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Clinical Trial Results:
A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled Trial of Two Fixed Doses of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children and Young Adults with Dravet Syndrome

Summary
EudraCT number	2015-004167-37
Trial protocol	GB DE BE NO DK SE ES FR IT
Global end of trial date	29 Jul 2020

Results information
Results version number	v2(current)
This version publication date	24 Dec 2022
First version publication date	10 Jul 2022
Other versions	v1
Version creation reason	Correction of full data set Alignment with final posting on ClinicalTrials.gov after NIH review.

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

ZX008-1502

ISRCTN number

US NCT number

NCT02826863

WHO universal trial number (UTN)

Other trial identifiers

Additional Sponsor Protocol Code: ZX008-1501

Sponsor organisation name

Zogenix International Limited

Sponsor organisation address

5959 Horton Street, 5th Floor, Emeryville, United States, CA 94608

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)

Yes

EMA paediatric investigation plan number(s)

EMEA-001990-PIP01-16

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?

Analysis stage

Final

Date of interim/final analysis

20 Aug 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

29 Jul 2020

Was the trial ended prematurely?

Main objective of the trial

To demonstrate that ZX008 0.8 mg/kg/day is superior to placebo as adjunctive therapy in the treatment of Dravet syndrome in children and young adults based on change in the frequency of convulsive seizures between Baseline and the combined Titration and Maintenance Periods (T+M).

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

15 Jan 2016

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

6 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 7

Country: Number of subjects enrolled

United States: 120

Country: Number of subjects enrolled

Australia: 12

Country: Number of subjects enrolled

Belgium: 8

Country: Number of subjects enrolled

Denmark: 10

Country: Number of subjects enrolled

France: 1

Country: Number of subjects enrolled

Germany: 29

Country: Number of subjects enrolled

Italy: 33

Country: Number of subjects enrolled

Japan: 13

Country: Number of subjects enrolled

Spain: 11

Country: Number of subjects enrolled

United Kingdom: 18

Worldwide total number of subjects

262

EEA total number of subjects

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)

177

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 1501 started to enroll participants in January 2016 and concluded in July 2020. The study 1502 started to enroll participants in July 2016 and concluded in July 2020. The consolidated results of Study 1 and Study 3 are included in this record. The Participant Flow refers to the Randomized Population.

Screening details

Due to slow enrollment into both trials, the databases for the two trials were combined. The first 72 enrolled participants from ZX008-1501 and first 47 from ZX008-1502 were combined for an analysis and reported as Study 1, whereas the final 55 participants from ZX008- 1501 and the final 88 from ZX008-1502 were combined and reported as Study 3.

Period 1 title

Overall Study (overall 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

Study 1: Placebo

Arm description

Participants received matching placebo as an oral solution, twice a day (bid) in equally divided doses with food for up to approximately 16 weeks. Study 1 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).

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 as an oral solution, bid in equally divided doses with food for up to approximately 16 weeks.

Study 1: ZX008 0.2 mg/kg/day

Arm description

Participants received ZX008 0.2 milligram per kilogram per day (mg/kg/day) as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 1 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).

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 0.2 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks.

Study 1: ZX008 0.8 mg/kg/day

Arm description

Participants received ZX008 0.8 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 1 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).

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 0.8 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks.

Study 3: Placebo

Arm description

Participants received matching placebo as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 3 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).

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 as an oral solution, bid in equally divided doses with food for up to approximately 16 weeks.

Study 3: ZX008 0.2 mg/kg/day

Arm description

Participants received ZX008 0.2 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 3 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).

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 0.2 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks.

Study 3: ZX008 0.8 mg/kg/day

Arm description

Participants received ZX008 0.8 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks. Study 3 is the merged analysis of 2 identical studies (ZX008-1501 and ZX008-1502).

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 0.8 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 16 weeks.

Number of subjects in period 1	Study 1: Placebo	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Started	40	39	40	48	46	49
Completed	37	39	34	43	45	46
Not completed	3	0	6	5	1	3
Adverse event, serious fatal	-	-	-	1	-	-
Consent withdrawn by subject	2	-	1	-	1	1
Adverse event, non-fatal	-	-	5	1	-	2
Unspecified	-	-	-	2	-	-
Lack of efficacy	1	-	-	1	-	-

Baseline characteristics

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Reporting group title

Study 1: Placebo

Reporting group description

Reporting group title

Study 1: ZX008 0.2 mg/kg/day

Reporting group description

Reporting group title

Study 1: ZX008 0.8 mg/kg/day

Reporting group description

Reporting group title

Study 3: Placebo

Reporting group description

Reporting group title

Study 3: ZX008 0.2 mg/kg/day

Reporting group description

Reporting group title

Study 3: ZX008 0.8 mg/kg/day

Reporting group description

Reporting group values	Study 1: Placebo	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day	Total
Number of subjects	40	39	40	48	46	49	262
Age Categorical
Units: participants
24 Months - <12 Years	27	28	31	31	30	30	177
12 - < 18 Years	10	11	7	17	15	16	76
18 – < 65 Years	3	0	2	0	1	3	9
Age Continuous
Units: years
arithmetic mean (standard deviation)	9.2 ( 5.10 )	9.0 ( 4.52 )	8.8 ( 4.41 )	9.0 ( 4.29 )	9.6 ( 4.42 )	9.5 ( 5.29 )	-
Sex: Female, Male
Units: participants
Female	19	17	19	21	22	27	125
Male	21	22	21	27	24	22	137

End points

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Reporting group title

Study 1: Placebo

Reporting group description

Reporting group title

Study 1: ZX008 0.2 mg/kg/day

Reporting group description

Reporting group title

Study 1: ZX008 0.8 mg/kg/day

Reporting group description

Reporting group title

Study 3: Placebo

Reporting group description

Reporting group title

Study 3: ZX008 0.2 mg/kg/day

Reporting group description

Reporting group title

Study 3: ZX008 0.8 mg/kg/day

Reporting group description

Primary: Change from Baseline in the mean convulsive seizures frequency (MCSF) to the combined Titration and Maintenance Periods (T+M) in participants receiving ZX008 0.8 mg/kg/day compared to placebo

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End point title

Change from Baseline in the mean convulsive seizures frequency (MCSF) to the combined Titration and Maintenance Periods (T+M) in participants receiving ZX008 0.8 mg/kg/day compared to placebo ^[1]

End point description

Monthly (28 day) convulsive seizure frequency (CSF) was based on electronic diary data obtained for each participant. Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). The number of convulsive seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day CSF. 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) plus 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 ZX008 0.2 mg/kg/day arm which was part of baseline period was not required for the primary endpoint assessment. Therefore, no data was reported for this arm.

End point values	Study 1: Placebo	Study 1: ZX008 0.8 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.8 mg/kg/day
Number of subjects analysed	40	40	48	48
Units: seizure frequency per 28 days
arithmetic mean (standard deviation)	-6.71 ( 24.263 )	-13.11 ( 25.500 )	1.54 ( 21.966 )	-3.54 ( 124.132 )

Statistical Analysis 2

Comparison groups

Study 3: Placebo v Study 3: ZX008 0.8 mg/kg/day

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

Method

Parameter type

Percentage difference from Placebo

Point estimate

64.75

Confidence interval

level

95%

sides

2-sided

lower limit

51.85

upper limit

74.19

Notes
[2] - Estimate was obtained from the LSMeans on the log scale as follows: 100 x [1 - exp(LS mean active - LS mean placebo).

Statistical Analysis 1

Comparison groups

Study 1: Placebo v Study 1: ZX008 0.8 mg/kg/day

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

Method

Parameter type

Percentage difference from Placebo

Point estimate

62.29

Confidence interval

level

95%

sides

2-sided

lower limit

47.72

upper limit

72.8

Notes
[3] - Estimate was obtained from the LSMeans on the log scale as follows: 100 x [1 - exp(LS mean active - LS mean placebo).

Secondary: Change from Baseline in the mean convulsive seizures frequency to the combined Titration and Maintenance Period (T+M) in participants receiving ZX008 0.2 mg/kg/day compared to placebo

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End point title

Change from Baseline in the mean convulsive seizures frequency to the combined Titration and Maintenance Period (T+M) in participants receiving ZX008 0.2 mg/kg/day compared to placebo ^[4]

End point description

Monthly (28 day) convulsive seizure frequency (CSF) was based on electronic diary data obtained for each participant. Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). The number of convulsive seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day CSF. 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) plus Maintenance Period (12 weeks)]

Notes
[4] - 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 ZX008 0.8 mg/kg/day arm was reported in primary endpoint therefore, this arm which was part of baseline period was not required for the secondary endpoint assessment. Hence, no data was reported for this arm.

End point values	Study 1: Placebo	Study 1: ZX008 0.2 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.2 mg/kg/day
Number of subjects analysed	40	39	48	46
Units: seizure frequency per 28 days
arithmetic mean (standard deviation)	-6.71 ( 24.263 )	-18.81 ( 90.640 )	1.54 ( 21.966 )	-5.89 ( 84.735 )

Statistical Analysis 2

Comparison groups

Study 3: Placebo v Study 3: ZX008 0.2 mg/kg/day

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

Method

Parameter type

Percentage difference from Placebo

Point estimate

49.88

Confidence interval

level

95%

sides

2-sided

lower limit

31.31

upper limit

63.43

Notes
[5] - Estimate was obtained from the LSMeans on the log scale as follows: 100 x [1 - exp(LS mean active - LS mean placebo).

