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Clinical Trial Results:
A Multicentre, Open-Label, Long-Term, Safety and Tolerability Study of Retigabine Immediate Release (IR) in Adults with Partial-Onset Seizures (Extension of Study RGB113905)

Summary
EudraCT number	2010-022777-34
Trial protocol	DE NL IT ES BG BE PL
Global end of trial date	13 Sep 2017

Results information
Results version number	v2
This version publication date	11 Feb 2018
First version publication date	22 Dec 2017
Other versions	v1 , v3
Version creation reason

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

113413

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline

Sponsor organisation address

980 Great West Road, Brentford, Middlesex, United Kingdom,

Public contact

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

Scientific contact

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

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

11 Apr 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

14 Dec 2016

Global end of trial reached?

Yes

Global end of trial date

13 Sep 2017

Was the trial ended prematurely?

Main objective of the trial

To assess long-term safety and tolerability of flexibly dosed retigabine immediate release (IR) as adjunctive therapy in adults with partial-onset seizures (POS) who completed open-label flexible dose Study RGB113905.

Protection of trial subjects

Background therapy

Evidence for comparator

Actual start date of recruitment

21 Feb 2011

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

6 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 1

Country: Number of subjects enrolled

Bulgaria: 5

Country: Number of subjects enrolled

France: 2

Country: Number of subjects enrolled

Germany: 1

Country: Number of subjects enrolled

Italy: 19

Country: Number of subjects enrolled

Netherlands: 1

Country: Number of subjects enrolled

Poland: 3

Country: Number of subjects enrolled

Russian Federation: 42

Country: Number of subjects enrolled

Thailand: 8

Country: Number of subjects enrolled

Ukraine: 16

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

Participants with partial-onset seizures (POS) who successfully completed the 20 weeks of treatment in parent study NCT01336621 were recruited in this open-label extension (OLE) study. The data from the treatment phase are presented here; the data from the Safety Follow Up Continuation phase will be added once the study has been completed.

Screening details

Screening was performed on the same day as the final visit of the parent study NCT01336621. A total of 98 participants completed the parent study and opted to enter into this study. All participants received at least one dose of retigabine immediate release (IR) tablets.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Retigabine IR

Arm description

Eligible participants continued on the same maintenance dose of retigabine IR and the concurrent anti-epileptic drugs (AEDs) as they were taking at Visit 7 (Week 20) in the parent study NCT01336621. After the first week of the study, the dose of retigabine IR could be increased or decreased by 50-150 milligrams per day (mg/day) on a weekly basis. The overall daily dose of retigabine IR was to be maintained between 300 mg/day (minimum) and 1200 mg/day (maximum).

Arm type

Experimental

Investigational medicinal product name

Retigabine immediate release (IR)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Five strengths of retigabine IR including 50 mg, 100 mg, 200 mg, 300 mg and 400 mg tablets were provided. Participants entering RTG113413 from the parent study continued on the same maintenance dose of retigabine IR as per parent study. The dose was increased in steps of 50 mg to 150 mg/day on a weekly basis. The overall daily dose of retigabine IR was maintained between 300 mg/day (minimum) and 1200 mg/day (maximum).

Number of subjects in period 1	Retigabine IR
Started	98
Completed	0
Not completed	98
Consent withdrawn by subject	28
Physician decision	3
Other: Reached stopping criteria	22
Adverse event, non-fatal	17
Other: study terminated	11
Other: lost to follow up	2
Lack of efficacy	3
Protocol deviation	12

Baseline characteristics

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Reporting group title

Retigabine IR

Reporting group description

Reporting group values	Retigabine IR	Total
Number of subjects	98
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	39.2 ( 13.19 )	-
Gender categorical
Units: Subjects
Female	48	48
Male	50	50
Race/Ethnicity, Customized
Units: Subjects
Asian: South East Asian Heritage	8	8
White- White/Caucasian/ European Heritage	90	90

End points

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Reporting group title

Retigabine IR

Reporting group description

Primary: Number of participants with treatment emergent adverse events (TEAEs) and serious AEs (TESAEs)

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End point title

Number of participants with treatment emergent adverse events (TEAEs) and serious AEs (TESAEs) ^[1]

End point description

An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth defect or is associated with liver injury or impaired liver function. TEAE refers to an AE for which the onset was on or after the date of the first retigabine dose in this study and on or before 30 days after the last retigabine dose date. AEs that started in the parent study that increased in severity during this study were also considered treatment-emergent. The analysis was performed on Safety Population, which included participants who took at least one dose of study medication after they had enrolled into this OLE study.

End point type

Primary

End point timeframe

Up to 5.8 years

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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[2]
Units: Participants
Any TEAE	67
Any TESAE	4

Notes
[2] - Safety Population

No statistical analyses for this end point

Primary: Number of participants withdrawn due to TEAEs

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End point title

Number of participants withdrawn due to TEAEs ^[3]

End point description

End point type

Primary

End point timeframe

Up to 5.8 years

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[4]
Units: Participants
Participants	16

Notes
[4] - Safety Population

No statistical analyses for this end point

Primary: Number of participants with retinal pigmentary abnormalities

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End point title

Number of participants with retinal pigmentary abnormalities ^[5]

End point description

Number of participants with abnormal findings after eye examination were evaluated. Only retinal pigmentary abnormalities detected on-treatment with retigabine were presented. Retinal pigmentary abnormalities included abnormalities in the macula, peripheral retina and unspecified location. Only those participants with >=1 ophthalmology exam on or before last dose of RTG are presented.

End point type

Primary

End point timeframe

Up to 5.8 years

Notes
[5] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	53 ^[6]
Units: Participants
Participants	8

Notes
[6] - Safety Population

No statistical analyses for this end point

Primary: Number of participants with pigmentation of non-retinal ocular tissue(s)

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End point title

Number of participants with pigmentation of non-retinal ocular tissue(s) ^[7]

End point description

Number of participants with abnormal findings after eye examination were evaluated. Pigmentation of non-retinal ocular tissue (s) detected on-treatment with retigabine were presented. Non-retinal pigmentary abnormalities included abnormalities in the sclera and/ or conjunctiva, cornea, iris and lens. Only those participants with >=1 ophthalmology exam on or before last dose of RTG are presented.

End point type

Primary

End point timeframe

Up to 5.8 years

Notes
[7] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	53 ^[8]
Units: Participants
Participants	15

Notes
[8] - Safety Population

No statistical analyses for this end point

Primary: Number of participants with abnormal discoloration of skin

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End point title

Number of participants with abnormal discoloration of skin ^[9]

End point description

Number of participants with Dermatologist-Confirmed abnormal discoloration of skin including skin around the eyes and eyelids, lips, nails, or mucosa were evaluated. Only abnormalities occurring on-treatment with retigabine were presented. Only those participants who had at least one skin exam by the investigator or dermatologist on or before the last dose of RTG or dermatologist-confirmed discoloration with start date on or before the date of last dose of RTG are presented.

End point type

Primary

End point timeframe

Up to 5.8 years

Notes
[9] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	58 ^[10]
Units: Participants
Any abnormal discoloration	11
Discoloration of skin	5
Discoloration of lips	3
Discoloration of nails	10
Discoloration of mucosa	9

Notes
[10] - Safety Population

No statistical analyses for this end point

Primary: Number of participants with a clinically significant decrease in visual acuity from initial examination

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End point title

Number of participants with a clinically significant decrease in visual acuity from initial examination ^[11]

End point description

Number of participants with a clinically significant decrease in visual acuity from initial examination were evaluated. Only abnormalities occurring on-treatment with retigabine were presented. Only those participants with both initial and at least 1 follow-up exam while on RTG treatment are presented.

End point type

Primary

End point timeframe

Up to 5.8 years

Notes
[11] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	48 ^[12]
Units: Participants
Participants	3

Notes
[12] - Safety Population

No statistical analyses for this end point

Primary: Number of participants with decrease in confrontational visual field from initial examination

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End point title

Number of participants with decrease in confrontational visual field from initial examination ^[13]

End point description

Number of participants with a clinically significant decrease in confrontational visual field from initial examination were evaluated. Only abnormalities occurring on-treatment with retigabine were presented. Only those subjects with both initial and at least 1 follow-up exam while on RTG treatment are presented.

End point type

Primary

End point timeframe

Up to 5.8 years

Notes
[13] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	48 ^[14]
Units: Participants
Participants	1

Notes
[14] - Safety Population

No statistical analyses for this end point

Primary: Number of participants with potential clinical concern (PCC) values of change from Baseline in vital signs and weight

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End point title

Number of participants with potential clinical concern (PCC) values of change from Baseline in vital signs and weight ^[15]

End point description

Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were measured after at least 5 minutes of rest. Body weight was measured without shoes and wearing light clothing. Baseline assessments in this OLE study were defined by and taken directly from the Baseline assessments in the parent study NCT01336621. Change from Baseline was calculated by subtracting the Baseline value from the post-baseline value. Increase or decrease of >=20 in SBP, increase or decrease of >=15 in DBP and HR were considered as PCC values. Number of participants with PCC values of vital signs for any visit post-Baseline are presented.

