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Clinical Trial Results:
A Multicenter, Open-Label Proof-of-Concept Trial of Ganaxolone in Children with PCDH19 Female Pediatric Epilepsy

Summary
EudraCT number	2015-001324-36
Trial protocol	IT
Global end of trial date	04 Jan 2019

Results information
Results version number	v1(current)
This version publication date	29 Dec 2023
First version publication date	29 Dec 2023
Other versions

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

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Trial information

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Sponsor protocol code

1042-900

ISRCTN number

US NCT number

NCT02358538

WHO universal trial number (UTN)

Sponsor organisation name

Marinus Pharmaceuticals, Inc.

Sponsor organisation address

5 Radnor Corporate Center, 100 Matsonford Rd, Suite 500, Radnor, United States, PA 19087

Public contact

Marinus Pharmaceuticals, Inc., Safety Department, 001 4846792138, clinicaltrials@marinuspharma.com

Scientific contact

Marinus Pharmaceuticals, Inc., Safety Department, 001 4846792138, clinicaltrials@marinuspharma.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

04 Jan 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

04 Jan 2019

Was the trial ended prematurely?

Main objective of the trial

To evaluate the efficacy of open-label ganaxolone as adjunctive therapy for uncontrolled seizures in female children with PCDH19 mutation.

Protection of trial subjects

At the first visit, prior to initiation of any study-related procedures, the parent(s) or legal guardian(s) of the subjects gave their written consent to participate in the study after having been informed about the nature and purpose of the study, participation / termination conditions, and risks and benefits. Before the informed consent document was signed, the investigator, or a person designated by the investigator, provided the subject or the subject's legally acceptable representative ample time and opportunity to inquire about details of the trial and to decide whether or not to participate in the trial. All questions about the trial were answered to the satisfaction of the subject or the subject's legally acceptable representative.

Background therapy

Evidence for comparator

Actual start date of recruitment

06 Nov 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 23

Country: Number of subjects enrolled

Italy: 7

Worldwide total number of subjects

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)

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

Recruitment period May 08, 2015

Screening details

None

Period 1 title

Through Week 26

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

CDKL5

Arm description

Cyclin-dependent kinase-like 5

Arm type

Experimental

Investigational medicinal product name

Ganaxolone

Investigational medicinal product code

Other name

CCD 1042

Pharmaceutical forms

Suspension for oral suspension

Routes of administration

Oral use

Dosage and administration details

Participants were administered with Maximum of 1800 milligrams per day (mg/day) or 63 milligrams per kilograms per day (mg/kg/day).

CSWS

Arm description

Continuous Spike Wave in Sleep

Arm type

Experimental

Investigational medicinal product name

Ganaxolone

Investigational medicinal product code

Other name

CCD 1042

Pharmaceutical forms

Suspension for oral suspension

Routes of administration

Oral use

Dosage and administration details

Participants were administered with Maximum of 1800 mg/day or 63 mg/kg/day

Lennox-Gastaut

Arm description

Lennox-Gastaut Syndrome pediatric epilepsy

Arm type

Experimental

Investigational medicinal product name

Ganaxolone

Investigational medicinal product code

Other name

CCD 1042

Pharmaceutical forms

Suspension for oral suspension

Routes of administration

Oral use

Dosage and administration details

Participants were administered with Maximum of 1800 mg/day or 63 mg/kg/day

PCDH19

Arm description

Protocadherin-19

Arm type

Experimental

Investigational medicinal product name

Ganaxolone

Investigational medicinal product code

Other name

CCD 1042

Pharmaceutical forms

Suspension for oral suspension

Routes of administration

Oral use

Dosage and administration details

Participants were administered with Maximum of 1800 mg/day or 63 mg/kg/day

Number of subjects in period 1	CDKL5	CSWS	Lennox-Gastaut	PCDH19
Started	7	2	10	11
Completed	4	0	5	6
Not completed	3	2	5	5
Consent withdrawn by subject	1	-	-	-
Family did not see benefit from IP	1	-	-	-
Adverse event, non-fatal	-	1	1	2
Non- Compliance	-	-	1	-
Lack of efficacy	1	1	3	3