Statistical Analysis 1

Comparison groups

Study 1: Placebo v Study 1: ZX008 0.2 mg/kg/day

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

Method

Parameter type

Percentage difference from Placebo

Point estimate

32.43

Confidence interval

level

95%

sides

2-sided

lower limit

6.19

upper limit

51.33

Notes
[6] - Estimate was obtained from the LSMeans on the log scale as follows: 100 x [1 - exp(LS mean active - LS mean placebo).

Secondary: Percentage of participants who achieved greater than or equal to 25% (≥25%) reduction in convulsive seizure frequency in each ZX008 treatment arm compared to placebo from Baseline during the Titration and Maintenance Period

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End point title

Percentage of participants who achieved greater than or equal to 25% (≥25%) reduction in convulsive seizure frequency in each ZX008 treatment arm compared to placebo from Baseline during the Titration and Maintenance Period

End point description

Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). A responder was a participant who experienced a 25% or greater reduction in convulsive seizure frequency 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) plus Maintenance Period (12 weeks)]

End point values	Study 1: Placebo	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Number of subjects analysed	40	39	40	48	46	48
Units: percentage of participants
number (not applicable)	35.0	66.7	90.0	27.1	71.7	83.3

No statistical analyses for this end point

Secondary: Percentage of participants who achieved a ≥50% reduction in convulsive seizure frequency in each ZX008 treatment arm compared to placebo from Baseline during the Titration and Maintenance Period

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End point title

Percentage of participants who achieved a ≥50% reduction in convulsive seizure frequency in each ZX008 treatment arm compared to placebo from Baseline during the Titration and Maintenance Period

End point description

Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). A responder was a participant who experienced a 50% or greater reduction in convulsive seizure frequency 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) plus Maintenance Period (12 weeks)]

End point values	Study 1: Placebo	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Number of subjects analysed	40	39	40	48	46	48
Units: percentage of participants
number (not applicable)	12.5	38.5	67.5	6.3	45.7	72.9

Statistical Analysis 1

Comparison groups

Study 1: Placebo v Study 1: ZX008 0.2 mg/kg/day

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.009

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

4.773

Confidence interval

level

95%

sides

2-sided

lower limit

1.475

upper limit

15.45

Statistical Analysis 3

Comparison groups

Study 3: Placebo v Study 3: ZX008 0.2 mg/kg/day

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

13.4

Confidence interval

level

95%

sides

2-sided

lower limit

3.6

upper limit

49.8

Statistical Analysis 4

Comparison groups

Study 3: Placebo v Study 3: ZX008 0.8 mg/kg/day

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

53.3

Confidence interval

level

95%

sides

2-sided

lower limit

12.9

upper limit

220.5

Statistical Analysis 2

Comparison groups

Study 1: Placebo v Study 1: ZX008 0.8 mg/kg/day

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

14.96

Confidence interval

level

95%

sides

2-sided

lower limit

4.484

upper limit

49.915

Secondary: Percentage of participants who achieved a ≥75% reduction in convulsive seizure frequency in each ZX008 treatment arm compared to placebo from Baseline during the Titration and Maintenance Period

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End point title

Percentage of participants who achieved a ≥75% reduction in convulsive seizure frequency in each ZX008 treatment arm compared to placebo from Baseline during the Titration and Maintenance Period

End point description

Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). A responder was a participant who experienced a 75% or greater reduction in convulsive seizure frequency 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) plus Maintenance Period (12 weeks)]

End point values	Study 1: Placebo	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Number of subjects analysed	40	39	40	48	46	48
Units: percentage of participants
number (not applicable)	2.5	23.1	50.0	4.2	28.3	47.9

No statistical analyses for this end point

Secondary: Percentage of participants who achieved a 100% reduction in convulsive seizure frequency in each ZX008 treatment arm compared to placebo from Baseline during the Titration and Maintenance Period

Top of page

End point title

Percentage of participants who achieved a 100% reduction in convulsive seizure frequency in each ZX008 treatment arm compared to placebo from Baseline during the Titration and Maintenance Period

End point description

Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). A responder was a participant who experienced a 100% reduction in convulsive seizure frequency 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) plus Maintenance Period (12 weeks)]

End point values	Study 1: Placebo	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Number of subjects analysed	40	39	40	48	46	48
Units: percentage of participants
number (not applicable)	0	7.7	7.5	0	0	12.5

No statistical analyses for this end point

Secondary: Longest convulsive seizure-free interval in each ZX008 treatment arm compared to placebo during the Titration and Maintenance Period

Top of page

End point title

Longest convulsive seizure-free interval in each ZX008 treatment arm compared to placebo during the Titration and Maintenance Period

End point description

The longest interval between convulsive seizures was calculated over the entire Titration and Maintenance Period and was derived as the maximum of the number of days between consecutive convulsive 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

During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)

End point values	Study 1: Placebo	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Number of subjects analysed	40	39	40	48	46	48
Units: days
median (full range (min-max))	9.50 (2.0 to 23.0)	15.00 (3.0 to 106.0)	25.00 (2.0 to 97.0)	10 (2 to 65)	18.5 (2 to 100)	30 (2 to 104)

Statistical Analysis 1

Comparison groups

Study 1: Placebo v Study 1: ZX008 0.2 mg/kg/day

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.035

Method

Wilcoxon rank sum test

Confidence interval

Statistical Analysis 2

Comparison groups

Study 1: Placebo v Study 1: ZX008 0.8 mg/kg/day

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Wilcoxon rank sum test

Confidence interval

Statistical Analysis 3

Comparison groups

Study 3: Placebo v Study 3: ZX008 0.2 mg/kg/day

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002

Method

Wilcoxon rank sum test

Confidence interval

Statistical Analysis 4

Comparison groups

Study 3: Placebo v Study 3: ZX008 0.8 mg/kg/day

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Wilcoxon rank sum test

Confidence interval

Secondary: Number of convulsive seizure-free days in each ZX008 treatment arm compared to placebo during the Titration and Maintenance Period

Top of page

End point title

Number of convulsive seizure-free days in each ZX008 treatment arm compared to placebo during the Titration and Maintenance Period

End point description

A convulsive seizure free day was defined as a day for which diary data are available and no convulsive seizures were reported. Convulsive seizure free days were taken from the electronic diary data. 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

During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)

End point values	Study 1: Placebo	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Number of subjects analysed	40	39	40	48	46	48
Units: seizure free days
median (full range (min-max))	15.14 (1.1 to 25.6)	20.86 (2.2 to 28.0)	24.43 (1.0 to 28.0)	20.20 (1.4 to 27.1)	23.36 (0.8 to 27.7)	25.33 (0.3 to 28.0)

No statistical analyses for this end point

Secondary: Change from Baseline in non-convulsive seizure frequency to the combined Titration and Maintenance Period in each ZX008 treatment arm compared to placebo

Top of page

End point title

Change from Baseline in non-convulsive seizure frequency to the combined Titration and Maintenance Period in each ZX008 treatment arm compared to placebo

End point description

Non-convulsive seizures included focal without clear observable motor signs, absence or atypical absence, myoclonic and atonic. The number of non-convulsive seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day non-convulsive seizure frequency. 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) plus Maintenance Period (12 weeks)]

End point values	Study 1: Placebo	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Number of subjects analysed	21	23	24	26	25	30
Units: seizure frequency per 28 days
median (full range (min-max))	-9.38 (-198.8 to 1886.1)	-4.85 (-1940.8 to 192.3)	-20.06 (-2064.8 to 9.4)	-0.68 (-160.0 to 1313.1)	-0.67 (-138.7 to 111.3)	-4.35 (-1410.6 to 107.5)

No statistical analyses for this end point

Secondary: Change from Baseline in convulsive + non-convulsive seizure frequency to the combined Titration and Maintenance Period in each ZX008 treatment arm compared to placebo

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End point title

Change from Baseline in convulsive + non-convulsive seizure frequency to the combined Titration and Maintenance Period in each ZX008 treatment arm compared to placebo

End point description

Total seizure frequency were defined as the combination of convulsive and non-convulsive seizures. Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). Non-convulsive seizures included focal without clear observable motor signs, absence or atypical absence, myoclonic and atonic. The seizure frequency was based on electronic diary data obtained for each participant. The number of all seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day convulsive or non-convulsive seizure frequency. 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) plus Maintenance Period (12 weeks)]

End point values	Study 1: Placebo	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Number of subjects analysed	40	39	40	48	46	48
Units: seizure frequency per 28 days
median (full range (min-max))	-4.45 (-198.4 to 1850.1)	-7.40 (-1955.1 to 187.1)	-22.95 (-2069.3 to 44.5)	-1.09 (-160.1 to 1310.5)	-6.54 (-153.0 to 525.9)	-11.39 (-1504.8 to 791.4)

No statistical analyses for this end point

Secondary: Percentage of participants with rescue medication usage in each ZX008 treatment arm compared to placebo during the Titration and Maintenance Period

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End point title

Percentage of participants with rescue medication usage in each ZX008 treatment arm compared to placebo during the Titration and Maintenance Period

End point description

Rescue medication was administered according to each participant’s usual or prescribed regimen consisting of 1 or more medications. The usage of rescue medication (number of days and number of medications used per seizure episode) was based on electronic diary data obtained for each participant. The number of days rescue medication was taken (normalized to 28 days) was calculated for each participant. Multiple medications taken on the same day were counted once for that day. 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) plus Maintenance Period (12 weeks)]

End point values	Study 1: Placebo	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Number of subjects analysed	40	39	40	48	46	48
Units: percentage of participants
number (not applicable)	77.5	59.0	45.0	60.4	65.2	47.9

No statistical analyses for this end point

Secondary: Percentage of participants with hospitalization and healthcare resource utilization to treat seizures in each ZX008 treatment arm compared to placebo during study

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End point title

Percentage of participants with hospitalization and healthcare resource utilization to treat seizures in each ZX008 treatment arm compared to placebo during study

End point description

Participants who utilized medical center care to treat a seizure during the study 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.