End point type

Primary

End point timeframe

Up to 5.8 years

Notes
[15] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[16]
Units: Participants
DBP; decrease of >=15	15
DBP; increase of >=15	7
HR; decrease of >=15	15
HR; increase of >=15	18
SBP; decrease of >=20	18
SBP; increase of >=20	8
Weight; decrease of >=7 percent	10
Weight; increase of >=7 percent	32

Notes
[16] - Safety Population

No statistical analyses for this end point

Primary: Change from Baseline in electrocardiogram (ECG) parameter including HR

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End point title

Change from Baseline in electrocardiogram (ECG) parameter including HR ^[17]

End point description

Single measurements of 12-lead ECG were obtained in supine position after at least 10 minutes of rest using an ECG machine to measure HR. Baseline was defined by and taken directly from the Baseline assessments in the parent study NCT01336621. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

End point type

Primary

End point timeframe

Baseline and up to 5.8 years

Notes
[17] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[18]
Units: Beats per minute (bpm)
arithmetic mean (standard deviation)
Visit 1 (Screening); n= 89	-2.2 ( 10.54 )
Visit 2 (Week 13); n= 90	-0.6 ( 9.77 )
Visit 3 (Week 26); n= 80	-1.5 ( 9.21 )
Visit 4 (Week 39); n= 71	-1.7 ( 8.72 )
Visit 5 (Week 52); n= 67	-0.6 ( 10.30 )
Visit 6 (Week 69); n= 63	-0.2 ( 9.96 )
Visit 7 (Week 86); n= 56	1.6 ( 8.89 )
Visit 8 (Week 104); n= 42	-1.8 ( 10.30 )
Visit 9 (Week 121); n= 38	1.7 ( 11.01 )
Visit 10 (Week 138); n= 37	1.6 ( 12.17 )
Visit 11 (Week 156); n= 30	1.1 ( 10.23 )
Visit 12 (Week 173); n= 24	-0.8 ( 13.43 )
Visit 13 (Week 190); n= 19	2.7 ( 11.29 )
Visit 14 (Week 208); n= 10	5.6 ( 10.41 )
Visit 15 (Week 225); n= 5	-0.2 ( 8.04 )
Visit 16 (Week 242); n= 4	-4.3 ( 13.30 )
Visit 17 (Week 260); n= 4	-7.3 ( 6.95 )
Visit 18 (Week 277); n= 2	2.5 ( 9.19 )
Withdrawal visit; n= 83	-1.8 ( 11.49 )
Follow up visit; n= 59	-1.1 ( 11.95 )

Notes
[18] - Safety Population

No statistical analyses for this end point

Primary: Change from Baseline in ECG parameter including PR interval, QRS duration, uncorrected QT interval, corrected QT by Bazett's formula (QTcB), corrected QT by Fridericia's formula (QTcF) and RR interval

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End point title

Change from Baseline in ECG parameter including PR interval, QRS duration, uncorrected QT interval, corrected QT by Bazett's formula (QTcB), corrected QT by Fridericia's formula (QTcF) and RR interval ^[19]

End point description

Single measurements of 12-lead ECG were obtained in supine position after at least 10 minutes of rest using an ECG machine to measure parameters including PR interval, QRS duration, uncorrected QT interval, QTcB, QTcF and RR interval. Baseline was defined by and taken directly from the Baseline assessments in the parent study NCT01336621. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

End point type

Primary

End point timeframe

Baseline and up to 5.8 years

Notes
[19] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[20]
Units: Milliseconds (msec)
arithmetic mean (standard deviation)
PR interval; Visit 1 (Screening); n= 86	2.4 ( 13.11 )
PR interval; Visit 2 (Week 13); n= 88	1.3 ( 15.42 )
PR interval; Visit 3 (Week 26); n= 78	3.2 ( 12.99 )
PR interval; Visit 4 (Week 39); n= 70	1.2 ( 13.25 )
PR interval; visit 5 (Week 52); n= 66	-0.2 ( 13.17 )
PR interval; Visit 6 (Week 69); n= 62	1.3 ( 13.93 )
PR interval; Visit 7 (Week 86); n= 54	-0.7 ( 12.58 )
PR interval; Visit 8 (Week 104); n= 42	3.1 ( 10.85 )
PR interval; Visit 9 (Week 121); n= 38	-1.1 ( 12.79 )
PR interval; Visit 10 (Week 138); n= 37	1.2 ( 15.13 )
PR interval; Visit 11 (Week 156); n= 30	-0.5 ( 13.50 )
PR interval; Visit 12 (Week 173); n= 24	4.8 ( 11.89 )
PR interval; Visit 13 (week 190); n= 19	-2.1 ( 10.19 )
PR interval; Visit 14 (Week 208); n= 10	7.8 ( 15.03 )
PR interval; Visit 15 (Week 225); n= 5	8.4 ( 7.23 )
PR interval; Visit 16 (Week 242); n= 4	-3.0 ( 8.04 )
PR interval; Visit 17 (Week 260); n= 4	9.3 ( 11.09 )
PR interval; Visit 18 (Week 277); n= 2	-5.5 ( 7.78 )
PR interval; Withdrawal visit; n= 81	3.6 ( 13.86 )
PR interval; follow up visit; n= 57	3.7 ( 12.43 )
QRS duration; Visit 1 (Screening); n= 88	-0.1 ( 6.37 )
QRS duration; Visit 2 (Week 13); n= 89	0.2 ( 6.99 )
QRS duration; Visit 3 (Week 26); n= 80	1.1 ( 8.77 )
QRS duration; Visit 4 (Week 39); n= 71	1.1 ( 7.10 )
QRS duration; Visit 5 (Week 52); n= 67	0.9 ( 9.81 )
QRS duration; Visit 6 (Week 69); n= 63	1.9 ( 8.56 )
QRS duration; Visit 7 (Week 86); n= 55	-0.4 ( 7.20 )
QRS duration; Visit 8 (Week 104); n= 42	0.1 ( 6.40 )
QRS duration; Visit 9 (Week 121); n= 38	-0.7 ( 7.79 )
QRS duration; Visit 10 (Week 138); n= 37	-2.0 ( 7.85 )
QRS duration; Visit 11 (Week 156); n= 30	-3.3 ( 9.54 )
QRS duration; Visit 12 (Week 173); n= 24	-1.3 ( 9.04 )
QRS duration; Visit 13 (Week 190); n= 19	-4.9 ( 8.80 )
QRS duration; Visit 14 (Week 208); n= 10	-6.1 ( 6.34 )
QRS duration; Visit 15 (Week 225); n= 5	-2.9 ( 3.44 )
QRS duration; Visit 16 (Week 242); n= 4	-5.9 ( 9.58 )
QRS duration; Visit 17 (Week 260); n= 4	-7.8 ( 5.19 )
QRS duration; Visit 18 (Week 277); n= 2	-4.5 ( 2.12 )
QRS duration; withdrawal visit; n= 82	-2.5 ( 9.49 )
QRS duration; follow up visit; n= 59	0.0 ( 11.90 )
Uncorrected QT interval;Visit 1 (Screening); n= 85	10.1 ( 26.19 )
Uncorrected QT interval; Visit 2 (Week 13); n= 88	4.9 ( 23.43 )
Uncorrected QT interval; Visit 3 (Week 26); n= 78	7.9 ( 23.44 )
Uncorrected QT interval; Visit 4 (Week 39); n= 69	9.3 ( 23.77 )
Uncorrected QT interval; Visit 5 (Week 52); n= 65	6.6 ( 25.18 )
Uncorrected QT interval; Visit 6 (Week 69); n= 61	7.4 ( 26.39 )
Uncorrected QT interval; Visit 7 (Week 86); n= 53	-1.6 ( 23.81 )
Uncorrected QT interval; Visit 8 (Week 104); n= 41	6.0 ( 26.77 )
Uncorrected QT interval; Visit 9 (Week 121); n= 37	-0.5 ( 24.52 )
Uncorrected QT interval; Visit 10 (Week 138);n= 36	-8.7 ( 33.60 )
Uncorrected QT interval; Visit 11 (Week 156);n= 29	-4.9 ( 33.01 )
Uncorrected QT interval; Visit 12 (Week 173);n= 23	4.7 ( 25.06 )
Uncorrected QT interval; Visit 13 (Week 190);n= 19	-1.9 ( 26.01 )
Uncorrected QT interval; Visit 14 (Week 208);n= 10	-17.0 ( 27.93 )
Uncorrected QT interval; Visit 15 (Week 225);n= 5	-1.5 ( 5.68 )
Uncorrected QT interval; Visit 16 (Week 242);n= 4	3.1 ( 26.90 )
Uncorrected QT interval; Visit 17 (Week 260);n= 4	17.5 ( 36.08 )
Uncorrected QT interval; Visit 18 (Week 277);n= 2	-3.5 ( 36.06 )
Uncorrected QT interval; withdrawal visit; n= 80	5.2 ( 29.01 )
Uncorrected QT interval; follow up visit; n= 56	2.7 ( 28.41 )
QTcB; Visit 1 (Screening); n= 85	5.0 ( 17.35 )
QTcB; Visit 2 (Week 13); n= 88	3.2 ( 18.52 )
QTcB; Visit 3 (Week 26); n= 78	4.0 ( 16.48 )
QTcB; Visit 4 (Week 39); n= 69	6.0 ( 17.27 )
QTcB; Visit 5 (Week 52); n= 65	5.8 ( 17.14 )
QTcB; Visit 6 (Week 69); n= 61	6.8 ( 15.01 )
QTcB; Visit 7 (Week 86); n= 53	4.3 ( 15.71 )
QTcB; Visit 8 (Week 104); n= 41	2.5 ( 20.70 )
QTcB; Visit 9 (Week 121); n= 37	4.9 ( 16.01 )
QTcB; Visit 10 (Week 138); n= 36	-2.8 ( 16.46 )
QTcB; Visit 11 (Week 156); n= 29	-0.3 ( 19.63 )
QTcB; Visit 12 (Week 173); n= 23	4.2 ( 24.12 )
QTcB; Visit 13 (Week 190); n= 19	3.9 ( 20.16 )
QTcB; Visit 14 (Week 208); n= 10	-1.6 ( 14.91 )
QTcB; Visit 15 (Week 225); n= 5	-1.9 ( 18.26 )
QTcB; Visit 16 (Week 242); n= 4	-9.8 ( 15.09 )
QTcB; Visit 17 (Week 260); n= 4	-2.0 ( 27.12 )
QTcB; Visit 18 (Week 277); n= 2	4.5 ( 17.68 )
QTcB; withdrawal visit; n= 80	-0.7 ( 20.78 )
QTcB; follow up visit; n= 56	-1.0 ( 17.84 )
QTcF; Visit 1 (Screening); n= 85	6.8 ( 16.11 )
QTcF; Visit 2 (Week 13); n= 88	3.7 ( 15.74 )
QTcF; Visit 3 (Week 26); n= 78	5.4 ( 15.01 )
QTcF; Visit 4 (Week 39); n= 69	7.1 ( 16.58 )
QTcF; Visit 5 (Week 52); n= 65	6.1 ( 14.92 )
QTcF; Visit 6 (Week 69); n= 61	7.1 ( 14.47 )
QTcF; Visit 7 (Week 86); n= 53	2.3 ( 16.04 )
QTcF; Visit 8 (Week 104); n= 41	3.7 ( 19.31 )
QTcF; Visit 9 (Week 121); n= 37	3.0 ( 12.90 )
QTcF; Visit 10 (Week 138); n= 36	-4.8 ( 18.22 )
QTcF; Visit 11 (Week 156); n= 29	-1.8 ( 21.86 )
QTcF; Visit 12 (Week 173); n= 23	4.6 ( 17.51 )
QTcF; Visit 13 (Week 190); n= 19	1.9 ( 17.47 )
QTcF; Visit 14 (Week 208); n= 10	-7.0 ( 14.99 )
QTcF; Visit 15 (Week 225); n= 5	-1.6 ( 10.53 )
QTcF; Visit 16 (Week 242); n= 4	-5.4 ( 8.96 )
QTcF; Visit 17 (Week 260); n= 4	5.3 ( 29.75 )
QTcF; Visit 18 (Week 277); n= 2	2.0 ( 24.04 )
QTcF; withdrawal visit; n= 80	1.3 ( 18.24 )
QTcF; follow up visit; n= 56	0.3 ( 15.49 )
RR interval; visit 1 (Screening); n= 89	27.9 ( 120.57 )
RR interval; visit 2 (Week 13); n= 90	12.2 ( 115.82 )
RR interval; visit 3 (Week 26); n= 80	20.5 ( 110.48 )
RR interval; visit 4 (Week 39); n= 71	22.4 ( 107.77 )
RR interval; visit 5 (Week 52); n= 67	10.3 ( 128.05 )
RR interval; visit 6 (Week 69); n= 63	6.2 ( 127.01 )
RR interval; visit 7 (Week 86); n= 56	-18.5 ( 102.45 )
RR interval; visit 8 (Week 104); n= 42	23.7 ( 121.17 )
RR interval; visit 9 (Week 121); n= 38	-17.5 ( 134.18 )
RR interval; visit 10 (Week 138); n= 37	-19.6 ( 145.64 )
RR interval; visit 11 (Week 156); n= 30	-16.0 ( 120.50 )
RR interval; visit 12 (Week 173); n= 24	12.9 ( 163.66 )
RR interval; visit 13 (Week 190); n= 19	-19.5 ( 138.03 )
RR interval; visit 14 (Week 208); n= 10	-70.7 ( 130.51 )
RR interval; visit 15 (Week 225); n= 5	-2.8 ( 108.30 )
RR interval; visit 16 (Week 242); n= 4	56.6 ( 165.75 )
RR interval; visit 17 (Week 260); n= 4	83.5 ( 91.72 )
RR interval; visit 18 (Week 277); n= 2	-30.0 ( 86.27 )
RR interval; withdrawal visit; n= 83	29.1 ( 152.19 )
RR interval; follow up visit; n= 59	15.9 ( 150.13 )