Period 2 title

52 Week Extension Period

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

CDKL5

Arm description

Cyclin-dependent kinase-like 5

Arm type

Experimental

Investigational medicinal product name

Ganaxolone

Investigational medicinal product code

Other name

CCD 1042

Pharmaceutical forms

Suspension for oral suspension

Routes of administration

Oral use

Dosage and administration details

Participants were administered with Maximum of 1800 mg/day or 63 mg/kg/day

CSWS

Arm description

Continuous Spike Wave in Sleep

Arm type

Experimental

Investigational medicinal product name

Ganaxolone

Investigational medicinal product code

Other name

CCD 1042

Pharmaceutical forms

Suspension for oral suspension

Routes of administration

Oral use

Dosage and administration details

Participants were administered with Maximum of 1800 mg/day or 63 mg/kg/day

Lennox-Gastaut

Arm description

Lennox-Gastaut Syndrome pediatric epilepsy

Arm type

Experimental

Investigational medicinal product name

Ganaxolone

Investigational medicinal product code

Other name

CCD 1042

Pharmaceutical forms

Suspension for oral suspension

Routes of administration

Oral use

Dosage and administration details

Participants were administered with Maximum of 1800 mg/day or 63 mg/kg/day

PCDH19

Arm description

Protocadherin-19

Arm type

Experimental

Investigational medicinal product name

Ganaxolone

Investigational medicinal product code

Other name

CCD 1042

Pharmaceutical forms

Suspension for oral suspension

Routes of administration

Oral use

Dosage and administration details

Participants were administered with Maximum of 1800 mg/day or 63 mg/kg/day

Number of subjects in period 2	CDKL5	CSWS	Lennox-Gastaut	PCDH19
Started	4	2	4	6
Completed	4	0	2	2
Not completed	0	2	2	4
Adverse event, non-fatal	-	1	-	-
Lack of efficacy	-	1	2	4

Baseline characteristics

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Reporting group title

CDKL5

Reporting group description

Cyclin-dependent kinase-like 5

Reporting group title

CSWS

Reporting group description

Continuous Spike Wave in Sleep

Reporting group title

Lennox-Gastaut

Reporting group description

Lennox-Gastaut Syndrome pediatric epilepsy

Reporting group title

PCDH19

Reporting group description

Protocadherin-19

Reporting group values	CDKL5	CSWS	Lennox-Gastaut	PCDH19	Total
Number of subjects	7	2	10	11	30
Age categorical
Units: Subjects
Children (2-11 years)	6	1	9	8	24
Adolescents (12-17 years)	1	1	1	3	6
Age continuous
Units: years
arithmetic mean (standard deviation)	7.57 ± 5.167	11.55 ± 5.728	9.12 ± 2.352	9.00 ± 3.956	-
Gender categorical
Units: Subjects
Female	6	1	7	11	25
Male	1	1	3	0	5

End points

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Reporting group title

CDKL5

Reporting group description

Cyclin-dependent kinase-like 5

Reporting group title

CSWS

Reporting group description

Continuous Spike Wave in Sleep

Reporting group title

Lennox-Gastaut

Reporting group description

Lennox-Gastaut Syndrome pediatric epilepsy

Reporting group title

PCDH19

Reporting group description

Protocadherin-19

Reporting group title

CDKL5

Reporting group description

Cyclin-dependent kinase-like 5

Reporting group title

CSWS

Reporting group description

Continuous Spike Wave in Sleep

Reporting group title

Lennox-Gastaut

Reporting group description

Lennox-Gastaut Syndrome pediatric epilepsy

Reporting group title

PCDH19

Reporting group description

Protocadherin-19

Primary: Summary of 28-day Seizure Frequency for Sum of Individual Seizures and Clusters for 52-week OLE Period (Mean Percent Change & Standard Deviation)

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End point title

Summary of 28-day Seizure Frequency for Sum of Individual Seizures and Clusters for 52-week OLE Period (Mean Percent Change & Standard Deviation) ^[1]

End point description

Percentage change from baseline in 28-day seizure frequency at 3 months (day 91), 26 weeks, 52 week OLE (Mean Percent Change & Standard Deviation). Modified Intent-to-Treat Population (mITT Population) included all subjects who entered into the study and received at least 1 dose of Ganaxolone and provided at least 1 day of post-baseline seizure calendar data. 99999 indicated both subjects (2 for CSWS) discontinued so data is not available. Only those subjects with data available at specified timepoints has been presented (represented by n=X in the category titles).

End point type

Primary

End point timeframe

Baseline through 52 week open label period

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Per protocol, statistical analysis was not planned for this endpoint.

End point values	CDKL5	CSWS	Lennox-Gastaut	PCDH19
Number of subjects analysed	7	2	10	11
Units: percentage of change of frequency
arithmetic mean (standard deviation)
At Day 91, n=7,2,10,11	-31.23 ± 41.438	99999 ± 99999	122.10 ± 321.124	52.83 ± 234.084
At Week 26, n=7,2,10,11	-20.55 ± 60.588	99999 ± 99999	125.38 ± 319.051	46.36 ± 235.661
52 Week OLE through month 6, n=4,2,2,6	-54.41 ± 40.286	99999 ± 99999	-38.74 ± 9.292	-19.98 ± 63.644
52 Week OLE period, n=4,2,2,6	-49.20 ± 50.206	99999 ± 99999	-37.75 ± 7.891	-19.95 ± 63.571

No statistical analyses for this end point

Primary: Summary of 28-day Seizure Frequency for Sum of Individual Seizures and Clusters Through 52-week OLE (Median Percent Change)