End point type

Secondary

End point timeframe

During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)

End point values	Study 1: Placebo	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Number of subjects analysed	40	39	40	48	46	48
Units: percentage of participants
number (not applicable)	22.5	17.9	15.0	12.5	19.6	14.6

No statistical analyses for this end point

Secondary: Percentage of participants with status epilepticus (SE) in each ZX008 treatment arm compared to placebo during the Titration and Maintenance Period

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End point title

Percentage of participants with status epilepticus (SE) in each ZX008 treatment arm compared to placebo during the Titration and Maintenance Period

End point description

The participants who either had SE episode recorded as an adverse event (AE) during treatment or a seizure greater than 10 minutes were reported for each treatment group. Additionally, a single participant who may had more than one episode of SE, and an episode of SE recorded as both an AE and as a seizure longer than 10 minutes was counted as a single event. 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

During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)

End point values	Study 1: Placebo	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Number of subjects analysed	40	39	40	48	46	48
Units: percentage of participants
number (not applicable)	27.5	28.2	35.0	16.7	19.6	25.0

No statistical analyses for this end point

Secondary: Distribution of Duration of convulsive seizures (in percentage) in each ZX008 treatment arm compared to placebo at Baseline and during the Titration and Maintenance Period

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End point title

Distribution of Duration of convulsive seizures (in percentage) in each ZX008 treatment arm compared to placebo at Baseline and during the Titration and Maintenance Period

End point description

Duration of single convulsive seizures during the Baseline and the duration over the Titration and Maintenance Period were reported by treatment group using categories as <2 minutes, 2 to 10 minutes and > 10 minutes as collected in the seizure diary. 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

At Baseline and 14 weeks of Titration (2 weeks) and Maintenance Period (12 weeks)

End point values	Study 1: Placebo	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Number of subjects analysed	40	39	40	48	46	48
Units: percentage of seizures
number (not applicable)
<2 min (Baseline)	69.28	64.13	71.61	64.21	63.90	74.11
2-10 min (Baseline)	26.86	34.95	24.22	34.83	33.66	22.78
>10 min (Baseline)	3.86	0.93	4.17	0.96	2.45	3.10
<2 min (Titration + Maintenance Period)	71.31	71.59	72.27	65.84	63.45	84.67
2-10 min (Titration + Maintenance Period)	26.31	25.61	22.91	33.74	31.34	13.71
>10 min (Titration + Maintenance Period)	2.38	2.79	4.82	0.43	5.22	1.62

No statistical analyses for this end point

Secondary: Percentage of participants with Clinical Global Impression – Improvement (CGI-I) rating score, as assessed by the Principal Investigator in each ZX008 treatment arm compared to placebo

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End point title

Percentage of participants with Clinical Global Impression – Improvement (CGI-I) rating score, as assessed by the Principal Investigator in each ZX008 treatment arm compared to placebo

End point description

CGI-I scale measures improvement in the participant's clinical status 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 Principal Investigator rated their global impression of the participant's condition during the study. 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

At Visit 6 (Day 15), 8 (Day 43), 10 (Day 71) and 12 (Day 99)

End point values	Study 1: Placebo	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Number of subjects analysed	40	39	40	48	46	48
Units: percentage of participants
number (not applicable)
1 = Very much improved (Visit 6)	5.0	23.1	17.5	4.2	21.7	16.7
2 = Much improved (Visit 6)	12.5	12.8	25.0	2.1	21.7	27.1
3 = Minimally improved (Visit 6)	20.0	20.5	20.0	27.1	17.4	27.1
4 = No change (Visit 6)	40.0	25.6	17.5	54.2	26.1	12.5
5 = Minimally worse (Visit 6)	5.0	7.7	5.0	4.2	2.2	2.1
6 = Much worse (Visit 6)	0	0	2.5	0	0	4.2
7 = Very much worse (Visit 6)	0	0	0	0	0	0
1 = Very much improved (Visit 8)	0	5.1	17.5	4.2	17.4	29.2
2 = Much improved (Visit 8)	12.5	30.8	37.5	6.3	10.9	31.3
3 = Minimally improved (Visit 8)	30.0	20.5	10.0	16.7	26.1	14.6
4 = No change (Visit 8)	30.0	17.9	10.0	50.0	34.8	8.3
5 = Minimally worse (Visit 8)	5.0	5.1	0	4.2	0	4.2
6 = Much worse (Visit 8)	2.5	5.1	2.5	2.1	0	0
7 = Very much worse (Visit 8)	0	0	2.5	0	0	0
1 = Very much improved (Visit 10)	2.5	17.9	20.0	4.2	15.2	35.4
2 = Much improved (Visit 10)	7.5	17.9	47.5	10.4	19.6	18.8
3 = Minimally improved (Visit 10)	30.0	25.6	5.0	12.5	26.1	16.7
4 = No change (Visit 10)	35.0	28.2	7.5	60.4	28.3	4.2
5 = Minimally worse (Visit 10)	10.0	7.7	0	0	0	0
6 = Much worse (Visit 10)	0	2.6	0	0	0	2.1
7 = Very much worse (Visit 10)	0	0	0	0	0	0
1 = Very much improved (Visit 12)	2.5	12.8	27.5	4.2	8.7	33.3
2 = Much improved (Visit 12)	7.5	28.2	35.0	4.2	28.3	31.3
3 = Minimally improved (Visit 12)	30.0	17.9	15.0	16.7	21.7	10.4
4 = No change (Visit 12)	47.5	28.2	12.5	58.3	28.3	16.7
5 = Minimally worse (Visit 12)	2.5	10.3	0	6.3	10.9	6.3
6 = Much worse (Visit 12)	2.5	2.6	0	0	0	0
7 = Very much worse (Visit 12)	0	0	2.5	0	0	0

No statistical analyses for this end point

Secondary: Percentage of participants with Clinical Global Impression – Improvement rating score, as assessed by the Parent/Caregiver in each ZX008 treatment arm compared to placebo

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End point title

Percentage of participants with Clinical Global Impression – Improvement rating score, as assessed by the Parent/Caregiver in each ZX008 treatment arm compared to placebo

End point description

CGI-I scale measures improvement in the participant's clinical status 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 Parent/Caregiver rated their global impression of the participant's condition during the study. 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

At Visit 6 (Day 15), 8 (Day 43), 10 (Day 71) and 12 (Day 99)

End point values	Study 1: Placebo	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Number of subjects analysed	40	39	40	48	46	48
Units: percentage of participants
number (not applicable)
1 = Very much improved (Visit 6)	2.5	17.9	15.0	6.3	13.0	16.7
2 = Much improved (Visit 6)	22.5	20.5	27.5	2.1	23.9	31.3
3 = Minimally improved (Visit 6)	12.5	28.2	22.5	25.0	26.1	31.3
4 = No change (Visit 6)	45.0	12.8	20.0	45.8	19.6	2.1
5 = Minimally worse (Visit 6)	2.5	7.7	2.5	10.4	2.2	6.3
6 = Much worse (Visit 6)	5.0	2.6	7.5	2.1	2.2	2.1
7 = Very much worse (Visit 6)	0	0	2.5	0	0	2.1
1 = Very much improved (Visit 8)	0	15.4	20.0	4.2	6.5	39.6
2 = Much improved (Visit 8)	15.0	25.6	37.5	8.3	30.4	29.2
3 = Minimally improved (Visit 8)	25.0	25.6	15.0	20.8	28.3	14.6
4 = No change (Visit 8)	20.0	12.8	5.0	47.9	17.4	6.3
5 = Minimally worse (Visit 8)	15.0	10.3	2.5	6.3	6.5	0
6 = Much worse (Visit 8)	2.5	5.1	5.0	4.2	2.2	2.1
7 = Very much worse (Visit 8)	0	0	2.5	4.2	0	0
1 = Very much improved (Visit 10)	2.5	20.5	35.0	2.1	8.7	41.7
2 = Much improved (Visit 10)	12.5	17.9	30.0	6.3	28.3	22.9
3 = Minimally improved (Visit 10)	22.5	20.5	7.5	25.0	26.1	8.3
4 = No change (Visit 10)	32.5	25.6	10.0	45.8	26.1	6.3
5 = Minimally worse (Visit 10)	12.5	7.7	0	6.3	0	4.2
6 = Much worse (Visit 10)	2.5	7.7	0	0	4.3	0
7 = Very much worse (Visit 10)	2.5	0	2.5	0	0	0
1 = Very much improved (Visit 12)	2.5	20.5	27.5	2.1	6.5	33.3
2 = Much improved (Visit 12)	7.5	20.5	27.5	6.3	28.3	29.2
3 = Minimally improved (Visit 12)	20.0	15.4	10.0	18.8	30.4	20.8
4 = No change (Visit 12)	35.0	20.5	15.0	50.0	13.0	4.2
5 = Minimally worse (Visit 12)	17.5	15.4	5.0	10.4	8.7	4.2
6 = Much worse (Visit 12)	7.5	7.7	5.0	2.1	4.3	2.1
7 = Very much worse (Visit 12)	0	0	2.5	0	2.2	2.1