Notes
[20] - Safety Population

No statistical analyses for this end point

Primary: Number of participants with clinical chemistry parameters of PCC

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End point title

Number of participants with clinical chemistry parameters of PCC ^[21]

End point description

Number of participants with chemistry parameters of PCC at 'any visit post-Baseline' are presented. Chemistry parameters for which PCC values were identified were alanine aminotransferase (ALT) (if value >=3 * upper limit of normal [ULN]), alkaline phosphatase (alk.phosphatase) (if value >=3*ULN), aspartate aminotransferase (AST) (if value >=3*ULN), calcium (if value <=1.8962 or >=2.8692), carbon-di-oxide (CO2) (if value <=18 or >=36), chloride (if value <=92 or >=112), creatine kinase (if value >=3*ULN), direct bilirubin (if value >=1.5*ULN), glucose (if value <=2.7755 or >=11.102), lactate dehydrogenase (LD) (if value >=3*ULN), magnesium (if value <0.36 or >2.50), potassium (if value <=3.0 or >=6.0), sodium (if value <=127 or >=153), total bilirubin (if value >=1.5*ULN), total protein (if value <45 or >100), blood urea nitrogen (BUN) (if value >=14.28). Only those participants with data available at specific time points were analyzed (represented by n=X in the category titles).

End point type

Primary

End point timeframe

Up to 5.8 years

Notes
[21] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[22]
Units: Participants
ALT; high; n= 98	2
Alk.phosphatase; high; n= 98	0
AST; high; n= 98	1
Calcium; high; n= 98	0
Calcium; low; n= 98	0
CO2 content/bicarbonate; high; n= 98	0
CO2 content/bicrbonate; low; n= 98	10
Chloride; high; n= 98	6
Chloride; low; n= 98	2
Creatine kinase; high; n= 98	6
Creatinine; high; n= 98	0
Direct bilirubin; high; n= 98	0
Glucose; high; n= 98	3
Glucose; low; n= 98	1
LD ; high; n= 98	1
Magnesium; high; n= 98	0
Magnesium; low; n= 98	0
Potassium; high; n= 98	1
Potassium; low; n= 98	0
Sodium; high; n= 91	0
Sodium; low; n= 91	2
Total bilirubin; high; n= 98	1
Total protein; high; n= 98	0
Total protein; low; n= 98	0
BUN; high; n= 91	0

Notes
[22] - Safety Population

No statistical analyses for this end point

Primary: Number of participants with hematology parameters of PCC

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End point title

Number of participants with hematology parameters of PCC ^[23]

End point description

Blood samples were collected from participants to evaluate hematology parameters. Number of participants with clinical hematology parameters of PCC at 'any visit post-Baseline' are presented. Hematology parameters for which PCC values were identified were eosinophils (if value is >0.8), hematocrit (if value is <=0.32 for males and <=0.28 for females), platelet count (if value is <=100 or >=550), total neutrophils (if value is <=1.8), white blood cells (WBC) (if value is <=2.8 or >=16). Only those participants with data available at specific time points were analyzed (represented by n=X in the category titles).

End point type

Primary

End point timeframe

Up to 5.8 years

Notes
[23] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[24]
Units: Participants
Eosinophils; high; n= 98	7
Hematocrit; low; n= 98	4
Hemoglobin; low; n= 98	3
Platelet count; high; n= 98	1
Platelet count; low; n= 98	4
Total neutrophils; low; n= 98	20
WBC; high; n= 91	2
WBC; low; n= 91	3

Notes
[24] - Safety Population

No statistical analyses for this end point

Primary: Number of participants with urinalysis parameters of PCC

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End point title

Number of participants with urinalysis parameters of PCC ^[25]

End point description

Urine samples were collected from participants at specific time points. Number of participants with urinalysis parameters of PCC at 'any visit post-Baseline' are presented. Urinalysis parameters for which PCC values were identified were albumin/creatinine ratio (if value is >11.3), red blood cells (RBC) (if value is 3-5 or higher), WBC (if value is 5-10 or higher for male and 10-15 or higher for females), specific gravity (if value is <1.001 or >1.035) and potential of hydrogen (pH) (if value is <4.6 or >8.0). Only those participants with data available at specific time points were analyzed (represented by n=X in the category titles).

