)	0	9.7
2=Much improved (OLE M12) (n=145,26)	53.8	39.3
3=Minimally improved (OLE M12) (n=145,26)	23.1	26.2
4=No Change (OLE M12) (n=145,26)	19.2	18.6
5=Minimally worse (OLE M12) (n=145,26)	3.8	3.4
6=Much worse (OLE M12) (n=145,26)	0	2.8
7=Very much worse (OLE M12) (n=145,26)	0	0
1=Very much improved (Last Assessment) (n=)	6.3	7.6
2=Much improved (Last Assessment) (n=237,32)	25.0	27.4
3=Minimally improved (Last Assessment) (n=237,32)	25.0	21.9
4=No Change (Last Assessment) (n=237,32)	40.6	28.3
5=Minimally worse (Last Assessment) (n=237,32)	3.1	7.2
6=Much worse (Last Assessment) (n=237,32)	0	7.6
7=Very much worse (Last Assessment) (n=237,32)	0	0

No statistical analyses for this end point

Secondary: Part 2: Change from Baseline in number of seizure-free days per 28 Days (ESC Confirmed) in OLE Period

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End point title

Part 2: Change from Baseline in number of seizure-free days per 28 Days (ESC Confirmed) in OLE Period

End point description

A day with no seizures leading to a drop was defined as a day for which ediary data were available and no drop seizures were reported. The OLE mITT population included all participants who received at least 1 dose of ZX008 and had a valid estimate of the frequency of seizures that resulted in drops from Part 1 and at least 1 month (30 days) of valid seizure data during the OLE.

End point type

Secondary

End point timeframe

From Part 2 Baseline until end of OLE Period (up to 72 months)

End point values	Part 2: Cohort B- Overall	Part 2: Cohort A- Overall
Number of subjects analysed	32	241
Units: seizure free days per 28 days
median (full range (min-max))	4.24 (-3.6 to 24.5)	2.16 (-23.0 to 27.8)

No statistical analyses for this end point

Secondary: Part 2: Change from Baseline in duration of Longest interval between seizures that result in drops (ESC Confirmed) in OLE Period

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End point title

Part 2: Change from Baseline in duration of Longest interval between seizures that result in drops (ESC Confirmed) in OLE Period

End point description

The longest interval between seizures leading to drops were obtained from the eDiary entries in OLE Period. The interval was derived as the maximum value of the number of days between consecutive drop seizures. The OLE mITT population included all participants who received at least 1 dose of ZX008 and had a valid estimate of the frequency of seizures that resulted in drops from Part 1 and at least 1 month (30 days) of valid seizure data during the OLE. Here, number of participants analyzed included those participants who were evaluable for the assessment.

End point type

Secondary

End point timeframe

From Part 2 Baseline until end of the OLE Period (up to 72 months)

End point values	Part 2: Cohort A- Overall	Part 2: Cohort B- Overall
Number of subjects analysed	241	27
Units: days
median (full range (min-max))	4.0 (-10 to 360)	6.0 (0 to 200)

No statistical analyses for this end point

Secondary: Part 2: Clinical Global Impression – Improvement as assessed by the Parent/Caregiver

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End point title

Part 2: Clinical Global Impression – Improvement as assessed by the Parent/Caregiver

End point description

CGI-I scale measures improvement in the participant's condition from Baseline. The severity of a participant's condition was 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 and 7-very much worse. The OLE mITT population included all participants who received at least 1 dose of ZX008 and had a valid estimate of the frequency of seizures that resulted in drops from Part 1 and at least 1 month (30 days) of valid seizure data during the OLE. Here, number of participants analyzed included those participants who were evaluable for the assessment. 'n' included those participants who were evaluable at specified time point.

End point type

Secondary

End point timeframe

At OLE Day 1, OLE Months (M) 1, 2, 3, 6, 9, 12, and Last Assessment (up to 72 months)