No statistical analyses for this end point

Secondary: Change from Baseline to Day 99 in the Quality of Life in Childhood Epilepsy (QOLCE) score to measure quality of life in each ZX008 treatment arm compared to placebo

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End point title

Change from Baseline to Day 99 in the Quality of Life in Childhood Epilepsy (QOLCE) score to measure quality of life in each ZX008 treatment arm compared to placebo

End point description

QOLCE is a low-burden parent/caregiver completed assessment that evaluates how epilepsy affects day-to day functioning of the participant in various life areas, including physical activities, well being, cognition, social activities, behavior, and general health. QOLCE scores items on 16 subscales with possible 5-point response for each, where scores of 5 was best possible response and 1 was worst possible response. Item scores were then transformed to a 0-100 scale as follows: 1-0, 2-25, 3-50, 4-75, 5-100. A score for each participant for each subscale was calculated by averaging that participant’s responses to each item in the subscale. Subscale scores per participant were averaged to obtain an overall QoL score for each participant. Higher the subscale and overall QoL scores, better the response. 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 to Day 99

End point values	Study 1: Placebo	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Number of subjects analysed	40	39	40	48	46	48
Units: score on a scale
arithmetic mean (standard deviation)	1.5 ( 8.73 )	0.8 ( 11.77 )	5.8 ( 11.70 )	1.2 ( 9.01 )	6.1 ( 12.47 )	5.5 ( 13.22 )

No statistical analyses for this end point

Secondary: Change from Baseline to Day 99 in the Overall Quality of Life Score from the Pediatric Quality of Life Inventory™ (PedsQL) score in each ZX008 treatment arm compared to placebo

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End point title

Change from Baseline to Day 99 in the Overall Quality of Life Score from the Pediatric Quality of Life Inventory™ (PedsQL) score in each ZX008 treatment arm compared to placebo

End point description

The Pediatric Quality of Life Inventory (PedsQL) is a pediatric modular measure of health related quality of life (QoL) completed by the parent/caregiver on behalf of the participant. It consisted of 23 items across 4 core scales that measure physical (8 items), emotional, social, and school functioning (5 items each). Each of the responses to the 23 items is initially scored on a 5-point Likert scale from 0 (Never) to 4 (Almost always). Scores are linearly transformed to a scale of 0 to 100, where 0=100, 1=75, 2=50, 3=25 and 4=0, and higher scores correspond to better health-related QoL. The Overall Quality of Life is the average of all the items over the number of items answered on all the Scales. 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 to Day 99

End point values	Study 1: Placebo	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Number of subjects analysed	40	39	40	48	46	48
Units: score on a scale
arithmetic mean (standard deviation)	-1.6 ( 10.43 )	6.8 ( 11.25 )	5.9 ( 15.11 )	1.9 ( 13.26 )	4.2 ( 17.65 )	2.1 ( 14.73 )

No statistical analyses for this end point

Secondary: Change from Baseline to Day 99 in the Total Score from PedsQL Family Impact module score in each ZX008 treatment arm compared to placebo

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End point title

Change from Baseline to Day 99 in the Total Score from PedsQL Family Impact module score in each ZX008 treatment arm compared to placebo

End point description

PedsQL Family Impact measured impact of pediatric chronic health conditions on parents and family by measuring parent self-reported physical, emotional, social, and cognitive functioning, communication, worry, and family daily activities and relationships. A total of 36 items in scale: 6 for Physical Functioning, 5 each for Emotional Functioning, Cognitive Functioning and Worry, 4 for Social Functioning, 3 for Communication, 3 questions for Daily Activities, and 5 for Family Relationships. Each of responses are initially scored on a 5-point Likert scale from 0 (Never) to 4 (Almost always) and then linearly transformed to scale of 0 to 100,where 0=100,1=75,2=50,3=25 and 4=0, and higher scores mean better health-related QoL. 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 to Day 99

End point values	Study 1: Placebo	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Number of subjects analysed	40	39	40	47	44	48
Units: score on a scale
arithmetic mean (standard deviation)	-4.4 ( 13.00 )	3.9 ( 9.44 )	5.4 ( 15.60 )	1.3 ( 14.88 )	0.7 ( 15.78 )	6.3 ( 14.64 )

No statistical analyses for this end point

Secondary: Quality of life (QoL) of the Parent/Caregiver using the EQ- 5D-5L scale in each ZX008 treatment arm compared to placebo at Baseline (BL) and Day 99 (D99)

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End point title

Quality of life (QoL) of the Parent/Caregiver using the EQ- 5D-5L scale in each ZX008 treatment arm compared to placebo at Baseline (BL) and Day 99 (D99)

End point description

The EuroQOL–5 Dimensions–5 Levels scale produced by European QOL Group (EQ-5D-5L) health questionnaire is health-related QOL instrument with 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The 5 dimensions of EQ-5D-5L health questionnaire were assessed on a Likert scale with 5 possible levels: no problems (NP), slight problems, moderate problems, severe problems, and extreme problems. The categories “slight problems”, “moderate problems”, “severe problems” and “extreme problems” are collapsed into one response category “problems” (Pb). The QOL of the parent/caregiver was assessed and percentage of participants was reported for each item. mITT population was used for analysis. Here, number of participants analyzed included those participants who were evaluable for the assessment and ‘n' signifies participants who were evaluable at specified time points.

End point type

Secondary

End point timeframe

At Baseline and Day 99

End point values	Study 1: Placebo	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Number of subjects analysed	39	37	39	42	43	45
Units: percentage of participants
number (not applicable)
Mobility- NP (BL) (n=39,34,39,40,33,35)	33.33	52.94	46.15	40.00	54.55	28.57
Mobility- Pb (BL) (n=39,34,39,40,33,35)	66.67	47.06	53.85	60.00	45.45	45.45
Mobility- NP (D99) (n=35,37,37,42,43,45)	40.00	45.95	51.35	52.38	51.16	46.67
Mobility- Pb (D99) (n=35,37,37,42,43,45)	60.00	54.05	48.65	47.62	48.84	53.33
Self-care- NP (BL) (n=39,34,39,40,33,35)	25.64	41.18	38.46	22.50	36.36	22.86
Self-care- Pb (BL) (n=39,34,39,40,33,35)	74.36	58.82	61.54	77.50	63.64	77.14
Self-care- NP (D99) n=35,37,37,42,43,45)	28.57	43.24	48.65	30.95	34.88	35.56
Self-care- Pb (D99) n=35,37,37,42,43,45)	71.43	56.76	51.35	69.05	65.12	64.44
Usual activities- NP (BL)(n=39,34,39,40,33,35)	23.08	41.18	35.90	25.00	39.39	20.00
Usual activities- Pb (BL) (n=39,34,39,40,33,35)	76.92	58.82	64.10	75.00	60.61	80.00
Usual activities- NP (D99)(n=35,37,37,42,43,45)	25.71	32.43	48.65	30.95	25.58	35.56
Usual activities- Pb (D99)(n=35,37,37,42,43,45)	74.29	67.57	51.35	69.05	74.42	64.44
Pain/discomfort- NP (BL)(n=39,34,39,40,33,35)	48.72	41.18	46.15	45.00	51.52	51.43
Pain/discomfort- Pb (BL)(n=39,34,39,40,33,35)	51.28	58.82	53.85	55.00	48.48	48.57
Pain/discomfort- NP (D99)(n=35,37,37,42,43,45)	48.57	51.35	64.86	76.19	46.51	64.44
Pain/discomfort- Pb (D99)(n=35,37,37,42,43,45)	51.43	48.65	35.14	45.24	53.49	35.56
Anxiety/depression- NP (BL)(n=39,34,39,40,33,35)	74.36	61.76	56.41	60.00	63.64	74.29
Anxiety/depression- Pb (BL)(n=39,34,39,40,33,35)	25.64	38.24	43.59	40.00	36.36	25.71
Anxiety/depression- NP (D99)(n=35,37,37,42,43,45)	65.71	67.57	67.57	69.05	67.44	73.33
Anxiety/depression- Pb (D99)(n=35,37,37,42,43,45)	34.29	32.43	32.43	30.95	32.56	26.67

No statistical analyses for this end point

Secondary: Change from Baseline to Day 99 in affective symptoms of the Parent/Caregiver using the Hospital Anxiety and Depression Scale (HADS) in each ZX008 treatment arm compared to placebo