End point type

Primary

End point timeframe

Up to 5.8 years

Notes
[25] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[26]
Units: Participants
Albumin/creatinine ratio; high; n= 96	4
RBC; high; n= 98	54
WBC; high; n= 91	59
Specific gravity; high; n= 91	4
Specific gravity; low; n= 91	0
pH; high; n= 98	1
pH; low; n= 98	0

Notes
[26] - Safety Population

No statistical analyses for this end point

Primary: Change from Baseline in albumin and total protein

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End point title

Change from Baseline in albumin and total protein ^[27]

End point description

Blood samples were collected from participants for evaluation of change from Baseline in clinical chemistry parameters including albumin and total protein. Baseline was defined by and taken directly from the Baseline assessments in the parent study NCT01336621. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

End point type

Primary

End point timeframe

Baseline and up to 5.8 years

Notes
[27] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[28]
Units: Gram per liter (G/L)
arithmetic mean (standard deviation)
Albumin; visit 1 (Screening); n= 83	-1.6 ( 2.72 )
Albumin; visit 2 (Week 13); n= 87	-0.9 ( 2.70 )
Albumin; visit 3 (Week 26); n= 75	-0.8 ( 2.83 )
Albumin; visit 4 (Week 39); n= 70	-0.7 ( 3.09 )
Albumin; visit 5 (Week 52); n= 65	-1.5 ( 3.25 )
Albumin; visit 6 (Week 69); n= 62	-1.1 ( 3.11 )
Albumin; visit 7 (Week 86); n= 54	-1.0 ( 2.70 )
Albumin; visit 8 (Week 104); n= 42	-1.6 ( 3.05 )
Albumin; visit 9 (Week 121); n= 39	-2.1 ( 2.88 )
Albumin; visit 10 (Week 138); n= 36	-2.2 ( 3.16 )
Albumin; visit 11 (Week 156); n= 30	-3.0 ( 3.62 )
Albumin; visit 12 (Week 173); n= 23	-1.7 ( 2.82 )
Albumin; visit 13 (Week 190); n= 19	-2.9 ( 3.62 )
Albumin; visit14 (Week 208); n= 10	-3.9 ( 3.78 )
Albumin; visit 15 (Week 225); n= 5	-3.4 ( 1.52 )
Albumin; visit 16 (Week242); n= 4	-4.3 ( 1.26 )
Albumin; visit 17 (Week 260); n= 4	-4.0 ( 1.15 )
Albumin; visit 18 (Week 277); n= 2	-4.5 ( 0.71 )
Albumin; withdrawal visit; n= 79	-1.8 ( 3.11 )
Albumin; follow up visit; n= 60	-2.3 ( 3.42 )
Total protein; visit 1 (Screening); n= 83	-2.0 ( 4.57 )
Total protein; visit 2 (Week 13); n= 87	-1.0 ( 4.59 )
Total protein; visit 3 (Week 26); n= 75	-1.5 ( 5.15 )
Total protein; visit 4 (Week 39); n= 70	-1.8 ( 4.13 )
Total protein; visit 5 (Week 52); n= 65	-2.6 ( 4.74 )
Total protein; visit 6 (Week 69); n= 62	-1.4 ( 4.09 )
Total protein; visit 7 (Week 86); n= 54	-1.0 ( 4.44 )
Total protein; visit 8 (Week 104); n= 42	-1.5 ( 4.65 )
Total protein; visit 9 (Week 121); n= 39	-2.1 ( 4.58 )
Total protein; visit 10 (Week 138); n= 36	-2.7 ( 4.90 )
Total protein; visit 11 (Week 156); n= 30	-3.2 ( 5.40 )
Total protein; visit 12 (Week 173); n= 23	-1.1 ( 4.07 )
Total protein; visit 13 (Week 190); n= 19	-1.9 ( 5.57 )
Total protein; visit 14 (Week 208); n= 10	-3.1 ( 3.41 )
Total protein; visit 15 (Week 225); n= 5	-3.4 ( 2.51 )
Total protein; visit 16 (Week 242); n= 4	-3.8 ( 4.99 )
Total protein; visit 17 (Week 260); n= 4	-2.3 ( 3.30 )
Total protein; visit 18 (Week 277); n= 2	-4.5 ( 2.12 )
Total protein; withdrawal visit; n= 79	-2.5 ( 5.27 )
Total protein; follow up visit; n= 60	-2.1 ( 6.12 )

Notes
[28] - Safety Population

No statistical analyses for this end point

Primary: Change from Baseline in alk. phosphatase, ALT, AST, creatine kinase and LD levels

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End point title

Change from Baseline in alk. phosphatase, ALT, AST, creatine kinase and LD levels ^[29]

End point description

Blood samples were collected from participants for evaluation of change from Baseline in clinical chemistry parameters including alk. phosphatase, ALT, AST, creatine kinase and LD. Baseline was defined by and taken directly from the Baseline assessments in the parent study NCT01336621. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

End point type

Primary

End point timeframe

Baseline and up to 5.8 years

Notes
[29] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[30]
Units: International unit per liter (IU/L)
arithmetic mean (standard deviation)
Alk. phosphatase; visit 1 (Screening); n= 82	-2.7 ( 15.51 )
Alk. phosphatase; visit 2 (Week 13); n= 86	1.1 ( 14.02 )
Alk. phosphatase; visit 3 (Week 26); n= 75	3.5 ( 15.80 )
Alk. phosphatase; visit 4 (week 39); n= 70	3.9 ( 15.46 )
Alk. phosphatase; visit 5 (Week 52); n= 65	1.0 ( 15.36 )
Alk. phosphatase; visit 6 (Week 69); n= 62	4.1 ( 14.22 )
Alk. phosphatase; visit 7 (Week 86); n= 54	4.0 ( 16.01 )
Alk. phosphatase; visit 8 (Week 104); n= 42	-0.3 ( 18.27 )
Alk. phosphatase; visit 9 (Week 121); n= 39	2.4 ( 16.33 )
Alk. phosphatase; visit 10 (Week 138); n= 36	2.2 ( 21.08 )
Alk. phosphatase; visit 11 (Week 156); n= 30	-1.4 ( 18.49 )
Alk. phosphatase; visit 12 (Week 173); n= 23	5.5 ( 20.76 )
Alk. phosphatase; visit 13 (Week 190); n= 19	6.3 ( 23.61 )
Alk. phosphatase; visit 14 (Week 208); n= 10	6.1 ( 19.84 )
Alk. phosphatase; visit 15 (Week 225); n= 5	5.8 ( 16.95 )
Alk. phosphatase; visit 16 (Week 242); n= 4	9.5 ( 15.55 )
Alk. phosphatase; visit 17 (Week 260); n= 4	7.3 ( 7.14 )
Alk. phosphatase; visit 18 (Week 277); n= 2	-4.5 ( 10.61 )
Alk. phosphatase; withdrawal visit; n= 78	2.5 ( 19.86 )
Alk. phosphatase; follow up visit; n= 60	-0.3 ( 19.59 )
ALT; visit 1 (Screening); n= 83	1.3 ( 10.90 )
ALT; visit 2 (Week 13); n= 87	3.4 ( 23.41 )
ALT; visit 3 (Week 26); n= 76	1.0 ( 23.35 )
ALT; visit 4 (Week 39); n= 70	-0.5 ( 10.22 )
ALT; visit 5 (Week 52); n= 65	-0.4 ( 8.21 )
ALT; visit 6 (Week 69); n= 62	0.0 ( 11.51 )
ALT; visit 7 (Week 86); n= 54	-1.9 ( 10.02 )
ALT; visit 8 (Week 104); n= 42	-1.5 ( 8.58 )
ALT; visit 9 (Week 121); n= 39	0.4 ( 8.80 )
ALT; visit 10 (Week 138); n= 36	3.4 ( 21.74 )
ALT; visit 11 (Week 156); n= 29	-1.1 ( 8.21 )
ALT; visit 12 (Week 173); n= 23	-1.3 ( 7.97 )
ALT; visit 13 (Week 190); n= 19	0.0 ( 8.10 )
ALT; visit 14 (Week 208); n= 10	0.7 ( 7.32 )
ALT; visit 15 (Week 225); n= 5	-2.0 ( 4.47 )
ALT; visit 16 (Week 242); n= 4	-0.5 ( 8.54 )
ALT; visit 17 (Week 260); n= 4	0.0 ( 6.98 )
ALT; visit 18 (Week 277); n= 2	3.5 ( 3.54 )
ALT; withdrawal visit; n= 79	0.7 ( 10.17 )
ALT; follow up visit; n= 60	0.1 ( 8.43 )
AST; visit 1 (Screening); n= 82	1.7 ( 7.97 )
AST; visit 2 (Week 13); n= 86	5.1 ( 31.13 )
AST; visit 3 (Week 26); n= 75	2.9 ( 23.95 )
AST; visit 4 (Week 39); n= 70	1.3 ( 8.23 )
AST; visit 5 (Week 52); n= 65	2.5 ( 6.01 )
AST; visit 6 (Week 69); n= 62	1.5 ( 7.55 )
AST; visit 7 (Week 86); n= 54	1.7 ( 8.20 )
AST; visit 8 (Week 104); n= 42	1.5 ( 7.94 )
AST; visit 9 (Week 121); n= 39	2.6 ( 7.99 )
AST; visit 10 (Week 138); n= 36	6.4 ( 17.36 )
AST; visit 11 (Week 156); n= 30	1.4 ( 7.38 )
AST; visit 12 (Week 173); n= 23	2.7 ( 4.71 )
AST; visit 13 (Week 190); n= 19	3.3 ( 5.21 )
AST; visit 14 (Week 208); n= 10	3.5 ( 6.42 )
AST; visit 15 (Week 225); n= 5	4.2 ( 2.95 )
AST; visit 16 (Week 242); n= 4	4.3 ( 4.72 )
AST; visit 17 (Week 260); n= 4	5.5 ( 3.11 )
AST; visit 18 (Week 277); n= 2	10.0 ( 9.90 )
AST; withdrawal visit; n= 78	1.8 ( 7.87 )
AST; follow up visit; n= 60	1.2 ( 6.99 )
Creatine kinase; Visit 1 (Screening); n= 82	16.4 ( 132.76 )
Creatine kinase; Visit 2 (Week 13); n= 86	11.3 ( 78.18 )
Creatine kinase; Visit 3 (Week 26); n= 74	11.7 ( 59.78 )
Creatine kinase; Visit 4 (Week 39); n= 70	49.4 ( 397.67 )
Creatine kinase; Visit 5 (Week 52); n= 65	31.3 ( 136.41 )
Creatine kinase; Visit 6 (Week 69); n= 62	11.1 ( 55.13 )
Creatine kinase; Visit 7 (Week 86); n= 54	23.6 ( 92.64 )
Creatine kinase; Visit 8 (Week 104); n= 42	33.2 ( 110.99 )
Creatine kinase; Visit 9 (Week 121); n= 39	22.5 ( 77.04 )
Creatine kinase; Visit 10 (Week 138); n= 36	24.8 ( 83.80 )
Creatine kinase; Visit 11 (Week 156); n= 30	31.9 ( 86.68 )
Creatine kinase; Visit 12 (Week 173); n= 23	29.1 ( 97.10 )
Creatine kinase; Visit 13 (Week 190); n= 19	50.2 ( 125.12 )
Creatine kinase; Visit 14 (Week 208); n= 10	-7.9 ( 101.39 )
Creatine kinase; Visit 15 (Week 225); n= 5	42.6 ( 99.09 )
Creatine kinase; Visit 16 (Week 242); n= 4	90.3 ( 127.49 )
Creatine kinase; Visit 17 (Week 260); n= 4	78.8 ( 110.78 )
Creatine kinase; Visit 18 (Week 277); n= 2	-27.5 ( 102.53 )
Creatine kinase; withdrawal visit; n= 78	28.7 ( 139.96 )
Creatine kinase; follow up visit; n= 60	33.9 ( 128.19 )
LD; visit 1(Screening); n= 82	3.7 ( 23.16 )
LD; visit 2 (Week 13); n= 86	4.3 ( 32.66 )
LD; visit 3 (Week 26); n= 74	0.0 ( 27.88 )
LD; visit 4 (Week 39); n= 69	0.4 ( 28.51 )
LD; visit 5 (Week 52); n= 64	2.1 ( 28.01 )
LD; visit 6 (Week 69); n= 61	-0.1 ( 25.98 )
LD; visit 7 (Week 86); n= 54	9.2 ( 30.42 )
LD; visit 8 (Week 104); n= 42	4.7 ( 29.37 )
LD; visit 9 (Week 121); n= 39	18.8 ( 53.56 )
LD; visit 10 (Week 138); n= 36	33.0 ( 131.87 )
LD; visit 11 (Week 156); n= 30	13.7 ( 33.18 )
LD; visit 12 (Week 173); n= 23	4.1 ( 31.91 )
LD; visit 13 (Week 190); n= 19	30.0 ( 58.17 )
LD; visit 14 (Week 208); n= 10	25.8 ( 42.76 )
LD; visit 15 (Week 225); n= 5	34.6 ( 25.93 )
LD; visit 16 (Week 242); n= 4	25.8 ( 15.97 )
LD; visit 17 (Week 260); n= 4	20.8 ( 25.86 )
LD; visit 18 (Week 277); n= 2	52.0 ( 60.81 )
LD; withdrawal visit; n= 78	7.8 ( 31.17 )
LD; follow up visit; n= 60	5.6 ( 36.94 )