End point values	Part 2: Cohort A- Overall	Part 2: Cohort B- Overall
Number of subjects analysed	237	32
Units: percentage of participants
number (not applicable)
1=Very much improved (OLE D1) (n=232,32)	6.9	9.4
2=Much improved (OLE D1) (n=232,32)	16.8	12.5
3=Minimally improved (OLE D1) (n=232,32)	24.6	28.1
4=No Change (OLE D1) (n=232,32)	40.1	43.8
5=Minimally worse (OLE D1) (n=232,32)	6.9	3.1
6=Much worse (OLE D1) (n=232,32)	3.9	3.1
7=Very much worse (OLE D1) (n=232,32)	0.9	0
1=Very much improved (OLE M1) (n=224,32)	7.1	12.5
2=Much improved (OLE M1) (n=224,32)	21.4	15.6
3=Minimally improved (OLE M1) (n=224,32)	32.1	31.3
4=No Change (OLE M1) (n=224,32)	29.5	40.6
5=Minimally worse (OLE M1) (n=224,32)	5.8	0
6=Much worse (OLE M1) (n=224,32)	4.0	0
7=Very much worse (OLE M1) (n=224,32)	0	0
1=Very much improved (OLE M2) (n=219,31)	7.3	12.9
2=Much improved (OLE M2) (n=219,31)	25.6	16.1
3=Minimally improved (OLE M2) (n=219,31)	32.0	41.9
4=No Change (OLE M2) (n=219,31)	25.6	22.6
5=Minimally worse (OLE M2) (n=219,31)	6.4	6.5
6=Much worse (OLE M2) (n=219,31)	2.3	0
7=Very much worse (OLE M2) (n=219,31)	0.9	0
1=Very much improved (OLE M3) (n=207,29)	9.7	13.8
2=Much improved (OLE M3) (n=207,29)	30.0	10.3
3=Minimally improved (OLE M3) (n=207,29)	29.5	37.9
4=No Change (OLE M3) (n=207,29)	19.3	37.9
5=Minimally worse (OLE M3) (n=207,29)	9.7	0
6=Much worse (OLE M3) (n=207,29)	0.5	0
7=Very much worse (OLE M3) (n=207,29)	1.4	0
1=Very much improved (OLE M6) (n=186,29)	13.4	10.3
2=Much improved (OLE M6) (n=186,29)	30.1	31.0
3=Minimally improved (OLE M6) (n=186,29)	27.4	34.5
4=No Change (OLE M6) (n=186,29)	23.1	20.7
5=Minimally worse (OLE M6) (n=186,29)	3.2	0
6=Much worse (OLE M6) (n=186,29)	2.2	3.4
7=Very much worse (OLE M6) (n=186,29)	0.5	0
1=Very much improved (OLE M9) (n=134,28)	13.4	14.3
2=Much improved (OLE M9) (n=134,28)	37.3	25.0
3=Minimally improved (OLE M9) (n=134,28)	26.1	21.4
4=No Change (OLE M9) (n=134,28)	14.2	32.1
5=Minimally worse (OLE M9) (n=134,28)	8.2	3.6
6=Much worse (OLE M9) (n=134,28)	0.7	3.6
7=Very much worse (OLE M9) (n=134,28)	0	0
1=Very much improved (OLE M12) (n=149,26)	16.8	19.2
2=Much improved (OLE M12) (n=149,26)	34.2	26.9
3=Minimally improved (OLE M12) (n=149,26)	26.8	46.2
4=No Change (OLE M12) (n=149,26)	14.8	3.8
5=Minimally worse (OLE M12) (n=149,26)	4.7	3.8
6=Much worse (OLE M12) (n=149,26)	2.0	0
7=Very much worse (OLE M12) (n=149,26)	0.7	0
1=Very much improved (Last Assessment) (n=237,32)	11.4	12.5
2=Much improved (Last Assessment) (n=237,32)	24.1	28.1
3=Minimally improved (Last Assessment) (n=237,32)	24.5	18.8
4=No Change (Last Assessment) (n=237,32)	25.3	28.1
5=Minimally worse (Last Assessment) (n=237,32)	9.3	9.4
6=Much worse (Last Assessment) (n=237,32)	3.4	3.1
7=Very much worse (Last Assessment) (n=237,32)	2.1	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From Day 1 up to 72 months

Adverse event reporting additional description

AEs with onset in Part 1 that are ongoing in Part 2 were not included in the count of AEs in Part 2. Safety Population and OLE Safety Population were assessed.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

20.1

Reporting group title

Part 1:Cohort A- Placebo

Reporting group description

Participants received matching placebo as an oral solution, twice a day (bid) over 2 weeks of Titration Period and an additional 12 weeks of Maintenance Period. Participants who completed the Maintenance Period and did not continue in Part 2, and participants who discontinued from Part 1 early, were tapered off study medication over 8 days.

Reporting group title

Part 1: Cohort A- ZX008 0.8 mg/kg/day

Reporting group description

Participants were titrated to their blinded randomized dose of ZX008 over the 2-week Titration from 0.2 mg/kg/day to ZX008 0.8 mg/kg/day (or a maximum dose of 30 mg/day or 20 mg/day for participants taking concomitant stiripentol [STP]). Following titration, participants continued to receive the randomized dose of ZX008 as an oral solution, bid for an additional 12 weeks during Maintenance Period. Participants who completed the Maintenance Period and did not continue in Part 2, and participants who discontinued from Part 1 early, were tapered off study medication over 8 days.

Reporting group title

Part 1: Cohort A- ZX008 0.2 mg/kg/day

Reporting group description

Participants received ZX008 0.2 milligram per kilogram per day (mg/kg/day) during the 2-week Titration. Following titration, participants received ZX008 0.2 mg/kg/day as an oral solution, bid for an additional 12 weeks during Maintenance Period. Participants who completed the Maintenance Period and did not continue in Part 2, and participants who discontinued from Part 1 early, were tapered off study medication over 8 days.

Reporting group title

Part 2: Cohort A- Overall

Reporting group description

Reporting group title

Part 1: Cohort B- ZX008 0.8 mg/kg/day

Reporting group description

Participants were titrated to their blinded randomized dose of ZX008 over the 2-week Titration from 0.2 mg/kg/day to ZX008 0.8 mg/kg/day (or a maximum dose of 30 mg/day or 20 mg/day for participants taking concomitant STP). Following titration, participants continued to receive the randomized dose of ZX008 as an oral solution, bid for an additional 12 weeks during Maintenance Period. Participants who completed the Maintenance Period and did not continue in Part 2, and participants who discontinued from Part 1 early, were tapered off study medication over 8 days.