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End point title

Change from Baseline to Day 99 in affective symptoms of the Parent/Caregiver using the Hospital Anxiety and Depression Scale (HADS) in each ZX008 treatment arm compared to placebo

End point description

The HADS is a tool that was validated to assess presence of anxiety or depression in an outpatient non-psychiatric population. The HADS a 14-item scale that generates ordinal data for 2 dimensions: 1) Anxiety (7 items), and 2) Depression (7 items). Each item has 4 possible answers rated 0 to 3, of which 0 = No distress and 3 = worst distress. All answers to the items for a dimension with their respective rating are added resulting in a range for each dimension from 0-21, out of which of 0-7 = normal; 8-10=borderline abnormal; 11-21=abnormal. Scores for the entire scale (emotional distress) range from 0 to 42, with higher scores indicating more distress. 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 to Day 99

End point values	Study 1: Placebo	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Number of subjects analysed	31	32	35	30	31	27
Units: score on a scale
arithmetic mean (standard deviation)
Anxiety	-0.4 ( 2.68 )	-0.8 ( 2.84 )	-0.8 ( 3.33 )	-0.6 ( 3.62 )	0.2 ( 3.89 )	-0.7 ( 4.00 )
Depression	0.8 ( 4.50 )	0.2 ( 4.52 )	0.1 ( 4.35 )	-0.7 ( 3.80 )	2.0 ( 4.77 )	-0.8 ( 4.03 )
Total emotional distress	0.4 ( 6.45 )	-0.6 ( 6.60 )	-0.7 ( 6.82 )	-1.2 ( 6.42 )	2.2 ( 7.52 )	-1.5 ( 6.61 )

No statistical analyses for this end point

Secondary: Maximum observed concentration of ZX008 determined directly from the concentration time profile [Cmax] at steady state

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End point title

Maximum observed concentration of ZX008 determined directly from the concentration time profile [Cmax] at steady state ^[7]

End point description

Cmax is the maximum observed concentration determined directly from the concentration-time profile. PK population for each study represents participants randomized to ZX008 and provided concentrations for use in the population PK analysis.

End point type

Secondary

End point timeframe

At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose

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: The descriptive results were planned to be reported for ZX008 arms only, as no PK parameters are collected for Placebo.

End point values	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Number of subjects analysed	39	36	45	44
Units: nanograms per milliliter (ng/mL)
geometric mean (geometric coefficient of variation)	17.7 ( 32.5 )	67.9 ( 37.4 )	17.4 ( 32.3 )	64.5 ( 36.6 )

No statistical analyses for this end point

Secondary: Area under the concentration time curve of ZX008 from time zero to time 24 hours [AUC0-24hours] at steady state

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End point title

Area under the concentration time curve of ZX008 from time zero to time 24 hours [AUC0-24hours] at steady state ^[8]

End point description

AUC0-24 is the area under the concentration time curve from time zero to 24 hours. PK population for each study represents participants randomized to ZX008 and provided concentrations for use in the population PK analysis. PK samples at Visit 8 (Day 43) taken pre-dose to 6 hours post-dose were used to develop a population PK model. The model was utilized to generate plasma concentration-time curve over 24 hours at steady-state in study participants. AUC0-24 was calculated by numerical integration of the individual predicted concentration-time curve.

End point type

Secondary

End point timeframe

At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose

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: The descriptive results were planned to be reported for ZX008 arms only, as no PK parameters are collected for Placebo.

End point values	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Number of subjects analysed	39	36	45	44
Units: nanogramhour per milliliter (ngh/mL)
geometric mean (geometric coefficient of variation)	356 ( 37.0 )	1390 ( 41.3 )	348 ( 37.1 )	1290 ( 42.6 )

No statistical analyses for this end point

Secondary: Time to maximum concentration [Tmax] of ZX008 at steady state

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End point title

Time to maximum concentration [Tmax] of ZX008 at steady state ^[9]

End point description

Tmax is the time to maximum concentration at steady state. PK population for each study represents participants randomized to ZX008 and provided concentrations for use in the population PK analysis.

End point type

Secondary

End point timeframe

At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose

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: The descriptive results were planned to be reported for ZX008 arms only, as no PK parameters are collected for Placebo.

End point values	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Number of subjects analysed	39	36	45	44
Units: hours (h)
median (full range (min-max))	2.90 (2.80 to 3.10)	3.00 (2.70 to 3.20)	2.90 (2.80 to 3.10)	2.90 (2.70 to 3.20)

No statistical analyses for this end point

Secondary: Elimination half-life [t1/2 beta] of ZX008 at steady state

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End point title

Elimination half-life [t1/2 beta] of ZX008 at steady state ^[10]

End point description

t1/2 beta is the elimination half-life. PK population for each study represents participants randomized to ZX008 and provided concentrations for use in the population PK analysis.

End point type

Secondary

End point timeframe

At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose

Notes
[10] - 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 descriptive results were planned to be reported for ZX008 arms only, as no PK parameters are collected for Placebo.

End point values	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Number of subjects analysed	39	36	45	44
Units: hours (h)
geometric mean (geometric coefficient of variation)	18.4 ( 32.3 )	21.1 ( 51.8 )	18.1 ( 32.1 )	18.6 ( 42.2 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From Titration Period until the Safety Follow-up Visit (up to Day 113)

Adverse event reporting additional description

A Treatment emergent adverse event (TEAE) was defined as any AE that based on start date information occurred after the first dose of study drug. The safety population included all randomized participants who received at least 1 dose of ZX008 or placebo.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Study 1: Placebo