Notes
[30] - Safety Population

No statistical analyses for this end point

Primary: Change from Baseline in direct bilirubin, total bilirubin and creatinine

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End point title

Change from Baseline in direct bilirubin, total bilirubin and creatinine ^[31]

End point description

Blood samples were collected from participants for evaluation of change from Baseline in clinical chemistry parameters including direct bilirubin, total bilirubin and creatinine. Baseline was defined by and taken directly from the Baseline assessments in the parent study NCT01336621. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

End point type

Primary

End point timeframe

Baseline and up to 5.8 years

Notes
[31] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[32]
Units: Micromole per liter (µmol/L)
arithmetic mean (standard deviation)
Direct bilirubin; visit 1 (Screening); n= 83	0.1 ( 0.95 )
Direct bilirubin; visit 2 (Week 13); n= 87	-0.1 ( 0.96 )
Direct bilirubin; visit 3 (Week 26); n= 75	-0.2 ( 0.94 )
Direct bilirubin; visit 4 (Week 39); n= 69	-0.1 ( 0.91 )
Direct bilirubin; visit 5 (Week 52); n= 65	0.0 ( 0.95 )
Direct bilirubin; visit 6 (Week 69); n= 62	0.0 ( 0.97 )
Direct bilirubin; visit 7 (Week 86); n= 54	-0.2 ( 1.17 )
Direct bilirubin; visit 8 (Week 104); n= 42	0.0 ( 0.91 )
Direct bilirubin; visit 9 (Week 121); n= 39	-0.2 ( 0.87 )
Direct bilirubin; visit 10 (Week 138); n= 36	-0.1 ( 1.27 )
Direct bilirubin; visit 11 (Week 156); n= 30	0.0 ( 0.72 )
Direct bilirubin; visit 12 (Week 173); n= 23	-0.1 ( 0.73 )
Direct bilirubin; visit 13 (Week 190); n= 19	0.1 ( 0.91 )
Direct bilirubin; visit 14 (Week 208); n= 10	0.0 ( 0.67 )
Direct bilirubin; visit 15 (Week 225); n= 5	-0.2 ( 0.84 )
Direct bilirubin; visit 16 (Week 242); n= 4	-0.5 ( 1.00 )
Direct bilirubin; visit 17 (Week 260); n= 4	-0.5 ( 1.29 )
Direct bilirubin; visit 18 (Week 277); n= 2	0.5 ( 2.12 )
Direct bilirubin; withdrawal visit; n= 79	0.0 ( 1.15 )
Direct bilirubin; follow up visit; n= 60	-0.2 ( 0.98 )
Total bilirubin; visit 1 (Screening); n= 83	2.5 ( 3.78 )
Total bilirubin; visit 2 (Week 13); n= 87	1.8 ( 4.28 )
Total bilirubin; visit 3 (Week 26); n= 76	1.8 ( 3.78 )
Total bilirubin; visit 4 (Week 39); n= 70	2.1 ( 4.46 )
Total bilirubin; visit 5 (Week 52); n= 65	2.6 ( 4.26 )
Total bilirubin; visit 6 (Week 69); n= 62	1.8 ( 4.21 )
Total bilirubin; visit 7 (Week 86); n= 54	1.4 ( 4.41 )
Total bilirubin; visit 8 (Week 104); n= 42	1.8 ( 3.28 )
Total bilirubin; visit 9 (Week 121); n= 39	1.1 ( 3.59 )
Total bilirubin; visit 10 (Week 138); n= 36	1.6 ( 6.50 )
Total bilirubin; visit 11 (Week 156); n= 30	0.5 ( 2.99 )
Total bilirubin; visit 12 (Week 173); n= 23	0.6 ( 2.81 )
Total bilirubin; visit 13 (Week 190); n= 19	0.2 ( 4.26 )
Total bilirubin; visit 14 (Week 208); n= 10	0.3 ( 3.27 )
Total bilirubin; visit 15 (Week 225); n= 5	0.8 ( 2.17 )
Total bilirubin; visit 16 (Week 242); n= 4	1.3 ( 1.89 )
Total bilirubin; visit 17 (Week 260); n= 4	-0.3 ( 2.63 )
Total bilirubin; visit 18 (Week 277); n= 2	1.5 ( 0.71 )
Total bilirubin; withdrawal visit; n= 79	1.2 ( 3.75 )
Total bilirubin; follow up visit; n= 60	-0.8 ( 3.97 )
Creatinine; visit 1 (Screening); n= 82	3.68 ( 9.813 )
Creatinine; visit 2 (Week 13); n= 86	0.42 ( 8.033 )
Creatinine; visit 3 (Week 26); n= 74	0.65 ( 8.879 )
Creatinine; visit 4 (Week 39); n= 70	1.82 ( 9.716 )
Creatinine; visit 5 (Week 52); n= 65	1.40 ( 9.394 )
Creatinine; visit 6 (Week 69); n= 62	1.25 ( 8.980 )
Creatinine; visit 7 (Week 86); n= 54	0.55 ( 9.053 )
Creatinine; visit 8 (Week 104); n= 42	4.78 ( 8.921 )
Creatinine; visit 9 (Week 121); n= 39	3.67 ( 9.581 )
Creatinine; visit 10 (Week 138); n= 36	2.10 ( 11.317 )
Creatinine; visit 11 (Week 156); n= 30	5.33 ( 11.211 )
Creatinine; visit 12 (Week 173); n= 23	-0.93 ( 10.097 )
Creatinine; visit 13 (Week 190); n= 19	1.67 ( 11.314 )
Creatinine; visit 14 (Week 208); n= 10	-1.74 ( 13.636 )
Creatinine; visit 15 (Week 225); n= 5	2.08 ( 6.680 )
Creatinine; visit 16 (Week 242); n= 4	5.80 ( 8.844 )
Creatinine; visit 17 (Week 260); n= 4	9.23 ( 14.076 )
Creatinine; visit 18 (Week 277); n= 2	3.45 ( 8.697 )
Creatinine; withdrawal visit; n= 78	0.88 ( 8.920 )
Creatinine; follow up visit; n= 60	0.16 ( 9.873 )