Reporting group title

Part 1: Cohort B- ZX008 0.2 mg/kg/day

Reporting group description

Participants received ZX008 0.2 mg/kg/day during the 2-week Titration. Following titration, participants received ZX008 0.2 mg/kg/day as an oral solution, bid for an additional 12 weeks during Maintenance Period. Participants who completed the Maintenance Period and did not continue in Part 2, and participants who discontinued from Part 1 early, were tapered off study medication over 8 days.

Reporting group title

Part 2: Cohort B- Overall

Reporting group description

Reporting group title

Part 1: Cohort B- Placebo

Reporting group description

Participants received matching placebo as an oral solution, bid over 2 weeks of Titration Period and an additional 12 weeks of Maintenance Period. Participants who completed the Maintenance Period and did not continue in Part 2, and participants who discontinued from Part 1 early, were tapered off study medication over 8 days.

Serious adverse events	Part 1:Cohort A- Placebo	Part 1: Cohort A- ZX008 0.8 mg/kg/day	Part 1: Cohort A- ZX008 0.2 mg/kg/day	Part 2: Cohort A- Overall	Part 1: Cohort B- ZX008 0.8 mg/kg/day	Part 1: Cohort B- ZX008 0.2 mg/kg/day	Part 2: Cohort B- Overall	Part 1: Cohort B- Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 87 (4.60%)	10 / 87 (11.49%)	4 / 89 (4.49%)	41 / 247 (16.60%)	0 / 11 (0.00%)	1 / 11 (9.09%)	6 / 32 (18.75%)	1 / 11 (9.09%)
number of deaths (all causes)	0	1	0	1	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0
Vascular disorders
Distributive shock
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Sudden unexplained death in epilepsy
subjects affected / exposed	0 / 87 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)	0 / 247 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Complication of device insertion
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Lung disorder
subjects affected / exposed	0 / 87 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)	0 / 247 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleurisy
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	3 / 247 (1.21%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 6	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Irritability
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)	0 / 247 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Stereotypy
subjects affected / exposed	0 / 87 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hallucination
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Agitation
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood prolactin increased
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Humerus fracture
subjects affected / exposed	0 / 87 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Foreign body in respiratory tract
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Facial bones fracture
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 247 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	1 / 32 (3.13%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Foreign body in gastrointestinal tract
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 247 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	1 / 32 (3.13%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Somnolence
subjects affected / exposed	0 / 87 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)	3 / 247 (1.21%)	0 / 11 (0.00%)	1 / 11 (9.09%)	1 / 32 (3.13%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	2 / 3	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	2 / 87 (2.30%)	0 / 87 (0.00%)	0 / 89 (0.00%)	3 / 247 (1.21%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Change in seizure presentation
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	2 / 89 (2.25%)	10 / 247 (4.05%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 4	3 / 12	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Status epilepticus
subjects affected / exposed	1 / 87 (1.15%)	3 / 87 (3.45%)	0 / 89 (0.00%)	8 / 247 (3.24%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0	2 / 25	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Generalised tonic-clonic seizure
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure cluster
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 247 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	2 / 32 (6.25%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Haemolytic uraemic syndrome
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Eye movement disorder