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End point title

Summary of 28-day Seizure Frequency for Sum of Individual Seizures and Clusters Through 52-week OLE (Median Percent Change) ^[2]

End point description

Percentage change from baseline in 28-day seizure frequency at 3 months (day 91), 26 weeks, 52 week OLE (Median Percent Change). 99999 indicates both subjects (2 for CSWS) discontinued so data is not available. 88888 indicates there is no data available to support this row for this arm. One subject in the CDKL5 cohort had duplications of data on 6 days. These data appeared to the investigator and sponsor to be erroneous. Excluding these days changes the median percent change from baseline at Week 26 to 44.4 for the CDKL5 cohort. This is reflected in the CDKL5 arm. Only those subjects with data available at specified timepoints has been presented (represented by n=X in the category titles)

End point type

Primary

End point timeframe

Baseline through 52-week open- label period

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Per protocol, statistical analysis was not planned for this endpoint.

End point values	CDKL5	CSWS	Lennox-Gastaut	PCDH19
Number of subjects analysed	7	2	10	11
Units: Median Percent Change in Frequency
median (full range (min-max))
At Day 91, n=7,2,10,11	-47.34 (-80.9 to 36.8)	99999 (99999 to 99999)	-10.22 (-68.1 to 904.3)	-25.98 (-100.00 to 723.2)
At Week 26, n=7,2,10,11	-37.70 (-85.3 to 99.9)	99999 (99999 to 99999)	-9.19 (-71.2 to 904.3)	-24.59 (-100.00 to 723.2)
At Week 26 ( duplicate entries deleted,n=7,2,10,11	-44.4 (-85.3 to 99.9)	99999 (99999 to 99999)	88888 (88888 to 88888)	88888 (88888 to 88888)
52 week OLE through month 6, n=4,2,10,2	-58.94 (-89.4 to -10.4)	99999 (99999 to 99999)	-38.74 (-45.3 to -32.2)	-13.48 (-100.0 to 59.6)
52 week OLE period, n=7,2,10,11	-61.93 (-89.5 to 16.6)	99999 (99999 to 99999)	-37.75 (-43.3 to -32.2)	-13.48 (-99.0 to 59.6)

No statistical analyses for this end point

Secondary: Summary of CGII-C

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End point title

Summary of CGII-C

End point description

Clinician Global Impression of Change score as assessed by questionnaire. [ Time Frame: 78 Weeks] CGII-C scale is qualitative values and not quantitative. Only those subjects with data available at specified timepoints has been presented (represented by n=X in the category titles). 99999 indicates both subjects (2 for CSWS) discontinued so data is not available.

End point type

Secondary

End point timeframe

End of Week 4, End of Week 8, End of Week 17, End of Week 26, Week 44, Week 62, Week 78