Notes
[32] - Safety Population

No statistical analyses for this end point

Primary: Change from Baseline in BUN/creatinine ratio

Top of page

End point title

Change from Baseline in BUN/creatinine ratio ^[33]

End point description

Blood samples were collected from participants for evaluation of change from Baseline in clinical chemistry parameters including BUN/creatinine ratio. Baseline was defined by and taken directly from the Baseline assessments in the parent study NCT01336621. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

End point type

Primary

End point timeframe

Baseline and up to 5.8 years

Notes
[33] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[34]
Units: Ratio of BUN to creatinine
arithmetic mean (standard deviation)
Visit 1 (Screening); n= 82	0.3 ( 20.71 )
Visit 2 (Week 13); n= 86	3.8 ( 23.49 )
Visit 3 (Week 26); n= 74	2.7 ( 20.38 )
Visit 4 (Week 39); n= 70	1.0 ( 23.43 )
Visit 5 (Week 52); n= 65	1.9 ( 27.30 )
Visit 6 (Week 69); n= 62	0.0 ( 22.69 )
Visit 7 (Week 86); n= 54	2.5 ( 24.05 )
Visit 8 (Week 104); n= 42	-2.5 ( 24.45 )
Visit 9 (Week 121); n= 39	0.6 ( 24.67 )
Visit 10 (Week 138); n= 36	0.2 ( 27.01 )
Visit 11 (Week 156); n= 30	-6.2 ( 24.68 )
Visit 12 (Week 173); n= 23	-5.7 ( 22.82 )
Visit 13 (Week 190); n= 19	1.1 ( 22.19 )
Visit 14 (Week 208); n= 10	-0.8 ( 23.37 )
Visit 15 (Week 225); n= 5	-8.8 ( 20.22 )
Visit 16 (Week 242); n= 4	4.0 ( 18.49 )
Visit 17 (Week 260); n= 4	2.0 ( 32.81 )
Visit 18 (Week 277); n= 2	3.0 ( 11.31 )
Withdrawal visit; n= 78	4.2 ( 23.96 )
Follow up visit; n= 60	0.4 ( 22.68 )

Notes
[34] - Safety Population

No statistical analyses for this end point

Primary: Change from Baseline in calcium, chloride, CO2, glucose, potassium, magnesium, sodium and BUN

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End point title

Change from Baseline in calcium, chloride, CO2, glucose, potassium, magnesium, sodium and BUN ^[35]

End point description

Blood samples were collected from participants for evaluation of change from Baseline in clinical chemistry parameters including calcium, chloride, CO2, glucose, potassium, magnesium, sodium and BUN. Baseline was defined by and taken directly from the Baseline assessments in the parent study NCT01336621. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