subjects affected / exposed	1 / 87 (1.15%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 247 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Keratoconus
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Constipation
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)	0 / 247 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)	2 / 247 (0.81%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 87 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)	0 / 247 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 87 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)	0 / 247 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tooth loss
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dental caries
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 247 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	1 / 32 (3.13%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 87 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)	0 / 247 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Thyroid mass
subjects affected / exposed	1 / 87 (1.15%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 247 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Infection
subjects affected / exposed	0 / 87 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)	0 / 247 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 87 (0.00%)	2 / 87 (2.30%)	1 / 89 (1.12%)	5 / 247 (2.02%)	0 / 11 (0.00%)	0 / 11 (0.00%)	1 / 32 (3.13%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1	0 / 6	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	0 / 87 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)	0 / 247 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dengue fever
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus bronchiolitis
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	2 / 247 (0.81%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterobacter bacteraemia
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 247 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	1 / 32 (3.13%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 87 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)	2 / 247 (0.81%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoalbuminaemia
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	2 / 247 (0.81%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Part 1:Cohort A- Placebo	Part 1: Cohort A- ZX008 0.8 mg/kg/day	Part 1: Cohort A- ZX008 0.2 mg/kg/day	Part 2: Cohort A- Overall	Part 1: Cohort B- ZX008 0.8 mg/kg/day	Part 1: Cohort B- ZX008 0.2 mg/kg/day	Part 2: Cohort B- Overall	Part 1: Cohort B- Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	60 / 87 (68.97%)	68 / 87 (78.16%)	64 / 89 (71.91%)	166 / 247 (67.21%)	7 / 11 (63.64%)	10 / 11 (90.91%)	30 / 32 (93.75%)	8 / 11 (72.73%)
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	11 / 87 (12.64%)	9 / 87 (10.34%)	11 / 89 (12.36%)	25 / 247 (10.12%)	0 / 11 (0.00%)	0 / 11 (0.00%)	7 / 32 (21.88%)	1 / 11 (9.09%)
occurrences all number	13	10	12	33	0	0	12	1
Oedema peripheral
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 247 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	2 / 32 (6.25%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0
Fatigue
subjects affected / exposed	11 / 87 (12.64%)	16 / 87 (18.39%)	8 / 89 (8.99%)	33 / 247 (13.36%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences all number	11	18	10	35	0	0	0	0
Asthenia
subjects affected / exposed	3 / 87 (3.45%)	5 / 87 (5.75%)	4 / 89 (4.49%)	7 / 247 (2.83%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences all number	5	5	4	8	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Rhinitis allergic
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 247 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	3 / 32 (9.38%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	4	0
Cough
subjects affected / exposed	3 / 87 (3.45%)	4 / 87 (4.60%)	2 / 89 (2.25%)	10 / 247 (4.05%)	0 / 11 (0.00%)	0 / 11 (0.00%)	2 / 32 (6.25%)	0 / 11 (0.00%)
occurrences all number	3	4	3	11	0	0	2	0
Psychiatric disorders
Sleep disorder
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)	5 / 247 (2.02%)	1 / 11 (9.09%)	0 / 11 (0.00%)	1 / 32 (3.13%)	0 / 11 (0.00%)
occurrences all number	0	0	1	5	1	0	1	0
Irritability
subjects affected / exposed	5 / 87 (5.75%)	4 / 87 (4.60%)	9 / 89 (10.11%)	6 / 247 (2.43%)	0 / 11 (0.00%)	0 / 11 (0.00%)	3 / 32 (9.38%)	0 / 11 (0.00%)
occurrences all number	5	4	9	6	0	0	3	0
Insomnia
subjects affected / exposed	3 / 87 (3.45%)	2 / 87 (2.30%)	0 / 89 (0.00%)	11 / 247 (4.45%)	0 / 11 (0.00%)	0 / 11 (0.00%)	2 / 32 (6.25%)	0 / 11 (0.00%)
occurrences all number	3	2	0	11	0	0	4	0