Reporting group description

Reporting group title

Study 1: ZX008 0.2 mg/kg/day

Reporting group description

Reporting group title

Study 1: ZX008 0.8 mg/kg/day

Reporting group description

Reporting group title

Study 3: Placebo

Reporting group description

Reporting group title

Study 3: ZX008 0.2 mg/kg/day

Reporting group description

Reporting group title

Study 3: ZX008 0.8 mg/kg/day

Reporting group description

Serious adverse events	Study 1: Placebo	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 40 (10.00%)	4 / 39 (10.26%)	5 / 40 (12.50%)	2 / 48 (4.17%)	3 / 46 (6.52%)	3 / 48 (6.25%)
number of deaths (all causes)	0	0	0	1	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0
Investigations
Hepatic enzyme increased
subjects affected / exposed	0 / 40 (0.00%)	0 / 39 (0.00%)	0 / 40 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	0 / 40 (0.00%)	0 / 39 (0.00%)	1 / 40 (2.50%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Head injury
subjects affected / exposed	1 / 40 (2.50%)	0 / 39 (0.00%)	0 / 40 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	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
Skull fracture
subjects affected / exposed	0 / 40 (0.00%)	0 / 39 (0.00%)	0 / 40 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	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
Toxicity to various agents
subjects affected / exposed	0 / 40 (0.00%)	0 / 39 (0.00%)	0 / 40 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Febrile convulsion
subjects affected / exposed	1 / 40 (2.50%)	0 / 39 (0.00%)	0 / 40 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	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
Generalised tonic-clonic seizure
subjects affected / exposed	1 / 40 (2.50%)	0 / 39 (0.00%)	0 / 40 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	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
Lethargy
subjects affected / exposed	0 / 40 (0.00%)	0 / 39 (0.00%)	1 / 40 (2.50%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 40 (2.50%)	1 / 39 (2.56%)	1 / 40 (2.50%)	1 / 48 (2.08%)	1 / 46 (2.17%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	1 / 1	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Somnolence
subjects affected / exposed	0 / 40 (0.00%)	0 / 39 (0.00%)	1 / 40 (2.50%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Status epilepticus
subjects affected / exposed	2 / 40 (5.00%)	1 / 39 (2.56%)	2 / 40 (5.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 3	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Adverse drug reaction
subjects affected / exposed	0 / 40 (0.00%)	0 / 39 (0.00%)	1 / 40 (2.50%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sudden unexplained death in epilepsy
subjects affected / exposed	0 / 40 (0.00%)	0 / 39 (0.00%)	0 / 40 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 40 (0.00%)	0 / 39 (0.00%)	1 / 40 (2.50%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Hypoxia
subjects affected / exposed	0 / 40 (0.00%)	1 / 39 (2.56%)	0 / 40 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	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
Respiratory distress
subjects affected / exposed	0 / 40 (0.00%)	0 / 39 (0.00%)	0 / 40 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	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
Infections and infestations
Gastroenteritis
subjects affected / exposed	0 / 40 (0.00%)	0 / 39 (0.00%)	0 / 40 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	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
Gastroenteritis viral
subjects affected / exposed	0 / 40 (0.00%)	0 / 39 (0.00%)	0 / 40 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 40 (0.00%)	1 / 39 (2.56%)	0 / 40 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 40 (2.50%)	0 / 39 (0.00%)	0 / 40 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	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
Varicella
subjects affected / exposed	0 / 40 (0.00%)	0 / 39 (0.00%)	0 / 40 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 40 (0.00%)	0 / 39 (0.00%)	1 / 40 (2.50%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	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	Study 1: Placebo	Study 1: ZX008 0.2 mg/kg/day	Study 1: ZX008 0.8 mg/kg/day	Study 3: Placebo	Study 3: ZX008 0.2 mg/kg/day	Study 3: ZX008 0.8 mg/kg/day
Total subjects affected by non serious adverse events
subjects affected / exposed	22 / 40 (55.00%)	35 / 39 (89.74%)	36 / 40 (90.00%)	37 / 48 (77.08%)	41 / 46 (89.13%)	41 / 48 (85.42%)
Investigations
Blood glucose decreased
subjects affected / exposed	0 / 40 (0.00%)	0 / 39 (0.00%)	0 / 40 (0.00%)	6 / 48 (12.50%)	11 / 46 (23.91%)	8 / 48 (16.67%)
occurrences all number	0	0	0	7	13	8
Blood pressure diastolic increased
subjects affected / exposed	1 / 40 (2.50%)	3 / 39 (7.69%)	3 / 40 (7.50%)	3 / 48 (6.25%)	3 / 46 (6.52%)	1 / 48 (2.08%)
occurrences all number	2	3	3	3	3	1
Echocardiogram abnormal
subjects affected / exposed	5 / 40 (12.50%)	7 / 39 (17.95%)	9 / 40 (22.50%)	5 / 48 (10.42%)	11 / 46 (23.91%)	8 / 48 (16.67%)
occurrences all number	5	7	13	5	11	8
Blood pressure increased
subjects affected / exposed	0 / 40 (0.00%)	3 / 39 (7.69%)	2 / 40 (5.00%)	4 / 48 (8.33%)	2 / 46 (4.35%)	2 / 48 (4.17%)
occurrences all number	0	4	2	4	2	2
Blood prolactin increased
subjects affected / exposed	0 / 40 (0.00%)	0 / 39 (0.00%)	3 / 40 (7.50%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)
occurrences all number	0	0	3	0	1	0
Blood pressure systolic increased
subjects affected / exposed	0 / 40 (0.00%)	2 / 39 (5.13%)	0 / 40 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	2	0	1	0	0
Heart rate increased
subjects affected / exposed	1 / 40 (2.50%)	3 / 39 (7.69%)	1 / 40 (2.50%)	3 / 48 (6.25%)	1 / 46 (2.17%)	0 / 48 (0.00%)
occurrences all number	1	3	1	4	1	0
Platelet count decreased
subjects affected / exposed	0 / 40 (0.00%)	1 / 39 (2.56%)	1 / 40 (2.50%)	0 / 48 (0.00%)	0 / 46 (0.00%)	4 / 48 (8.33%)
occurrences all number	0	1	1	0	0	4
Weight decreased
subjects affected / exposed	0 / 40 (0.00%)	5 / 39 (12.82%)	1 / 40 (2.50%)	0 / 48 (0.00%)	1 / 46 (2.17%)	4 / 48 (8.33%)
occurrences all number	0	5	1	0	1	4
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	2 / 40 (5.00%)	4 / 39 (10.26%)	0 / 40 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)
occurrences all number	2	5	0	0	0	1
Nervous system disorders
Lethargy
subjects affected / exposed	2 / 40 (5.00%)	4 / 39 (10.26%)	7 / 40 (17.50%)	2 / 48 (4.17%)	1 / 46 (2.17%)	3 / 48 (6.25%)
occurrences all number	2	6	8	2	1	4
Somnolence
subjects affected / exposed	3 / 40 (7.50%)	6 / 39 (15.38%)	3 / 40 (7.50%)	5 / 48 (10.42%)	5 / 46 (10.87%)	10 / 48 (20.83%)
occurrences all number	4	6	3	5	6	10
Ataxia
subjects affected / exposed	0 / 40 (0.00%)	2 / 39 (5.13%)	3 / 40 (7.50%)	1 / 48 (2.08%)	0 / 46 (0.00%)	2 / 48 (4.17%)
occurrences all number	0	2	3	1	0	2
Balance disorder
subjects affected / exposed	0 / 40 (0.00%)	2 / 39 (5.13%)	1 / 40 (2.50%)	1 / 48 (2.08%)	0 / 46 (0.00%)	2 / 48 (4.17%)
occurrences all number	0	2	1	1	0	2
Drooling
subjects affected / exposed	0 / 40 (0.00%)	3 / 39 (7.69%)	2 / 40 (5.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	2 / 48 (4.17%)
occurrences all number	0	3	2	0	1	2
Hypotonia
subjects affected / exposed	0 / 40 (0.00%)	0 / 39 (0.00%)	3 / 40 (7.50%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	0	3	0	0	1
Headache
subjects affected / exposed	1 / 40 (2.50%)	3 / 39 (7.69%)	0 / 40 (0.00%)	1 / 48 (2.08%)	1 / 46 (2.17%)	0 / 48 (0.00%)
occurrences all number	1	5	0	1	1	0
Sedation
subjects affected / exposed	0 / 40 (0.00%)	0 / 39 (0.00%)	0 / 40 (0.00%)	3 / 48 (6.25%)	0 / 46 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	0	0	3	0	0
Seizure
subjects affected / exposed	4 / 40 (10.00%)	3 / 39 (7.69%)	2 / 40 (5.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	1 / 48 (2.08%)
occurrences all number	4	5	4	1	0	1
Seizure cluster
subjects affected / exposed	0 / 40 (0.00%)	2 / 39 (5.13%)	0 / 40 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)
occurrences all number	0	2	0	0	1	0
Status epilepticus
subjects affected / exposed	0 / 40 (0.00%)	1 / 39 (2.56%)	0 / 40 (0.00%)	0 / 48 (0.00%)	3 / 46 (6.52%)	0 / 48 (0.00%)
occurrences all number	0	1	0	0	5	0
Tremor
subjects affected / exposed	1 / 40 (2.50%)	1 / 39 (2.56%)	1 / 40 (2.50%)	1 / 48 (2.08%)	1 / 46 (2.17%)	6 / 48 (12.50%)
occurrences all number	1	1	1	1	1	6
General disorders and administration site conditions
Fatigue
subjects affected / exposed	1 / 40 (2.50%)	4 / 39 (10.26%)	4 / 40 (10.00%)	1 / 48 (2.08%)	3 / 46 (6.52%)	5 / 48 (10.42%)
occurrences all number	1	4	4	1	3	5
Pyrexia
subjects affected / exposed	8 / 40 (20.00%)	7 / 39 (17.95%)	2 / 40 (5.00%)	4 / 48 (8.33%)	5 / 46 (10.87%)	9 / 48 (18.75%)
occurrences all number	12	12	3	5	7	11
Asthenia
subjects affected / exposed	0 / 40 (0.00%)	1 / 39 (2.56%)	0 / 40 (0.00%)	1 / 48 (2.08%)	2 / 46 (4.35%)	3 / 48 (6.25%)
occurrences all number	0	1	0	1	2	3
Gait disturbance
subjects affected / exposed	0 / 40 (0.00%)	0 / 39 (0.00%)	0 / 40 (0.00%)	0 / 48 (0.00%)	3 / 46 (6.52%)	1 / 48 (2.08%)
occurrences all number	0	0	0	0	3	1
Gastrointestinal disorders
Vomiting
subjects affected / exposed	4 / 40 (10.00%)	4 / 39 (10.26%)	3 / 40 (7.50%)	3 / 48 (6.25%)	0 / 46 (0.00%)	3 / 48 (6.25%)
occurrences all number	5	5	3	4	0	3
Diarrhoea
subjects affected / exposed	3 / 40 (7.50%)	12 / 39 (30.77%)	7 / 40 (17.50%)	4 / 48 (8.33%)	7 / 46 (15.22%)	7 / 48 (14.58%)
occurrences all number	3	14	7	4	8	7
Salivary hypersecretion
subjects affected / exposed	0 / 40 (0.00%)	2 / 39 (5.13%)	1 / 40 (2.50%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)
occurrences all number	0	2	1	0	1	0
Constipation
subjects affected / exposed	0 / 40 (0.00%)	1 / 39 (2.56%)	4 / 40 (10.00%)	0 / 48 (0.00%)	2 / 46 (4.35%)	1 / 48 (2.08%)
occurrences all number	0	1	4	0	2	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 40 (5.00%)	1 / 39 (2.56%)	1 / 40 (2.50%)	1 / 48 (2.08%)	2 / 46 (4.35%)	3 / 48 (6.25%)
occurrences all number	2	1	1	1	2	3
Rhinorrhoea
subjects affected / exposed	1 / 40 (2.50%)	2 / 39 (5.13%)	1 / 40 (2.50%)	0 / 48 (0.00%)	3 / 46 (6.52%)	1 / 48 (2.08%)
occurrences all number	1	2	1	0	3	1
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	1 / 40 (2.50%)	2 / 39 (5.13%)	2 / 40 (5.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	4 / 48 (8.33%)
occurrences all number	2	2	2	1	0	4
Psychiatric disorders
Abnormal behaviour
subjects affected / exposed	0 / 40 (0.00%)	0 / 39 (0.00%)	3 / 40 (7.50%)	1 / 48 (2.08%)	1 / 46 (2.17%)	2 / 48 (4.17%)
occurrences all number	0	0	4	1	1	2
Enuresis
subjects affected / exposed	0 / 40 (0.00%)	2 / 39 (5.13%)	0 / 40 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	2	0	0	0	0
Irritability
subjects affected / exposed	0 / 40 (0.00%)	0 / 39 (0.00%)	1 / 40 (2.50%)	3 / 48 (6.25%)	2 / 46 (4.35%)	1 / 48 (2.08%)
occurrences all number	0	0	1	3	2	1
Negativism
subjects affected / exposed	1 / 40 (2.50%)	2 / 39 (5.13%)	0 / 40 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	3	0	0	0	0
Renal and urinary disorders
Urinary incontinence
subjects affected / exposed	0 / 40 (0.00%)	2 / 39 (5.13%)	1 / 40 (2.50%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	2	1	0	0	1
Infections and infestations
Nasopharyngitis
subjects affected / exposed	5 / 40 (12.50%)	4 / 39 (10.26%)	7 / 40 (17.50%)	5 / 48 (10.42%)	4 / 46 (8.70%)	1 / 48 (2.08%)
occurrences all number	6	4	8	8	7	1
Upper respiratory tract infection
subjects affected / exposed	5 / 40 (12.50%)	8 / 39 (20.51%)	0 / 40 (0.00%)	2 / 48 (4.17%)	3 / 46 (6.52%)	4 / 48 (8.33%)
occurrences all number	7	13	0	3	4	5
Croup infectious
subjects affected / exposed	0 / 40 (0.00%)	3 / 39 (7.69%)	1 / 40 (2.50%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)
occurrences all number	0	3	1	0	1	0
Ear infection
subjects affected / exposed	0 / 40 (0.00%)	2 / 39 (5.13%)	1 / 40 (2.50%)	2 / 48 (4.17%)	3 / 46 (6.52%)	0 / 48 (0.00%)
occurrences all number	0	2	1	2	3	0
Influenza
subjects affected / exposed	4 / 40 (10.00%)	0 / 39 (0.00%)	0 / 40 (0.00%)	2 / 48 (4.17%)	1 / 46 (2.17%)	1 / 48 (2.08%)
occurrences all number	4	0	0	2	3	1
Rhinitis
subjects affected / exposed	1 / 40 (2.50%)	3 / 39 (7.69%)	1 / 40 (2.50%)	0 / 48 (0.00%)	0 / 46 (0.00%)	2 / 48 (4.17%)
occurrences all number	1	3	1	0	0	2
Sinusitis
subjects affected / exposed	0 / 40 (0.00%)	0 / 39 (0.00%)	1 / 40 (2.50%)	1 / 48 (2.08%)	3 / 46 (6.52%)	1 / 48 (2.08%)
occurrences all number	0	0	1	1	4	1
Urinary tract infection
subjects affected / exposed	0 / 40 (0.00%)	2 / 39 (5.13%)	0 / 40 (0.00%)	0 / 48 (0.00%)	2 / 46 (4.35%)	1 / 48 (2.08%)
occurrences all number	0	2	0	0	3	3
Viral infection
subjects affected / exposed	0 / 40 (0.00%)	0 / 39 (0.00%)	0 / 40 (0.00%)	0 / 48 (0.00%)	3 / 46 (6.52%)	2 / 48 (4.17%)
occurrences all number	0	0	0	0	3	3
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	2 / 40 (5.00%)	8 / 39 (20.51%)	14 / 40 (35.00%)	3 / 48 (6.25%)	12 / 46 (26.09%)	18 / 48 (37.50%)
occurrences all number	2	11	15	3	12	22
Hypoglycaemia
subjects affected / exposed	0 / 40 (0.00%)	1 / 39 (2.56%)	1 / 40 (2.50%)	1 / 48 (2.08%)	0 / 46 (0.00%)	3 / 48 (6.25%)
occurrences all number	0	1	1	1	0	3