End point values	CDKL5	CSWS	Lennox-Gastaut	PCDH19
Number of subjects analysed	7	2	8	11
Units: participants
number (not applicable)
End of Week 4-Very much improved, n= 7, 2, 8, 11	0	99999	2	1
End of Week 4-much improved, n= 7, 2, 8, 11	3	99999	4	4
End of Week 4-minimally improved, n= 7, 2, 8, 11	2	99999	2	3
End of Week 4-No change, n= 7, 2, 8, 11	2	99999	0	3
End of Week 4-minimally worse, n= 7, 2, 8, 11	0	99999	0	0
End of Week 4- much worse, n= 7, 2, 8, 11	0	99999	0	0
End of Week 4- very much worse, n= 7, 2, 8, 11	0	99999	0	0
End of Week 8-Very much improved, n= 7, 2, 8, 7	0	99999	1	0
End of Week 8-much improved, n= 7, 2, 8, 7	4	99999	4	2
End of Week 8-minimally improved, n= 7, 2, 8, 7	2	99999	2	2
End of Week 8-No change, n= 7, 2, 8, 7	1	99999	1	1
End of Week 8-minimally worse, n= 7, 2, 8, 7	0	99999	0	2
End of Week 8- much worse, n= 7, 2, 8, 7	0	99999	0	0
End of Week 8- very much worse, n= 7, 2, 8, 7	0	99999	0	0
End of Week 17-Very much improved, n= 5, 2, 6, 6	1	99999	2	1
End of Week 17-much improved, n= 5, 2, 6, 6	2	99999	3	1
End of Week 17-minimally improved, n= 5, 2, 6, 6	2	99999	0	4
End of Week 17-No change, n= 5, 2, 6, 6	0	99999	1	0
End of Week 17-minimally worse, n= 5, 2, 6, 6	0	99999	0	0
End of Week 17- much worse, n= 5, 2, 6, 6	0	99999	0	0
End of Week 17- very much worse, n= 5, 2, 6, 6	0	99999	0	0
End of Week 26-Very much improved, n= 7, 2, 9, 9	0	99999	1	2
End of Week 26-much improved, n= 7, 2, 9, 9	3	99999	1	2
End of Week 26-minimally improved, n= 7, 2, 9, 9	1	99999	1	2
End of Week 26-No change, n=7, 2, 9, 9	2	99999	2	2
End of Week 26-minimally worse, n= 7, 2, 9, 9	0	99999	1	0
End of Week 26- much worse, n= 7, 2, 9, 9	1	99999	1	1
End of Week 26- very much worse, n= 7, 2, 9, 9	0	99999	0	0
End of Week 44-Very much improved, n= 4, 2, 2, 2	0	99999	0	2
End of Week 44-much improved, n= 4, 2, 2, 2	3	99999	0	0
End of Week 44-minimally improved, n= 4, 2, 2, 2	1	99999	0	0
End of Week 44-No change, n=4, 2, 2, 2	0	99999	1	0
End of Week 44-minimally worse, n= 4, 2, 2, 2	0	99999	1	0
End of Week 44- much worse, n= 4, 2, 2, 2	0	99999	0	0
End of Week 44- very much worse, n= 4, 2, 2, 2	0	99999	0	0
End of Week 62-Very much improved, n= 4, 2, 1, 2	0	99999	0	2
End of Week 62-much improved, n= 4, 2, 1, 2	4	99999	0	0
End of Week 62-minimally improved, n= 4, 2, 1, 2	0	99999	1	0
End of Week 62-No change, n=4, 2, 1, 2	0	99999	0	0
End of Week 62-minimally worse, n= 4, 2, 1, 2	0	99999	0	0
End of Week 62- much worse, n= 4, 2, 1, 2	0	99999	0	0
End of Week 62- very much worse, n= 4, 2, 1, 2	0	99999	0	0
End of Week 78-Very much improved, n= 3, 2, 1, 4	0	99999	0	2
End of Week 78-much improved, n= 3, 2, 1, 4	3	99999	0	0
End of Week 78-minimally improved, n= 3, 2, 1, 4	0	99999	1	0
End of Week 78-No change, n=3, 2, 1, 4	0	99999	0	0
End of Week 78-minimally worse, n= 3, 2, 1, 4	0	99999	0	1
End of Week 78 much worse, n= 3, 2, 1, 4	0	99999	0	1
End of Week 78- very much worse, n= 3, 2, 1, 4	0	99999	0	0

No statistical analyses for this end point

Secondary: Summary of CGII-P

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End point title

Summary of CGII-P

End point description

Patient Global Impression of Change score as assessed by questionnaire. [ Time Frame: 78 Weeks ] CGII-P scale is qualitative values and not quantitative. 99999 indicates both subjects (2 for CSWS) discontinued so data is not available. Only those subjects with data available at specified timepoints has been presented (represented by n=X in the category titles).

End point type

Secondary

End point timeframe

Patient Global Impression of Change score as assessed by questionnaire. [ Time Frame: 78 Weeks ]