Affective disorder
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	1 / 11 (9.09%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	0	3	0	0
Agitation
subjects affected / exposed	3 / 87 (3.45%)	1 / 87 (1.15%)	1 / 89 (1.12%)	4 / 247 (1.62%)	0 / 11 (0.00%)	0 / 11 (0.00%)	2 / 32 (6.25%)	0 / 11 (0.00%)
occurrences all number	3	1	2	4	0	0	3	0
Investigations
Echocardiogram abnormal
subjects affected / exposed	6 / 87 (6.90%)	2 / 87 (2.30%)	2 / 89 (2.25%)	6 / 247 (2.43%)	0 / 11 (0.00%)	0 / 11 (0.00%)	2 / 32 (6.25%)	0 / 11 (0.00%)
occurrences all number	6	2	2	7	0	0	2	0
Weight decreased
subjects affected / exposed	2 / 87 (2.30%)	7 / 87 (8.05%)	3 / 89 (3.37%)	12 / 247 (4.86%)	4 / 11 (36.36%)	2 / 11 (18.18%)	4 / 32 (12.50%)	1 / 11 (9.09%)
occurrences all number	2	7	3	12	4	2	4	1
Blood prolactin increased
subjects affected / exposed	1 / 87 (1.15%)	3 / 87 (3.45%)	0 / 89 (0.00%)	9 / 247 (3.64%)	0 / 11 (0.00%)	1 / 11 (9.09%)	8 / 32 (25.00%)	0 / 11 (0.00%)
occurrences all number	1	4	0	10	0	1	14	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 87 (1.15%)	5 / 87 (5.75%)	2 / 89 (2.25%)	7 / 247 (2.83%)	0 / 11 (0.00%)	0 / 11 (0.00%)	3 / 32 (9.38%)	1 / 11 (9.09%)
occurrences all number	1	5	3	10	0	0	5	1
Face injury
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	3 / 247 (1.21%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	3	0	0	0	1
Laceration
subjects affected / exposed	1 / 87 (1.15%)	3 / 87 (3.45%)	2 / 89 (2.25%)	13 / 247 (5.26%)	0 / 11 (0.00%)	0 / 11 (0.00%)	2 / 32 (6.25%)	0 / 11 (0.00%)
occurrences all number	1	3	2	13	0	0	2	0
Hand fracture
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	1 / 89 (1.12%)	2 / 247 (0.81%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	1	2	0	0	0	1
Ligament sprain
subjects affected / exposed	2 / 87 (2.30%)	1 / 87 (1.15%)	1 / 89 (1.12%)	4 / 247 (1.62%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	1 / 11 (9.09%)
occurrences all number	2	1	1	4	0	0	0	1
Lip injury
subjects affected / exposed	0 / 87 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)	6 / 247 (2.43%)	0 / 11 (0.00%)	0 / 11 (0.00%)	3 / 32 (9.38%)	0 / 11 (0.00%)
occurrences all number	0	1	0	7	0	0	3	0
Wound
subjects affected / exposed	2 / 87 (2.30%)	1 / 87 (1.15%)	1 / 89 (1.12%)	2 / 247 (0.81%)	0 / 11 (0.00%)	0 / 11 (0.00%)	4 / 32 (12.50%)	0 / 11 (0.00%)
occurrences all number	2	1	1	2	0	0	4	0
Cardiac disorders
Mitral valve incompetence
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 247 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Nervous system disorders
Lethargy
subjects affected / exposed	3 / 87 (3.45%)	5 / 87 (5.75%)	4 / 89 (4.49%)	13 / 247 (5.26%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences all number	3	5	4	13	0	0	0	0
Change in seizure presentation
subjects affected / exposed	2 / 87 (2.30%)	0 / 87 (0.00%)	0 / 89 (0.00%)	17 / 247 (6.88%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	0	0	19	0	0	0	0
Seizure cluster
subjects affected / exposed	1 / 87 (1.15%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	2 / 32 (6.25%)	1 / 11 (9.09%)
occurrences all number	1	0	0	1	0	0	5	2
Seizure
subjects affected / exposed	4 / 87 (4.60%)	5 / 87 (5.75%)	11 / 89 (12.36%)	24 / 247 (9.72%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences all number	4	6	13	28	0	0	0	0
Somnolence
subjects affected / exposed	10 / 87 (11.49%)	15 / 87 (17.24%)	10 / 89 (11.24%)	24 / 247 (9.72%)	3 / 11 (27.27%)	4 / 11 (36.36%)	11 / 32 (34.38%)	1 / 11 (9.09%)
occurrences all number	10	16	11	26	3	5	16	1
Tremor
subjects affected / exposed	1 / 87 (1.15%)	2 / 87 (2.30%)	2 / 89 (2.25%)	7 / 247 (2.83%)	1 / 11 (9.09%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences all number	1	2	2	7	1	0	0	0
Eye disorders
Diplopia
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 247 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	2 / 32 (6.25%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	4 / 87 (4.60%)	10 / 87 (11.49%)	10 / 89 (11.24%)	13 / 247 (5.26%)	2 / 11 (18.18%)	3 / 11 (27.27%)	5 / 32 (15.63%)	0 / 11 (0.00%)
occurrences all number	4	11	10	15	2	3	5	0
Breath odour
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 247 (0.00%)	1 / 11 (9.09%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Constipation
subjects affected / exposed	5 / 87 (5.75%)	8 / 87 (9.20%)	5 / 89 (5.62%)	18 / 247 (7.29%)	0 / 11 (0.00%)	0 / 11 (0.00%)	5 / 32 (15.63%)	0 / 11 (0.00%)
occurrences all number	5	10	5	22	0	0	7	0
Dental caries
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	2 / 89 (2.25%)	2 / 247 (0.81%)	0 / 11 (0.00%)	1 / 11 (9.09%)	1 / 32 (3.13%)	0 / 11 (0.00%)