More information

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Were there any global substantial amendments to the protocol? Yes

18 Dec 2015

Protocol 1501 Amendment 1: Clarifications and changes were made to the protocol and included the following: • Sponsor name change • Added new section of transition for subjects who would be entering the open-label extension study • Removed the following clinical laboratory tests at Visits 1 and 6: luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, testosterone, growth hormone (GH), prolactin, and insulin-like growth factor-1 (IGF-1) • Clarified the maximum dose of ZX008 is 30 mg/day • Clarified the collection duration of prior and concomitant antiepileptic drug (AEDs) • Clarified data to be collected with the use of rescue medication • Moved the BRIEF-P description from the efficacy section to the safety section • Added new section of collection of data for AEs requiring hospitalization Additional clarifications and changes were made, based on feedback received from the US Food and Drug Administration (FDA), and included the following: • Clarified randomization inclusion criteria, post-treatment cardiac follow-up, and adverse event of special interest (AESI) regarding valve regurgitation seen on echocardiogram (ECHO) • Clarified that the central cardiac reader would provide consultation to the Independent Data and Safety Monitoring Committee (IDSMC) when a subject was removed from the study due to development of signs or symptoms indicative of valvulopathy, regurgitation, or pulmonary hypertension • Clarified expedited reporting of cardiac events other than serious adverse events (SAEs) • Added section on grading of and follow-up for ECHO findings.

11 Jan 2016

Protocol 1502 Amendment 1: Clarifications and changes were made to the protocol and included the following: • Sponsor name change • Removed the following clinical laboratory tests at Visits 1 and 6: LH, FSH, estradiol, testosterone, GH, prolactin, and IGF-1 • Clarified the maximum dose of ZX008 is 30 mg/day • Clarified the collection duration of prior and concomitant AEDs • Clarified data to be collected with the use of rescue medication • Added new section of collection of data for AEs requiring hospitalization • Replaced CHU9D with PedsQL • Updated statistical analysis section, to be consistent with the separate statistical analysis plan • Clarified study duration for participants • Clarified Inclusion Criterion regarding the requirement for a whole blood sample for a broad epilepsy-related gene panel • Added requirement that subjects qualified for and planned to enroll into the separate open-label extension study at the end of this study should be consented prior to Visit 12 • Clarified, for all questionnaires and rating scales, when rater substitution was acceptable for the clinic staff and the arent/caregiver Clarifications and changes were made based on feedback received from the US FDA, and included the following: • Clarified randomization inclusion criteria, post-treatment cardiac follow-up, and AESI regarding valve regurgitation seen on ECHO • Clarified that the central cardiac reader would provide consultation to the IDSMC when a subject was to be removed from the study due to development of signs or symptoms indicative of valvulopathy, regurgitation, or pulmonary hypertension.

11 Jan 2016

Continuation of Protocol 1502 Amendment 1• Clarified expedited reporting of cardiac events other than SAEs • Added section on grading of and follow-up for ECHO findings • Added the assessment of cognition for subjects ≥5 years of age, so that all study participants were being assessed for cognition using the BRIEF. The description of the BRIEF was moved from the efficacy section to the safety section. Clarifications and changes were made based on feedback received from the European VHP Clinical Trials Group, and included the following: • Updated contraception requirements for the study • Clarified when subjects must have been discontinued from the study • Clarified that the investigator could discontinue a subject from the study in the case of a medical emergency • Added statistical information regarding sensitivity analyses for concomitant AED medication changes during the study.

18 Jan 2016

Protocol 1501 Amendment 2: Clarifications and changes were made to the protocol and included the following: • Replaced Child Health Utility Instrument (CHU9D) with PedsQL • Updated statistical analysis section, to be consistent with the separate statistical analysis plan • Clarified Inclusion Criterion regarding the requirement for a whole blood sample for a broad epilepsy-related gene panel A change was made based on feedback received from the US FDA, and included the following: • Added the assessment of cognition for subjects ≥5 years of age, so that all study participants were assessed for cognition using the BRIEF. The description of the BRIEF was moved from the efficacy section to the safety section. Clarifications and changes were made based on feedback received from the European Voluntary Harmonization Procedure (VHP) Clinical Trials Group, and included the following: • Updated contraception requirements for the study • Clarified when subjects must be discontinued from the study • Clarified that the investigator could discontinue a subject from the study in the case of a medical emergency • Added statistical information regarding sensitivity analyses for concomitant AED medication changes during the study.

31 Oct 2016

Protocol 1501 Amendment 3: Clarifications and changes were made to the protocol and included the following: • Removed atonic seizures from and added tonic-atonic to the types of convulsive seizures in Inclusion Criterion • Removal of Inclusion Criterion, to clarify that participation in the epilepsy-related genetic testing was not required at screening for participation • Updated the preclinical data information and, based on this information, revised the list of prohibited concomitant medications • Clarified that the number of convulsive seizures during the 6-week Baseline period is ≥ 6 versus > 6 as originally stated • Added PedsQL Family Impact module to the efficacy measures as intended • Clarified study days of Screening during the Baseline period and the timing of assessments in that period • Collection of blood sample for epilepsy genotype panel was mandatory but not required at screening. Added the list of countries in which Diacomit® (stiripentol) is approved • Added supporting references to existing citations of data • Clarified the safety objective • Specified that the number of study centers was approximate • Clarified the duration of use of contraception after the last dose of study drug • Removal of social media policy from the reason for removing a subject from therapy or assessment.