End point values	CDKL5	CSWS	Lennox-Gastaut	PCDH19
Number of subjects analysed	7	2	8	11
Units: participants
number (not applicable)
End of Week 4-Very much improved, n= 7, 2, 8, 11	0	99999	3	1
End of Week 4-much improved, n= 7, 2, 8, 11	1	99999	2	2
End of Week 4-minimally improved, n= 7, 2, 8, 11	4	99999	3	5
End of Week 4-No change, n= 7, 2, 8, 11	2	99999	0	3
End of Week 4-minimally worse, n= 7, 2, 8, 11	0	99999	0	0
End of Week 4- much worse, n= 7, 2, 8, 11	0	99999	0	0
End of Week 4- very much worse, n= 7, 2, 8, 11	0	99999	0	0
End of Week 8-Very much improved, n= 7, 2, 8, 7	0	99999	2	0
End of Week 8-much improved, n= 7, 2, 8, 7	1	99999	2	2
End of Week 8-minimally improved, n= 7, 2, 8, 7	5	99999	3	2
End of Week 8-No change, n= 7, 2, 8, 7	0	99999	1	1
End of Week 8-minimally worse, n= 7, 2, 8, 7	1	99999	0	1
End of Week 8- much worse, n= 7, 2, 8, 7	0	99999	0	1
End of Week 8- very much worse, n= 7, 2, 8, 7	0	99999	0	0
End of Week 17-Very much improved, n= 5, 2, 6, 6	1	99999	1	1
End of Week 17-much improved, n= 5, 2, 6, 6	2	99999	1	1
End of Week 17-minimally improved, n= 5, 2, 6, 6	2	99999	3	4
End of Week 17-No change, n= 5, 2, 6, 6	0	99999	0	0
End of Week 17-minimally worse, n= 5, 2, 6, 6	0	99999	1	0
End of Week 17- much worse, n= 5, 2, 6, 6	0	99999	0	0
End of Week 17- very much worse, n= 5, 2, 6, 6	0	99999	0	0
End of Week 26-Very much improved, n= 7, 2, 7, 9	0	99999	1	2
End of Week 26-much improved, n= 7, 2, 7, 9	4	99999	1	2
End of Week 26-minimally improved, n= 7, 2, 7, 9	0	99999	3	3
End of Week 26-No change, n=7, 2, 7, 9	1	99999	1	0
End of Week 26-minimally worse, n= 7, 2, 7, 9	1	99999	0	1
End of Week 26- much worse, n= 7, 2, 7, 9	1	99999	1	1
End of Week 26- very much worse, n= 7, 2, 7, 9	0	99999	0	0
End of Week 44-Very much improved, n= 4, 2, 2, 2	0	99999	0	2
End of Week 44-much improved, n= 4, 2, 2, 2	2	99999	0	0
End of Week 44-minimally improved, n= 4, 2, 2, 2	0	99999	0	0
End of Week 44-No change, n=4, 2, 2, 2	2	99999	1	0
End of Week 44-minimally worse, n= 4, 2, 2, 2	0	99999	1	0
End of Week 44- much worse, n= 4, 2, 2, 2	0	99999	0	0
End of Week 44- very much worse, n= 4, 2, 2, 2	0	99999	0	0
End of Week 62-Very much improved, n= 4, 2, 1, 2	2	99999	0	2
End of Week 62-much improved, n= 4, 2, 1, 2	2	99999	0	0
End of Week 62-minimally improved, n= 4, 2, 1, 2	0	99999	1	0
End of Week 62-No change, n=4, 2, 1, 2	0	99999	0	0
End of Week 62-minimally worse, n= 4, 2, 1, 2	0	99999	0	0
End of Week 62- much worse, n= 4, 2, 1, 2	0	99999	0	0
End of Week 62- very much worse, n= 4, 2, 1, 2	0	99999	0	0
End of Week 78-Very much improved, n= 3, 2, 1, 4	1	99999	0	2
End of Week 78-much improved, n= 3, 2, 1, 4	2	99999	0	0
End of Week 78-minimally improved, n= 3, 2, 1, 4	0	99999	1	1
End of Week 78-No change, n=3, 2, 1, 4	0	99999	0	0
End of Week 78-minimally worse, n= 3, 2, 1, 4	0	99999	0	0
End of Week 78 much worse, n= 3, 2, 1, 4	0	99999	0	1
End of Week 78- very much worse, n= 3, 2, 1, 4	0	99999	0	0

No statistical analyses for this end point

Secondary: Number of Participants With Responder Rate of Seizure Frequency

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End point title

Number of Participants With Responder Rate of Seizure Frequency

End point description

Responder Rate in Terms of 28-day Seizure Frequency Based on the Sum of Individual Seizures and Clusters. 99999 indicates both subjects (2 for CSWS) discontinued so data is not available.

End point type

Secondary

End point timeframe

Month 3 and Week 26

End point values	CDKL5	CSWS	Lennox-Gastaut	PCDH19
Number of subjects analysed	7	2	10	11
Units: Participants
number (not applicable)
Post-baseline through Month 3 - 25% Responder	4	99999	4	6
Post-baseline through Month 3 - 50% Responder	3	99999	2	4
Post-baseline through Month 3 - 75% Responder	1	99999	0	1
Post-baseline 26-week open-label - 25% Responder	4	99999	3	5
Post-baseline 26-week open-label - 50% Responder	2	99999	1	3
Post-baseline 26-week open-label - 75% Responder	1	99999	0	1

No statistical analyses for this end point

Secondary: Mean Percentage Change of Individual Seizure-free Days

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End point title

Mean Percentage Change of Individual Seizure-free Days

End point description

Mean Percentage Change of Individual Seizure-free days per 28-day period (through 52-week OLE) period relative to baseline. 99999 indicates both subjects (2 for CSWS) discontinued so data is not available. Only those subjects with data available at specified time points has been presented (represented by n=X in the category titles).

End point type

Secondary

End point timeframe

Baseline, Day 91, Week 26, 52-week OLE through month 6, 52-week OLE Period

End point values	CDKL5	CSWS	Lennox-Gastaut	PCDH19
Number of subjects analysed	7	2	10	11
Units: Percentage Change
arithmetic mean (standard deviation)
Baseline to Day 91, n=7, 2, 10, 11	11.84 ± 18.472	99999 ± 99999	-1.12 ± 24.928	7.87 ± 17.843
Baseline to Week 26, n=7, 2, 10, 11	11.80 ± 20.968	99999 ± 99999	-2.13 ± 22.042	7.94 ± 18.016
Baseline to 52-week OLE (181 days), n=4, 2, 2, 6	21 ± 30.85	99999 ± 99999	16.35 ± 2.916	17.12 ± 27.040
Baseline to 52-week OLE period, n=4, 2, 2, 6	20.44 ± 28.788	99999 ± 99999	14.95 ± 4.897	17.02 ± 26.904