occurrences all number	0	0	2	2	0	1	1	0
Vomiting
subjects affected / exposed	5 / 87 (5.75%)	9 / 87 (10.34%)	11 / 89 (12.36%)	13 / 247 (5.26%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	1 / 11 (9.09%)
occurrences all number	5	44	16	17	0	0	0	1
Haemorrhoids
subjects affected / exposed	1 / 87 (1.15%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	2 / 32 (6.25%)	0 / 11 (0.00%)
occurrences all number	1	0	0	2	0	0	3	0
Skin and subcutaneous tissue disorders
Alopecia areata
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	1 / 11 (9.09%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0
Acne
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	3 / 247 (1.21%)	0 / 11 (0.00%)	1 / 11 (9.09%)	1 / 32 (3.13%)	0 / 11 (0.00%)
occurrences all number	0	0	0	3	0	1	1	0
Eczema
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	2 / 89 (2.25%)	2 / 247 (0.81%)	1 / 11 (9.09%)	0 / 11 (0.00%)	5 / 32 (15.63%)	0 / 11 (0.00%)
occurrences all number	0	0	2	2	1	0	7	0
Dermatitis diaper
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	1 / 11 (9.09%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0
Dermatitis atopic
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 247 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	2
Miliaria
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 247 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	2 / 32 (6.25%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0
Endocrine disorders
Hyperprolactinaemia
subjects affected / exposed	0 / 87 (0.00%)	3 / 87 (3.45%)	0 / 89 (0.00%)	3 / 247 (1.21%)	1 / 11 (9.09%)	0 / 11 (0.00%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	3	0	4	1	0	0	0
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 87 (0.00%)	2 / 87 (2.30%)	2 / 89 (2.25%)	2 / 247 (0.81%)	0 / 11 (0.00%)	0 / 11 (0.00%)	3 / 32 (9.38%)	0 / 11 (0.00%)
occurrences all number	0	2	2	2	0	0	3	0
Conjunctivitis
subjects affected / exposed	0 / 87 (0.00%)	2 / 87 (2.30%)	1 / 89 (1.12%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	2 / 32 (6.25%)	0 / 11 (0.00%)
occurrences all number	0	2	1	1	0	0	2	0
Corona virus infection
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	2 / 247 (0.81%)	0 / 11 (0.00%)	0 / 11 (0.00%)	12 / 32 (37.50%)	0 / 11 (0.00%)
occurrences all number	0	0	0	2	0	0	14	0
Beta haemolytic streptococcal infection
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 247 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	0 / 32 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	0	0	1
Gastroenteritis
subjects affected / exposed	2 / 87 (2.30%)	0 / 87 (0.00%)	0 / 89 (0.00%)	2 / 247 (0.81%)	0 / 11 (0.00%)	0 / 11 (0.00%)	2 / 32 (6.25%)	0 / 11 (0.00%)
occurrences all number	2	0	0	2	0	0	3	0
Urinary tract infection bacterial
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	0 / 247 (0.00%)	0 / 11 (0.00%)	1 / 11 (9.09%)	0 / 32 (0.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Upper respiratory tract infection
subjects affected / exposed	4 / 87 (4.60%)	6 / 87 (6.90%)	7 / 89 (7.87%)	16 / 247 (6.48%)	1 / 11 (9.09%)	0 / 11 (0.00%)	1 / 32 (3.13%)	0 / 11 (0.00%)
occurrences all number	4	7	10	20	1	0	1	0
Sinusitis
subjects affected / exposed	0 / 87 (0.00%)	1 / 87 (1.15%)	1 / 89 (1.12%)	5 / 247 (2.02%)	0 / 11 (0.00%)	0 / 11 (0.00%)	2 / 32 (6.25%)	0 / 11 (0.00%)
occurrences all number	0	1	1	5	0	0	2	0
Rhinitis
subjects affected / exposed	0 / 87 (0.00%)	1 / 87 (1.15%)	1 / 89 (1.12%)	5 / 247 (2.02%)	0 / 11 (0.00%)	0 / 11 (0.00%)	2 / 32 (6.25%)	0 / 11 (0.00%)
occurrences all number	0	1	2	5	0	0	2	0
Oral herpes
subjects affected / exposed	0 / 87 (0.00%)	1 / 87 (1.15%)	0 / 89 (0.00%)	0 / 247 (0.00%)	0 / 11 (0.00%)	0 / 11 (0.00%)	2 / 32 (6.25%)	0 / 11 (0.00%)
occurrences all number	0	1	0	0	0	0	2	0
Nasopharyngitis
subjects affected / exposed	8 / 87 (9.20%)	7 / 87 (8.05%)	4 / 89 (4.49%)	31 / 247 (12.55%)	0 / 11 (0.00%)	2 / 11 (18.18%)	9 / 32 (28.13%)	2 / 11 (18.18%)
occurrences all number	10	8	5	43	0	2	18	2
Influenza
subjects affected / exposed	1 / 87 (1.15%)	1 / 87 (1.15%)	4 / 89 (4.49%)	3 / 247 (1.21%)	0 / 11 (0.00%)	0 / 11 (0.00%)	3 / 32 (9.38%)	1 / 11 (9.09%)
occurrences all number	1	1	4	3	0	0	3	1
Herpes zoster
subjects affected / exposed	0 / 87 (0.00%)	0 / 87 (0.00%)	0 / 89 (0.00%)	1 / 247 (0.40%)	0 / 11 (0.00%)	0 / 11 (0.00%)	2 / 32 (6.25%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	0	0	2	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	13 / 87 (14.94%)	32 / 87 (36.78%)	18 / 89 (20.22%)	39 / 247 (15.79%)	3 / 11 (27.27%)	3 / 11 (27.27%)	4 / 32 (12.50%)	2 / 11 (18.18%)
occurrences all number	15	35	18	42	3	4	4	2