31 Oct 2016

Protocol 1502 Amendment 2: Clarifications and changes were made to the protocol and included the following: • Removed atonic seizures and added tonic-atonic from the types of convulsive seizures in Inclusion Criterion • Removal of Inclusion Criterion to clarify that participation in the epilepsy-related genetic testing was not required at screening for participation. • Updated the preclinical data information and, based on this information, revised the list of prohibited concomitant medications. • Clarified that the number of convulsive seizures during the 6-week Baseline period was ≥6 versus >6 as originally stated. • Added PedsQL Family Impact module to the efficacy measures as intended • Clarified study days of Screening during the Baseline period and the timing of assessments in that period • Collection of blood sample for epilepsy genotype panel was mandatory but not required at screening.• Added the list of countries in which Diacomit® (stiripentol) is approved • Added supporting references to existing citations of data • Clarified the safety objective • Specified that the number of study centers was approximate. • Clarified the duration of use of contraception after the last dose of study drug. • Removal of social media policy from the reason for removing a subject from therapy or assessment.

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.

This posting consists of pooled analysis (PA) 1 and 2 of ZX008-1501 and ZX008-1502. PA1 is referenced as Study 1 in SAP and CSR. PA2 is referenced as Study 2 in respective SAP and Study 3 in corresponding CSR due to timing of regulatory submissions.

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Clinical trials

Clinical Trial Results: A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled Trial of Two Fixed Doses of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children and Young Adults with Dravet Syndrome

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from Baseline in the mean convulsive seizures frequency (MCSF) to the combined Titration and Maintenance Periods (T+M) in participants receiving ZX008 0.8 mg/kg/day compared to placebo

Primary: Change from Baseline in the mean convulsive seizures frequency (MCSF) to the combined Titration and Maintenance Periods (T+M) in participants receiving ZX008 0.8 mg/kg/day compared to placebo

Secondary: Change from Baseline in the mean convulsive seizures frequency to the combined Titration and Maintenance Period (T+M) in participants receiving ZX008 0.2 mg/kg/day compared to placebo

Secondary: Change from Baseline in the mean convulsive seizures frequency to the combined Titration and Maintenance Period (T+M) in participants receiving ZX008 0.2 mg/kg/day compared to placebo

Secondary: Percentage of participants who achieved greater than or equal to 25% (≥25%) reduction in convulsive seizure frequency in each ZX008 treatment arm compared to placebo from Baseline during the Titration and Maintenance Period

Secondary: Percentage of participants who achieved greater than or equal to 25% (≥25%) reduction in convulsive seizure frequency in each ZX008 treatment arm compared to placebo from Baseline during the Titration and Maintenance Period

Secondary: Percentage of participants who achieved a ≥50% reduction in convulsive seizure frequency in each ZX008 treatment arm compared to placebo from Baseline during the Titration and Maintenance Period

Secondary: Percentage of participants who achieved a ≥50% reduction in convulsive seizure frequency in each ZX008 treatment arm compared to placebo from Baseline during the Titration and Maintenance Period

Secondary: Percentage of participants who achieved a ≥75% reduction in convulsive seizure frequency in each ZX008 treatment arm compared to placebo from Baseline during the Titration and Maintenance Period

Secondary: Percentage of participants who achieved a ≥75% reduction in convulsive seizure frequency in each ZX008 treatment arm compared to placebo from Baseline during the Titration and Maintenance Period

Secondary: Percentage of participants who achieved a 100% reduction in convulsive seizure frequency in each ZX008 treatment arm compared to placebo from Baseline during the Titration and Maintenance Period

Secondary: Percentage of participants who achieved a 100% reduction in convulsive seizure frequency in each ZX008 treatment arm compared to placebo from Baseline during the Titration and Maintenance Period

Secondary: Longest convulsive seizure-free interval in each ZX008 treatment arm compared to placebo during the Titration and Maintenance Period

Secondary: Longest convulsive seizure-free interval in each ZX008 treatment arm compared to placebo during the Titration and Maintenance Period

Secondary: Number of convulsive seizure-free days in each ZX008 treatment arm compared to placebo during the Titration and Maintenance Period

Secondary: Number of convulsive seizure-free days in each ZX008 treatment arm compared to placebo during the Titration and Maintenance Period

Secondary: Change from Baseline in non-convulsive seizure frequency to the combined Titration and Maintenance Period in each ZX008 treatment arm compared to placebo

Secondary: Change from Baseline in non-convulsive seizure frequency to the combined Titration and Maintenance Period in each ZX008 treatment arm compared to placebo

Secondary: Change from Baseline in convulsive + non-convulsive seizure frequency to the combined Titration and Maintenance Period in each ZX008 treatment arm compared to placebo

Secondary: Change from Baseline in convulsive + non-convulsive seizure frequency to the combined Titration and Maintenance Period in each ZX008 treatment arm compared to placebo

Secondary: Percentage of participants with rescue medication usage in each ZX008 treatment arm compared to placebo during the Titration and Maintenance Period

Secondary: Percentage of participants with rescue medication usage in each ZX008 treatment arm compared to placebo during the Titration and Maintenance Period

Secondary: Percentage of participants with hospitalization and healthcare resource utilization to treat seizures in each ZX008 treatment arm compared to placebo during study

Secondary: Percentage of participants with hospitalization and healthcare resource utilization to treat seizures in each ZX008 treatment arm compared to placebo during study

Secondary: Percentage of participants with status epilepticus (SE) in each ZX008 treatment arm compared to placebo during the Titration and Maintenance Period

Secondary: Percentage of participants with status epilepticus (SE) in each ZX008 treatment arm compared to placebo during the Titration and Maintenance Period

Secondary: Distribution of Duration of convulsive seizures (in percentage) in each ZX008 treatment arm compared to placebo at Baseline and during the Titration and Maintenance Period

Secondary: Distribution of Duration of convulsive seizures (in percentage) in each ZX008 treatment arm compared to placebo at Baseline and during the Titration and Maintenance Period

Secondary: Percentage of participants with Clinical Global Impression – Improvement (CGI-I) rating score, as assessed by the Principal Investigator in each ZX008 treatment arm compared to placebo

Secondary: Percentage of participants with Clinical Global Impression – Improvement (CGI-I) rating score, as assessed by the Principal Investigator in each ZX008 treatment arm compared to placebo

Secondary: Percentage of participants with Clinical Global Impression – Improvement rating score, as assessed by the Parent/Caregiver in each ZX008 treatment arm compared to placebo

Secondary: Percentage of participants with Clinical Global Impression – Improvement rating score, as assessed by the Parent/Caregiver in each ZX008 treatment arm compared to placebo

Secondary: Change from Baseline to Day 99 in the Quality of Life in Childhood Epilepsy (QOLCE) score to measure quality of life in each ZX008 treatment arm compared to placebo

Secondary: Change from Baseline to Day 99 in the Quality of Life in Childhood Epilepsy (QOLCE) score to measure quality of life in each ZX008 treatment arm compared to placebo

Secondary: Change from Baseline to Day 99 in the Overall Quality of Life Score from the Pediatric Quality of Life Inventory™ (PedsQL) score in each ZX008 treatment arm compared to placebo

Secondary: Change from Baseline to Day 99 in the Overall Quality of Life Score from the Pediatric Quality of Life Inventory™ (PedsQL) score in each ZX008 treatment arm compared to placebo

Secondary: Change from Baseline to Day 99 in the Total Score from PedsQL Family Impact module score in each ZX008 treatment arm compared to placebo

Secondary: Change from Baseline to Day 99 in the Total Score from PedsQL Family Impact module score in each ZX008 treatment arm compared to placebo

Secondary: Quality of life (QoL) of the Parent/Caregiver using the EQ- 5D-5L scale in each ZX008 treatment arm compared to placebo at Baseline (BL) and Day 99 (D99)

Secondary: Quality of life (QoL) of the Parent/Caregiver using the EQ- 5D-5L scale in each ZX008 treatment arm compared to placebo at Baseline (BL) and Day 99 (D99)

Secondary: Change from Baseline to Day 99 in affective symptoms of the Parent/Caregiver using the Hospital Anxiety and Depression Scale (HADS) in each ZX008 treatment arm compared to placebo

Secondary: Change from Baseline to Day 99 in affective symptoms of the Parent/Caregiver using the Hospital Anxiety and Depression Scale (HADS) in each ZX008 treatment arm compared to placebo

Secondary: Maximum observed concentration of ZX008 determined directly from the concentration time profile [Cmax] at steady state

Secondary: Maximum observed concentration of ZX008 determined directly from the concentration time profile [Cmax] at steady state

Secondary: Area under the concentration time curve of ZX008 from time zero to time 24 hours [AUC0-24hours] at steady state

Secondary: Area under the concentration time curve of ZX008 from time zero to time 24 hours [AUC0-24hours] at steady state

Secondary: Time to maximum concentration [Tmax] of ZX008 at steady state

Secondary: Time to maximum concentration [Tmax] of ZX008 at steady state

Secondary: Elimination half-life [t1/2 beta] of ZX008 at steady state

Secondary: Elimination half-life [t1/2 beta] of ZX008 at steady state

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled Trial of Two Fixed Doses of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children and Young Adults with Dravet Syndrome