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Combined 26-week open label period and 52-week open label extension period

Adverse event reporting additional description

Overall Summary of Adverse Events (Safety Population)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.0

Reporting group title

CDKL5

Reporting group description

Reporting group title

CSWS

Reporting group description

Reporting group title

Lennox-Gastaut

Reporting group description

Reporting group title

PCDH19

Reporting group description

Serious adverse events	CDKL5	CSWS	Lennox-Gastaut	PCDH19
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 7 (14.29%)	1 / 2 (50.00%)	2 / 10 (20.00%)	3 / 11 (27.27%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Nervous system disorders
Seizure
subjects affected / exposed	0 / 7 (0.00%)	0 / 2 (0.00%)	0 / 10 (0.00%)	2 / 11 (18.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 4
Somnolence
subjects affected / exposed	0 / 7 (0.00%)	1 / 2 (50.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
General disorders and administration site conditions
Unintentional Medical Device Removal
subjects affected / exposed	1 / 7 (14.29%)	0 / 2 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic failure
subjects affected / exposed	0 / 7 (0.00%)	0 / 2 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 7 (0.00%)	0 / 2 (0.00%)	0 / 10 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Psychiatric disorders
Mental status changes
subjects affected / exposed	0 / 7 (0.00%)	1 / 2 (50.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	0 / 7 (0.00%)	0 / 2 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
Pneumonia Viral
subjects affected / exposed	0 / 7 (0.00%)	0 / 2 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0

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

Non-serious adverse events	CDKL5	CSWS	Lennox-Gastaut	PCDH19
Total subjects affected by non serious adverse events
subjects affected / exposed	7 / 7 (100.00%)	1 / 2 (50.00%)	7 / 10 (70.00%)	11 / 11 (100.00%)
Investigations
Weight decreased
subjects affected / exposed	1 / 7 (14.29%)	0 / 2 (0.00%)	0 / 10 (0.00%)	1 / 11 (9.09%)
occurrences all number	1	0	0	1
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 7 (14.29%)	0 / 2 (0.00%)	0 / 10 (0.00%)	1 / 11 (9.09%)
occurrences all number	1	0	0	1
Fall
subjects affected / exposed	0 / 7 (0.00%)	0 / 2 (0.00%)	0 / 10 (0.00%)	3 / 11 (27.27%)
occurrences all number	0	0	0	3
Surgical and medical procedures
Gastrostomy
subjects affected / exposed	2 / 7 (28.57%)	0 / 2 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)
occurrences all number	2	0	0	0
Nervous system disorders
Ataxia
subjects affected / exposed	0 / 7 (0.00%)	0 / 2 (0.00%)	0 / 10 (0.00%)	2 / 11 (18.18%)
occurrences all number	0	0	0	2
Balance Disorder
subjects affected / exposed	0 / 7 (0.00%)	0 / 2 (0.00%)	1 / 10 (10.00%)	1 / 11 (9.09%)
occurrences all number	0	0	1	1
Dizziness
subjects affected / exposed	0 / 7 (0.00%)	1 / 2 (50.00%)	1 / 10 (10.00%)	1 / 11 (9.09%)
occurrences all number	0	2	1	1
Headache
subjects affected / exposed	1 / 7 (14.29%)	0 / 2 (0.00%)	0 / 10 (0.00%)	4 / 11 (36.36%)
occurrences all number	1	0	0	4
Hypersomnia
subjects affected / exposed	0 / 7 (0.00%)	0 / 2 (0.00%)	2 / 10 (20.00%)	0 / 11 (0.00%)
occurrences all number	0	0	2	0
Sedation
subjects affected / exposed	0 / 7 (0.00%)	0 / 2 (0.00%)	0 / 10 (0.00%)	2 / 11 (18.18%)
occurrences all number	0	0	0	2
Seizure
subjects affected / exposed	1 / 7 (14.29%)	0 / 2 (0.00%)	2 / 10 (20.00%)	4 / 11 (36.36%)
occurrences all number	1	0	4	6
Somnolence
subjects affected / exposed	0 / 7 (0.00%)	1 / 2 (50.00%)	2 / 10 (20.00%)	6 / 11 (54.55%)
occurrences all number	0	1	2	6
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 7 (0.00%)	0 / 2 (0.00%)	0 / 10 (0.00%)	4 / 11 (36.36%)
occurrences all number	0	0	0	4
Pyrexia
subjects affected / exposed	5 / 7 (71.43%)	0 / 2 (0.00%)	1 / 10 (10.00%)	7 / 11 (63.64%)
occurrences all number	22	0	2	16
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	0 / 7 (0.00%)	0 / 2 (0.00%)	0 / 10 (0.00%)	2 / 11 (18.18%)
occurrences all number	0	0	0	2
Vomiting
subjects affected / exposed	3 / 7 (42.86%)	1 / 2 (50.00%)	1 / 10 (10.00%)	3 / 11 (27.27%)
occurrences all number	9	1	3	3
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 7 (0.00%)	0 / 2 (0.00%)	0 / 10 (0.00%)	2 / 11 (18.18%)
occurrences all number	0	0	0	2
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	1 / 7 (14.29%)	0 / 2 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)
occurrences all number	1	0	1	0
Rash
subjects affected / exposed	1 / 7 (14.29%)	0 / 2 (0.00%)	1 / 10 (10.00%)	1 / 11 (9.09%)
occurrences all number	1	0	1	1
Psychiatric disorders
Abnormal behavior
subjects affected / exposed	0 / 7 (0.00%)	0 / 2 (0.00%)	1 / 10 (10.00%)	1 / 11 (9.09%)
occurrences all number	0	0	1	2
Emotional disorder
subjects affected / exposed	0 / 7 (0.00%)	0 / 2 (0.00%)	0 / 10 (0.00%)	2 / 11 (18.18%)
occurrences all number	0	0	0	2
Restlessness
subjects affected / exposed	0 / 7 (0.00%)	0 / 2 (0.00%)	0 / 10 (0.00%)	2 / 11 (18.18%)
occurrences all number	0	0	0	2
Renal and urinary disorders
Enuresis
subjects affected / exposed	0 / 7 (0.00%)	0 / 2 (0.00%)	0 / 10 (0.00%)	2 / 11 (18.18%)
occurrences all number	0	0	0	2
Infections and infestations
Fungal Infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 2 (0.00%)	2 / 10 (20.00%)	0 / 11 (0.00%)
occurrences all number	0	0	2	0
Influenza
subjects affected / exposed	2 / 7 (28.57%)	0 / 2 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)
occurrences all number	5	0	1	0
Nasopharyngitis
subjects affected / exposed	2 / 7 (28.57%)	0 / 2 (0.00%)	0 / 10 (0.00%)	1 / 11 (9.09%)
occurrences all number	8	0	0	2
Otitis media
subjects affected / exposed	0 / 7 (0.00%)	0 / 2 (0.00%)	0 / 10 (0.00%)	2 / 11 (18.18%)
occurrences all number	0	0	0	2
Pneumonia
subjects affected / exposed	1 / 7 (14.29%)	0 / 2 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)
occurrences all number	1	0	2	0
Rhinitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 2 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)
occurrences all number	3	0	1	0
Sinusitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 2 (50.00%)	0 / 10 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	1	0	1
Upper respiratory tract infection
subjects affected / exposed	3 / 7 (42.86%)	0 / 2 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)
occurrences all number	3	0	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 7 (0.00%)	0 / 2 (0.00%)	0 / 10 (0.00%)	3 / 11 (27.27%)
occurrences all number	0	0	0	4