More information

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Were there any global substantial amendments to the protocol? Yes

10 Jan 2018

Amendment 1.0 provided updates and clarifications on the cardiac follow-up windows, added MS that result in a drop to the types of seizures assessed in the secondary endpoints, clarified inclusion and exclusion criteria, and clarified information to be recorded for adverse event reporting.

29 Jul 2019

Amendment 2.1 combined details from all country-specific protocols into 1 global document, incorporated corrections of the maximum daily dose for subjects taking concomitant STP, updated background information about completed and ongoing clinical trials, and provided updated information about the following: ECHO alert levels for trace regurgitation, endpoints and objectives, statistical analyses, increases in enrollment numbers, visit window allowances during the transition between Part 1 and Part 2, options for continuation of treatment after the end of the trial, prohibited medications, acceptable collection methods for urinalysis samples, phone visit options for Visit 13 and 23, and parameters regarding repeat laboratory sample collection during Baseline. It also included corrections to blood collection volumes and edits for consistency throughout.

02 Jul 2020

Amendment 3.1 provided study conduct information for the COVID-19 pandemic. This amendment also removed the Vineland Adaptive Behavior Scale (VABS) from the study assessments, included updated study drug storage excursions to align with updates to the Pharmacy Manual, and provided updated background information related to existing treatments for Lennox-Gastaut syndrome (LGS) and additional clinical and nonclinical study data.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part 1: Percent change from Baseline in the frequency of seizures that result in drops (ESC-confirmed) in the combined Titration and Maintenance Period (T+M) in the ZX008 0.8 mg/kg/day group compared to the placebo group

Primary: Part 1: Percent change from Baseline in the frequency of seizures that result in drops (ESC-confirmed) in the combined Titration and Maintenance Period (T+M) in the ZX008 0.8 mg/kg/day group compared to the placebo group

Primary: Part 2: Percentage of participants with treatment-emergent adverse events (TEAEs)

Primary: Part 2: Percentage of participants with treatment-emergent adverse events (TEAEs)

Primary: Part 2: Percentage of participants with Serious TEAEs

Primary: Part 2: Percentage of participants with Serious TEAEs

Secondary: Part 1: Percent change from Baseline in the frequency of seizures that result in drops (ESC-confirmed) in T+M in the ZX008 0.2 mg/kg/day group compared to the placebo group

Secondary: Part 1: Percent change from Baseline in the frequency of seizures that result in drops (ESC-confirmed) in T+M in the ZX008 0.2 mg/kg/day group compared to the placebo group

Secondary: Part 1: Percentage of participants who achieve a >=50% reduction from Baseline in the frequency of seizures that result in drops comparing the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

Secondary: Part 1: Percentage of participants who achieve a >=50% reduction from Baseline in the frequency of seizures that result in drops comparing the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

Secondary: Part 1: Percentage of participants who achieve improvement (minimally, much or very much improved) in the CGI-I scale as assessed by Principal Investigator comparing ZX008 0.8 and 0.2 mg/kg/day groups independently versus placebo

Secondary: Part 1: Percentage of participants who achieve improvement (minimally, much or very much improved) in the CGI-I scale as assessed by Principal Investigator comparing ZX008 0.8 and 0.2 mg/kg/day groups independently versus placebo

Secondary: Part 1: Percent change from Baseline in frequency of all seizures that typically result in drops in T+M, whether ESC-confirmed as drop or not in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

Secondary: Part 1: Percent change from Baseline in frequency of all seizures that typically result in drops in T+M, whether ESC-confirmed as drop or not in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

Secondary: Part 1: Percent change from Baseline in the frequency of all countable motor seizures in T+M in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

Secondary: Part 1: Percent change from Baseline in the frequency of all countable motor seizures in T+M in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

Secondary: Part 1: Change from Baseline in the frequency of all countable non-motor seizures in T+M in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

Secondary: Part 1: Change from Baseline in the frequency of all countable non-motor seizures in T+M in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

Secondary: Part 1: Percent change from Baseline in the frequency of all countable seizures (motor and non-motor) in T+M in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

Secondary: Part 1: Percent change from Baseline in the frequency of all countable seizures (motor and non-motor) in T+M in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

Secondary: Part 1: Percent change from Baseline in the frequency of seizures that typically result in drops in the Maintenance Period in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

Secondary: Part 1: Percent change from Baseline in the frequency of seizures that typically result in drops in the Maintenance Period in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

Secondary: Part 1: Percent change from Baseline in the frequency of seizures that result in drops (ESC confirmed) between Baseline and the Maintenance Period

Secondary: Part 1: Percent change from Baseline in the frequency of seizures that result in drops (ESC confirmed) between Baseline and the Maintenance Period

Secondary: Part 1: Percent change from Baseline in the frequency of all countable motor seizures in the Maintenance Period in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

Secondary: Part 1: Percent change from Baseline in the frequency of all countable motor seizures in the Maintenance Period in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

Secondary: Part 1: Change from Baseline in the frequency of all countable non-motor seizures in the Maintenance Period in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

Secondary: Part 1: Change from Baseline in the frequency of all countable non-motor seizures in the Maintenance Period in the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

Secondary: Part 1: Percent change from Baseline in the frequency of all countable seizures (motor and non-motor) in the Maintenance Period in ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

Secondary: Part 1: Percent change from Baseline in the frequency of all countable seizures (motor and non-motor) in the Maintenance Period in ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

Secondary: Part 1: Percent change from Baseline in frequency of countable seizures that do not result in drops (ESC Confirmed)

Secondary: Part 1: Percent change from Baseline in frequency of countable seizures that do not result in drops (ESC Confirmed)

Secondary: Part 1: Percentage of participants who achieved a worsening from Baseline (ie <=0% reduction), or >0, >=25%, >=50%, >=75%, 100% reduction, and “near seizure freedom” between Baseline and T+M, and Baseline and M, in seizures that result in drops

Secondary: Part 1: Percentage of participants who achieved a worsening from Baseline (ie <=0% reduction), or >0, >=25%, >=50%, >=75%, 100% reduction, and “near seizure freedom” between Baseline and T+M, and Baseline and M, in seizures that result in drops

Secondary: Part 1: Percentage of participants who achieved a worsening from Baseline, or >0%, >=25%, >=50%, >=75%, 100% reduction, and “near seizure freedom” between Baseline and T+M, and Baseline and M, in seizures that typically results in drops

Secondary: Part 1: Percentage of participants who achieved a worsening from Baseline, or >0%, >=25%, >=50%, >=75%, 100% reduction, and “near seizure freedom” between Baseline and T+M, and Baseline and M, in seizures that typically results in drops

Secondary: Part 1: Percentage of participants who achieved a worsening from Baseline, or >0%, >=25%, >=50%, >=75%, 100% reduction, and “near seizure freedom” between Baseline and T+M, and Baseline and M, in all countable motor seizures