End point type

Primary

End point timeframe

Baseline and up to 5.8 years

Notes
[35] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[36]
Units: Millimoles per liter (mmol/L)
arithmetic mean (standard deviation)
Calcium; visit 1 (Screening); n= 82	-0.028 ( 0.0940 )
Calcium; visit 2 (Week 13); n= 86	-0.011 ( 0.1067 )
Calcium; visit 3 (Week 26); n= 74	-0.026 ( 0.1061 )
Calcium; visit 4 (Week 39); n= 69	-0.025 ( 0.1024 )
Calcium; visit 5 (Week 52); n= 64	-0.026 ( 0.1100 )
Calcium; visit 6 (Week 69); n= 61	-0.019 ( 0.0942 )
Calcium; visit 7 (Week 86); n= 54	-0.016 ( 0.0911 )
Calcium; visit 8 (Week 104); n= 42	-0.008 ( 0.0975 )
Calcium; visit 9 (Week 121); n= 39	-0.024 ( 0.1096 )
Calcium; visit 10 (Week 138); n= 36	-0.038 ( 0.1335 )
Calcium; visit 11 (Week 156); n= 30	-0.053 ( 0.1181 )
Calcium; visit 12 (Week 173); n= 23	-0.059 ( 0.1031 )
Calcium; visit 13 (Week 190); n= 19	-0.074 ( 0.1000 )
Calcium; visit 14 (Week 208); n= 10	-0.094 ( 0.0950 )
Calcium; visit 15 (Week 225); n= 5	-0.108 ( 0.0858 )
Calcium; visit 16 (Week 242); n= 4	-0.093 ( 0.0877 )
Calcium; visit 17 (Week 260); n= 4	-0.073 ( 0.0670 )
Calcium; visit 18 (Week 277); n= 2	-0.125 ( 0.02122 )
Calcium; withdrawal visit; n= 78	-0.033 ( 0.1148 )
Calcium; follow up visit; n= 60	-0.050 ( 0.1059 )
Chloride; visit 1 (Screening); n= 83	0.5 ( 2.88 )
Chloride; visit 2 (Week 13); n= 87	0.4 ( 2.73 )
Chloride; visit 3 (Week 26); n=75	0.1 ( 2.79 )
Chloride; visit 4 (Week 39); n= 70	1.5 ( 2.80 )
Chloride; visit 5 (Week 52); n= 65	1.2 ( 3.58 )
Chloride; visit 6 (Week 69); n= 62	0.4 ( 2.68 )
Chloride; visit 7 (Week 86); n= 54	1.5 ( 3.34 )
Chloride; visit 8 (Week 104); n= 42	1.3 ( 2.83 )
Chloride; visit 9 (Week 121); n= 39	1.4 ( 3.28 )
Chloride; visit 10 (Week 138); n= 36	1.2 ( 3.35 )
Chloride; visit 11 (Week 156); n= 30	2.0 ( 2.99 )
Chloride; visit 12 (Week 173); n= 23	1.6 ( 2.74 )
Chloride; visit 13 (Week 190); n= 19	2.4 ( 2.09 )
Chloride; visit 14 (Week 208); n= 10	1.2 ( 2.49 )
Chloride; visit 15 (Week 225); n= 5	1.2 ( 3.11 )
Chloride; visit 16 (Week 242); n= 4	2.0 ( 2.00 )
Chloride; visit 17 (Week 260); n= 4	3.5 ( 3.11 )
Chloride; visit 18 (Week 277); n= 2	-0.5 ( 0.71 )
Chloride; withdrawal visit; n= 79	0.6 ( 2.89 )
Chloride; follow up visit; n= 60	0.0 ( 2.79 )
CO2; visit 1 (Screening); n= 82	-0.2 ( 3.07 )
CO2; visit 2 (Week 13); n= 86	0.3 ( 2.42 )
CO2; visit 3 (Week 26); n= 74	0.5 ( 2.82 )
CO2; visit 4 (Week 39); n= 69	-0.2 ( 3.03 )
CO2; visit 5 (Week 52); n= 64	-0.2 ( 2.88 )
CO2; visit 6 (Week 69); n= 61	-0.5 ( 2.99 )
CO2; visit 7 (Week 86); n= 54	-0.6 ( 2.71 )
CO2; visit 8 (Week 104); n= 42	-0.6 ( 2.64 )
CO2; visit 9 (Week 121); n= 39	-1.0 ( 3.02 )
CO2; visit 10 (Week 138); n= 36	-0.9 ( 3.42 )
CO2; visit 11 (Week 156); n= 30	-1.0 ( 2.48 )
CO2; visit 12 (Week 173); n= 23	-0.9 ( 2.80 )
CO2; visit 13 (Week 190); n= 19	-1.5 ( 3.39 )
CO2; visit 14 (Week 208); n= 10	-3.6 ( 4.53 )
CO2; visit 15 (Week 225); n= 5	-2.4 ( 1.82 )
CO2; visit 16 (Week 242); n= 4	-1.0 ( 1.41 )
CO2; visit 17 (Week 260); n= 4	-0.5 ( 0.58 )
CO2; visit 18 (Week 277); n= 2	-0.5 ( 0.71 )
CO2; withdrawal visit; n= 78	0.0 ( 2.33 )
CO2; follow up visit; n= 60	-0.8 ( 2.92 )
Glucose; visit 1 (Screening); n= 83	0.20 ( 1.303 )
Glucose; visit 2 (Week 13); n= 87	0.16 ( 0.933 )
Glucose; visit 3 (Week 26); n= 75	0.17 ( 0.765 )
Glucose; visit 4 (Week 39); n= 70	0.40 ( 1.259 )
Glucose; visit 5 (Week 52); n= 65	0.23 ( 0.814 )
Glucose; visit 6 (Week 69); n= 62	0.25 ( 1.103 )
Glucose; visit 7 (Week 86); n= 54	0.21 ( 0.985 )
Glucose; visit 8 (Week 104); n= 42	0.21 ( 0.679 )
Glucose; visit 9 (Week 121); n= 39	0.31 ( 1.073 )
Glucose; visit 10 (Week 138); n= 36	0.30 ( 1.007 )
Glucose; visit 11 (Week 156); n= 30	0.10 ( 0.511 )
Glucose; visit 12 (Week 173); n= 23	-0.03 ( 0.820 )
Glucose; visit 13 (Week 190); n= 19	0.21 ( 1.446 )
Glucose; visit 14 (Week 208); n= 10	0.15 ( 0.412 )
Glucose; visit 15 (Week 225); n= 5	0.38 ( 0.981 )
Glucose; visit 16 (Week 242); n= 4	1.95 ( 3.313 )
Glucose; visit 17 (Week 260); n= 4	-0.10 ( 0.648 )
Glucose; visit 18 (Week 277); n= 2	-0.30 ( 0.141 )
Glucose; withdrawal visit; n= 79	0.14 ( 1.035 )
Glucose; follow up visit; n= 60	0.39 ( 1.162 )
Potassium; visit 1 (Screening); n= 82	-0.04 ( 0.467 )
Potassium; visit 2 (Week 13); n= 86	-0.07 ( 0.403 )
Potassium; visit 3 (Week 26); n= 74	-0.09 ( 0.453 )
Potassium; visit 4 (Week 39); n= 69	-0.11 ( 0.432 )
Potassium; visit 5 (Week 52); n= 64	-0.13 ( 0.430 )
Potassium; visit 6 (Week 69); n= 61	-0.21 ( 0.420 )
Potassium; visit 7 (Week 86); n= 54	-0.13 ( 0.411 )
Potassium; visit 8 (Week 104); n= 42	-0.05 ( 0.433 )
Potassium; visit 9 (Week 121); n= 39	-0.09 ( 0.376 )
Potassium; visit 10 (Week 138); n= 36	-0.07 ( 0.388 )
Potassium; visit 11 (Week 156); n= 30	-0.16 ( 0.390 )
Potassium; visit 12 (Week 173); n= 23	-0.13 ( 0.411 )
Potassium; visit 13 (Week 190); n= 19	-0.02 ( 0.351 )
Potassium; visit 14 (Week 208); n= 10	-0.16 ( 0.430 )
Potassium; visit 15 (Week 225); n= 5	0.14 ( 0.321 )
Potassium; visit 16 (Week 242); n= 4	0.30 ( 0.294 )
Potassium; visit 17 (Week 260); n= 4	0.25 ( 0.351 )
Potassium; visit 18 (Week 277); n= 2	0.10 ( 0.424 )
Potassium; withdrawal visit; n= 78	-0.04 ( 0.367 )
Potassium; follow up visit; n= 60	-0.20 ( 0.478 )
Magnesium; visit 1 (Screening); n= 83	-0.017 ( 0.0576 )
Magnesium; visit 2 (Week 13); n= 87	-0.012 ( 0.0558 )
Magnesium; visit 3 (Week 26); n= 75	-0.007 ( 0.0619 )
Magnesium; visit 4 (Week 39); n= 70	-0.004 ( 0.0580 )
Magnesium; visit 5 (Week 52); n= 65	-0.008 ( 0.0625 )
Magnesium; visit 6 (Week 69); n= 62	-0.012 ( 0.0599 )
Magnesium; visit 7 (Week 86); n= 54	-0.018 ( 0.0627 )
Magnesium; visit 8 (Week 104); n= 42	0.007 ( 0.0632 )
Magnesium; visit 9 (Week 121); n= 39	-0.011 ( 0.0763 )
Magnesium; visit 10 (Week 138); n= 36	-0.007 ( 0.0543 )
Magnesium; visit 11 (Week 156); n= 30	0.005 ( 0.0651 )
Magnesium; visit 12 (Week 173); n= 23	-0.003 ( 0.0688 )
Magnesium; visit 13 (Week 190); n= 19	0.000 ( 0.0627 )
Magnesium; visit 14 (Week 208); n= 10	-0.013 ( 0.0579 )
Magnesium; visit 15 (Week 225); n= 5	0.000 ( 0.0474 )
Magnesium; visit 16 (Week 242); n= 4	-0.008 ( 0.1075 )
Magnesium; visit 17 (Week 260); n= 4	0.053 ( 0.1258 )
Magnesium; visit 18 (Week 277); n= 2	0.070 ( 0.0424 )
Magnesium; withdrawal visit; n= 79	-0.003 ( 0.0763 )
Magnesium; follow up visit; n= 60	-0.007 ( 0.0727 )
Sodium; visit 1 (Screening); n= 83	0.2 ( 2.88 )
Sodium; visit 2 (Week 13); n= 80	0.2 ( 2.83 )
Sodium; visit 3 (Week 26); n= 69	-0.2 ( 2.79 )
Sodium; visit 4 (Week 39); n= 64	0.7 ( 2.37 )
Sodium; visit 5 (Week 52); n= 59	0.5 ( 3.35 )
Sodium; visit 6 (Week 69); n= 58	-0.2 ( 2.34 )
Sodium; visit 7 (Week 86); n= 51	0.6 ( 3.03 )
Sodium; visit 8 (Week 104); n= 39	0.9 ( 2.28 )
Sodium; visit 9 (Week 121); n= 36	0.7 ( 2.78 )
Sodium; visit 10 (Week 138); n= 35	0.3 ( 3.06 )
Sodium; visit 11 (Week 156); n= 28	0.9 ( 3.47 )
Sodium; visit 12 (Week 173); n= 21	0.7 ( 3.38 )
Sodium; visit 13 (Week 190); n= 17	0.6 ( 1.73 )
Sodium; visit 14 (Week 208); n= 10	-1.2 ( 1.03 )
Sodium; visit 15 (Week 225); n= 5	-0.4 ( 1.52 )
Sodium; visit 16 (Week 242); n= 4	-0.8 ( 1.89 )
Sodium; visit 17 (Week 260); n= 4	0.8 ( 2.63 )
Sodium; visit 18 (Week 277); n= 2	-1.0 ( 0.00 )
Sodium; withdrawal visit; n= 71	0.2 ( 2.85 )
Sodium; follow up visit; n= 53	-0.7 ( 2.45 )
BUN; visit 1 (Screening); n= 83	0.32 ( 1.317 )
BUN; visit 2 (Week 13); n= 80	0.44 ( 1.483 )
BUN; visit 3 (Week 26); n= 69	0.31 ( 1.287 )
BUN; visit 4 (Week 39); n= 64	0.22 ( 1.322 )
BUN; visit 5 (Week 52); n= 59	0.37 ( 1.643 )
BUN; visit 6 (Week 69); n= 58	0.13 ( 1.329 )
BUN; visit 7 (Week 86); n= 51	0.22 ( 1.467 )
BUN; visit 8 (Week 104); n= 39	0.22 ( 1.477 )
BUN; visit 9 (Week 121); n= 36	0.35 ( 1.444 )
BUN; visit 10 (Week 138); n= 35	0.18 ( 1.578 )
BUN; visit 11 (Week 156); n= 28	-0.06 ( 1.515 )
BUN; visit 12 (Week 173); n= 21	-0.40 ( 1.362 )
BUN; visit 13 (Week 190); n= 17	0.23 ( 1.088 )
BUN; visit 14 (Week 208); n= 10	-0.11 ( 1.604 )
BUN; visit 15 (Week 225); n= 5	-0.40 ( 1.416 )
BUN; visit 16 (Week 242); n= 4	0.80 ( 0.707 )
BUN; visit 17 (Week 260); n= 4	1.10 ( 2.889 )
BUN; visit 18 (Week 277); n= 2	0.50 ( 0.141 )
BUN; withdrawal visit; n= 71	0.49 ( 1.450 )
BUN; follow up visit; n= 53	0.14 ( 1.468 )

Notes
[36] - Safety Population

No statistical analyses for this end point

Primary: Change from Baseline in absolute basophils, absolute eosinophils, absolute lymphocytes, absolute monocytes, absolute total neutrophils, platelet count and WBC count

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End point title

Change from Baseline in absolute basophils, absolute eosinophils, absolute lymphocytes, absolute monocytes, absolute total neutrophils, platelet count and WBC count ^[37]

End point description

Blood samples were collected from participants for evaluation of change from Baseline in clinical hematology parameters including absolute basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelet count and WBC count. Baseline was defined by and taken directly from the Baseline assessments in the parent study NCT01336621. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