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Were there any global substantial amendments to the protocol? Yes

10 Dec 2014

Amendment 1: Minor edits and clarifications.

12 Jan 2015

Amendment 2: Minor edits and clarifications. Statement added to Section 9.5.4 regarding the blood collection to measure allopregnanolone and related neurosteroids at Visits 2 and 4.

23 Jan 2015

Amendment 3: Dosing regimen revised. A visit at Week 2 and procedures for unscheduled visits added. Collection of blood for Liver Function Test and other laboratory assessments added at the Week 26 visit. Guidance on missed doses for the capsules and suspension clarified.

08 Jun 2015

Amendment 4: Collection of electroencephalograms (EEG’s) added to Visits 2, 5 and 7.

15 Jul 2015

Amendment 5: Addition of cyclin-dependent kinase-like 5 (CDKL5) Deficiency Disorder (CDD) and Dravet Syndrome Subjects. Background section updated. Seizure criteria updated for CDD and Dravet Syndrome subjects. Contraindicated medications for Dravet patients added. Male children became eligible for inclusion. Age increased from 2 to 10 years to 2 to 18 years age. Pregnancy testing was added for women of childbearing potential (WCBP). Tanner Scale score added under Physical Exam.

30 Sep 2015

Amendment 5.1 Local Amendment: Stiripentol was added as an Exclusion Criteria in Section 9.3.3 and to the list in Appendix 3 of “Prohibited Strong and Moderate CYP 3A4 Inhibitors”.

08 Apr 2016

Amendment 6.0 Local Amendment: Inclusion of other genetic epilepsies added. These included, but were not limited to children with PCDH19 mutation, CDD, Dravet Syndrome and other epileptic syndromes such as LGS, CSWS, and other potential genetic or clinical conditions with or without corresponding genetic condition (referred as genetic epilepsies) in an open-label proof-of concept study. Inclusion of additional EEG assessments. Addition of the Visual Analogue Scale (VAS)-Targeted Behavior at baseline, Visits 5, Visit 7, Visit 9 and Visit 10. Stiripentol (Italy specific) added as an Exclusion Criteria in Section 9.3.3 and added to the list in Appendix 3 of “Prohibited Strong and Moderate CYP 3A4 Inhibitors.”