Secondary: Part 1: Percentage of participants who achieved a worsening from Baseline, or >0%, >=25%, >=50%, >=75%, 100% reduction, and “near seizure freedom” between Baseline and T+M, and Baseline and M, in all countable motor seizures

Secondary: Part 1: Percentage of participants who achieved a worsening from Baseline, or >0%, >=25%, >=50%, >=75%, 100% reduction, and “near seizure freedom” between Baseline and T+M, and Baseline and M, in countable motor seizures that do not result in drops

Secondary: Part 1: Percentage of participants who achieved a worsening from Baseline, or >0%, >=25%, >=50%, >=75%, 100% reduction, and “near seizure freedom” between Baseline and T+M, and Baseline and M, in countable motor seizures that do not result in drops

Secondary: Part 1: Percentage of participants who achieved a worsening from Baseline (ie <= 0% reduction), or >0%, >=25%, >=50%, >=75%, 100% reduction, and “near seizure freedom” between Baseline and T+M, and Baseline and M, in all countable seizures

Secondary: Part 1: Percentage of participants who achieved a worsening from Baseline (ie <= 0% reduction), or >0%, >=25%, >=50%, >=75%, 100% reduction, and “near seizure freedom” between Baseline and T+M, and Baseline and M, in all countable seizures

Secondary: Part 1: Percentage of participants who achieved a worsening from Baseline, or >0%, >=25%, >=50%, >=75%, 100% reduction, and “near seizure freedom” between Baseline and T+M, and Baseline and M, in all countable non-motor seizures

Secondary: Part 1: Percentage of participants who achieved a worsening from Baseline, or >0%, >=25%, >=50%, >=75%, 100% reduction, and “near seizure freedom” between Baseline and T+M, and Baseline and M, in all countable non-motor seizures

Secondary: Part 1: Change from Baseline in number of seizure-free days during T+M and M Period

Secondary: Part 1: Change from Baseline in number of seizure-free days during T+M and M Period

Secondary: Part 1: Duration of longest interval (days) between seizures that result in drops comparing the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

Secondary: Part 1: Duration of longest interval (days) between seizures that result in drops comparing the ZX008 0.8 mg/kg/day and 0.2 mg/kg/day groups independently versus placebo

Secondary: Part 1: Clinical Global Impression – Improvement as assessed by the Parent/Caregiver

Secondary: Part 1: Clinical Global Impression – Improvement as assessed by the Parent/Caregiver

Secondary: Part 1: Percentage of participants with TEAEs

Secondary: Part 1: Percentage of participants with TEAEs

Secondary: Part 1: Percentage of participants with Serious TEAEs

Secondary: Part 1: Percentage of participants with Serious TEAEs

Secondary: Part 1: Minimum observed plasma concentration of fenfluramine and norfenfluramine at steady state determined directly from the concentration-time profile [Cmin] at steady state

Secondary: Part 1: Minimum observed plasma concentration of fenfluramine and norfenfluramine at steady state determined directly from the concentration-time profile [Cmin] at steady state

Secondary: Part 1: Maximum observed Plasma concentration of fenfluramine and norfenfluramine determined directly from the concentration time profile [Cmax] at steady state

Secondary: Part 1: Maximum observed Plasma concentration of fenfluramine and norfenfluramine determined directly from the concentration time profile [Cmax] at steady state

Secondary: Part 1: Area under the concentration-time curve of of fenfluramine and norfenfluramine from time zero to time 24 hours [AUC0-24hours] at steady state

Secondary: Part 1: Area under the concentration-time curve of of fenfluramine and norfenfluramine from time zero to time 24 hours [AUC0-24hours] at steady state

Secondary: Part 2: Percent change from Baseline in the frequency of seizures that result in drops (ESC Confirmed) in OLE Period

Secondary: Part 2: Percent change from Baseline in the frequency of seizures that result in drops (ESC Confirmed) in OLE Period

Secondary: Part 2: Percent change from Baseline in the frequency all seizures that typically result in drops between Baseline and the OLE Period whether ESC confirmed as drop or not

Secondary: Part 2: Percent change from Baseline in the frequency all seizures that typically result in drops between Baseline and the OLE Period whether ESC confirmed as drop or not

Secondary: Part 2: Percent change from Baseline in the frequency of all countable motor seizures in OLE Period

Secondary: Part 2: Percent change from Baseline in the frequency of all countable motor seizures in OLE Period

Secondary: Part 2: Percentage of participants who achieved a worsening from Baseline, or > 0%, >=25%, >= 50%, >= 75%, 100% reduction, and “near seizure freedom” from Baseline in frequency of seizures that result in drops (ESC confirmed)

Secondary: Part 2: Percentage of participants who achieved a worsening from Baseline, or > 0%, >=25%, >= 50%, >= 75%, 100% reduction, and “near seizure freedom” from Baseline in frequency of seizures that result in drops (ESC confirmed)

Secondary: Part 2: Change from Baseline in the frequency of all countable non-motor seizures in OLE Period

Secondary: Part 2: Change from Baseline in the frequency of all countable non-motor seizures in OLE Period

Secondary: Part 2: Percent change from Baseline in the frequency of all countable seizures (ESC confirmed or not) in OLE Period