14 Sep 2016

Amendment 7: Sponsor address and Sponsor Medical Representative updated. Minor editorial changes made. Removed “and other potential genetic or clinical conditions with or without corresponding genetic condition (referred to as genetic epilepsies) or similar throughout the clinical study protocol. Primary and Secondary Efficacy evaluations modified. Columbia-Suicide Severity Rating Scale (C-SSRS) added to Safety evaluations Statistical Methods clarified; EEG added. Background on Ganaxolone – double-blind, Phase 3 study information added and relevant sections summarizing the Phase 2 data modified. Inclusion Criteria 2 and 3 revised. Addition of a 24-hour continuous EEG at baseline, Visit 4 and Visit 7 for the Continuous Spike Wave in Sleep (CSWS) subjects. Intent-to-treat (ITT) population changed to modified intent to treat (MITT) population throughout the clinical study protocol. Analysis of Primary and Secondary Efficacy Variables modified. Interim Analysis text added. Serious adverse events (SAE) reporting medical telephone number changed.

22 Jun 2017

Amendment 8: Synopsis-Study Population and Main Criteria for Inclusion/Exclusion revised Inclusion criteria #10 revised. Exclusion criteria #6 and #11 revised • Section 9.5.5.11 Visit 11 (Post drug follow-up visit) revised. Section 10.5.3.1 SAE Reporting – administrative change made.

24 Aug 2017

Amendment 8.1 Local Amendment: Minor editorial and format changes made. Section 9.3.4.2 Early Termination Procedures revised. Section 9.5.3 Safety Assessments revised. Section 9.5.4.1 Laboratory Samples revised. Section 9.5.4.2 Efficacy Assessments revised. Section 9.5.4.3 VAS revised. Section 9.5.5.10 Visit 10 (End of Week 78 ±Days, Final Investigative Visit) revised. Section 9.5.5.12 Visit 12-Visit 97 added. Section 9.5.5.13 Visit 98 added. Section 9.5.5.14 Visit 99 added. Section 13.3 Appendix 2 and Appendix 3, minor deletion/addition; footnote 7 added. Section 13.4 Appendix 4 added.

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.

CSWS cohort was not included in efficacy summaries as only 2 subjects were enrolled in cohort; however, cohort was included in the subject data listings. Overall number of participants affected is associated with all TEAEs and not >-5%.

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Clinical Trial Results:
A Multicenter, Open-Label Proof-of-Concept Trial of Ganaxolone in Children with PCDH19 Female Pediatric Epilepsy

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Primary: Summary of 28-day Seizure Frequency for Sum of Individual Seizures and Clusters for 52-week OLE Period (Mean Percent Change & Standard Deviation)

Primary: Summary of 28-day Seizure Frequency for Sum of Individual Seizures and Clusters for 52-week OLE Period (Mean Percent Change & Standard Deviation)

Primary: Summary of 28-day Seizure Frequency for Sum of Individual Seizures and Clusters Through 52-week OLE (Median Percent Change)

Primary: Summary of 28-day Seizure Frequency for Sum of Individual Seizures and Clusters Through 52-week OLE (Median Percent Change)

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Secondary: Summary of CGII-P

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Secondary: Number of Participants With Responder Rate of Seizure Frequency

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Clinical trials

Clinical Trial Results: A Multicenter, Open-Label Proof-of-Concept Trial of Ganaxolone in Children with PCDH19 Female Pediatric Epilepsy

Trial information

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Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Summary of 28-day Seizure Frequency for Sum of Individual Seizures and Clusters for 52-week OLE Period (Mean Percent Change & Standard Deviation)

Primary: Summary of 28-day Seizure Frequency for Sum of Individual Seizures and Clusters for 52-week OLE Period (Mean Percent Change & Standard Deviation)

Primary: Summary of 28-day Seizure Frequency for Sum of Individual Seizures and Clusters Through 52-week OLE (Median Percent Change)

Primary: Summary of 28-day Seizure Frequency for Sum of Individual Seizures and Clusters Through 52-week OLE (Median Percent Change)

Secondary: Summary of CGII-C

Secondary: Summary of CGII-C

Secondary: Summary of CGII-P

Secondary: Summary of CGII-P

Secondary: Number of Participants With Responder Rate of Seizure Frequency

Secondary: Number of Participants With Responder Rate of Seizure Frequency

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Secondary: Mean Percentage Change of Individual Seizure-free Days

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Substantial protocol amendments (globally)

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Limitations and caveats

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Clinical Trial Results:
A Multicenter, Open-Label Proof-of-Concept Trial of Ganaxolone in Children with PCDH19 Female Pediatric Epilepsy