End point type

Primary

End point timeframe

Baseline and up to 5.8 years

Notes
[37] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[38]
Units: Giga cells per liter (GI/L)
arithmetic mean (standard deviation)
Basophils; visit 1 (Screening); n= 84	-0.001 ( 0.0203 )
Basophils; visit 2 (Week 13); n= 85	-0.005 ( 0.0159 )
Basophils; visit 3 (Week 26); n= 71	-0.003 ( 0.0197 )
Basophils; visit 4 (Week 39); n= 65	0.001 ( 0.0231 )
Basophils; visit 5 (Week 52); n= 60	0.002 ( 0.0170 )
Basophils; visit 6 (Week 69); n= 58	-0.002 ( 0.0202 )
Basophils; visit 7 (Week 86); n= 53	-0.002 ( 0.0188 )
Basophils; visit 8 (Week 104); n= 36	0.003 ( 0.0165 )
Basophils; visit 9 (Week 121); n= 35	-0.002 ( 0.0183 )
Basophils; visit 10 (Week 138); n= 33	-0.002 ( 0.0142 )
Basophils; visit 11 (Week 156); n= 29	-0.001 ( 0.0151 )
Basophils; visit 12 (Week 173); n= 24	-0.004 ( 0.0125 )
Basophils; visit 13 (Week 190); n= 17	0.000 ( 0.0255 )
Basophils; visit 14 (Week 208); n= 10	-0.004 ( 0.0165 )
Basophils; visit 15 (Week 225); n= 4	-0.010 ( 0.0115 )
Basophils; visit 16 (Week 242); n= 4	-0.003 ( 0.0050 )
Basophils; visit 17 (Week 260); n= 4	-0.005 ( 0.0129 )
Basophils; visit 18 (Week 277); n= 2	0.000 ( 0.0000 )
Basophils; withdrawal visit; n= 78	0.001 ( 0.0186 )
Basophils; follow up visit; n= 56	-0.008 ( 0.0190 )
Eosinophils; visit 1 (Screening); n= 84	-0.011 ( 0.1103 )
Eosinophils; visit 2 (Week 13); n= 85	-0.018 ( 0.2505 )
Eosinophils; visit 3 (Week 26); n= 71	-0.029 ( 0.2191 )
Eosinophils; visit 4 (Week 39); n= 65	-0.050 ( 0.2523 )
Eosinophils; visit 5 (Week 52); n= 60	-0.065 ( 0.3016 )
Eosinophils; visit 6 (Week 69); n= 58	-0.025 ( 0.1586 )
Eosinophils; visit 7 (Week 86); n= 53	-0.016 ( 0.1585 )
Eosinophils; visit 8 (Week 104); n= 36	-0.020 ( 0.1992 )
Eosinophils; visit 9 (Week 121); n= 35	-0.015 ( 0.1721 )
Eosinophils; visit 10 (Week 138); n= 33	-0.052 ( 0.1918 )
Eosinophils; visit 11 (Week 156); n= 29	-0.046 ( 0.1846 )
Eosinophils; visit 12 (Week 173); n= 24	-0.065 ( 0.3068 )
Eosinophils; visit 13 (Week 190); n= 17	-0.104 ( 0.3376 )
Eosinophils; visit 14 (Week 208); n= 10	-0.158 ( 0.1591 )
Eosinophils; visit 15 (Week 225); n= 4	-0.140 ( 0.0589 )
Eosinophils; visit 16 (Week 242); n= 4	-0.070 ( 0.1131 )
Eosinophils; visit 17 (Week 260); n= 4	-0.055 ( 0.0850 )
Eosinophils; visit 18 (Week 277); n= 2	0.005 ( 0.0636 )
Eosinophils; withdrawal visit; n= 78	-0.056 ( 0.2713 )
Eosinophils; follow up visit; n= 56	-0.091 ( 0.3022 )
Lymphocytes; visit 1 (Screening); n= 84	-0.225 ( 0.6631 )
Lymphocytes; visit 2 (Week 13); n= 85	-0.170 ( 0.5506 )
Lymphocytes; visit 3 (Week 26); n= 71	-0.133 ( 0.6123 )
Lymphocytes; visit 4 (Week 39); n= 65	-0.210 ( 0.5412 )
Lymphocytes; visit 5 (Week 52); n= 60	-0.214 ( 0.6446 )
Lymphocytes; visit 6 (Week 69); n= 58	-0.178 ( 0.5194 )
Lymphocytes; visit 7 (Week 86); n= 53	-0.093 ( 0.5793 )
Lymphocytes; visit 8 (Week 104); n= 36	-0.111 ( 0.5839 )
Lymphocytes; visit 9 (Week 121); n= 35	0.008 ( 0.8295 )
Lymphocytes; visit 10 (Week 138); n= 33	-0.177 ( 0.6622 )
Lymphocytes; visit 11 (Week 156); n= 29	-0.324 ( 0.6801 )
Lymphocytes; visit 12 (Week 173); n= 24	-0.226 ( 0.5720 )
Lymphocytes; visit 13 (Week 190); n= 17	-0.325 ( 0.7086 )
Lymphocytes; visit 14 (Week 208); n= 10	-0.354 ( 0.6563 )
Lymphocytes; visit 15 (Week 225); n= 4	-0.990 ( 0.6633 )
Lymphocytes; visit 16 (Week 242); n= 4	-0.818 ( 0.9694 )
Lymphocytes; visit 17 (Week 260); n= 4	-0.993 ( 0.7200 )
Lymphocytes; visit 18 (Week 277); n= 2	-1.465 ( 0.6718 )
Lymphocytes; withdrawal visit; n= 78	-0.153 ( 0.6466 )
Lymphocytes; follow up visit; n= 56	-0.081 ( 0.7105 )
Monocytes; visit 1 (Screening); n= 84	-0.043 ( 0.1800 )
Monocytes; visit 2 (Week 13); n= 85	-0.009 ( 0.1603 )
Monocytes; visit 3 (Week 26); n= 71	0.039 ( 0.2031 )
Monocytes; visit 4 (Week 39); n= 65	-0.005 ( 0.1940 )
Monocytes; visit 5 (Week 52); n= 60	-0.006 ( 0.1876 )
Monocytes; visit 6 (Week 69); n= 58	0.018 ( 0.1697 )
Monocytes; visit 7 (Week 86); n= 53	0.055 ( 0.2375 )
Monocytes; visit 8 (Week 104); n= 36	-0.032 ( 0.1911 )
Monocytes; visit 9 (Week 121); n= 35	0.023 ( 0.1777 )
Monocytes; visit 10 (Week 138); n= 33	0.005 ( 0.1796 )
Monocytes; visit 11 (Week 156); n= 29	-0.028 ( 0.1982 )
Monocytes; visit 12 (Week 173); n= 24	-0.032 ( 0.1648 )
Monocytes; visit 13 (Week 190); n= 17	-0.078 ( 0.2279 )
Monocytes; visit 14 (Week 208); n= 10	-0.090 ( 0.2821 )
Monocytes; visit 15 (Week 225); n= 4	-0.037 ( 0.0450 )
Monocytes; visit 16 (Week 242); n= 4	-0.020 ( 0.0829 )
Monocytes; visit 17 (Week 260); n= 4	0.025 ( 0.1173 )
Monocytes; visit 18 (Week 277); n= 2	0.080 ( 0.0000 )
Monocytes; withdrawal visit; n= 78	0.041 ( 0.2417 )
Monocytes; follow up visit; n= 56	-0.021 ( 0.2091 )
Total neutrophils; visit 1 (Screening); n= 84	-0.108 ( 1.6418 )
Total neutrophils; visit 2 (Week 13); n= 85	-0.354 ( 1.4357 )
Total neutrophils; visit 3 (Week 26); n= 71	-0.175 ( 1.4304 )
Total neutrophils; visit 4 (Week 39); n= 65	-0.582 ( 1.5237 )
Total neutrophils; visit 5 (Week 52); n= 60	0.165 ( 1.9517 )
Total neutrophils; visit 6 (Week 69); n= 58	-0.159 ( 1.5356 )
Total neutrophils; visit 7 (Week 86); n= 53	-0.046 ( 2.0418 )
Total neutrophils; visit 8 (Week 104); n= 36	-0.403 ( 1.5416 )
Total neutrophils; visit 9 (Week 121); n= 35	0.519 ( 1.9016 )
Total neutrophils; visit 10 (Week 138); n= 33	0.412 ( 1.9080 )
Total neutrophils; visit 11 (Week 156); n= 29	0.361 ( 1.5062 )
Total neutrophils; visit 12 (Week 173); n= 24	0.144 ( 1.7867 )
Total neutrophils; visit 13 (Week 190); n= 17	0.669 ( 2.6453 )
Total neutrophils; visit 14 (Week 208); n= 10	0.113 ( 1.7471 )
Total neutrophils; visit 15 (Week 225); n= 4	-0.825 ( 1.9404 )
Total neutrophils; visit 16 (Week 242); n= 4	-1.183 ( 1.9538 )
Total neutrophils; visit 17 (Week 260); n= 4	-0.990 ( 2.1510 )
Total neutrophils; visit 18 (Week 277); n= 2	-2.210 ( 2.6446 )
Total neutrophils; withdrawal visit; n= 78	0.209 ( 1.6761 )
Total neutrophils; follow up visit; n= 56	0.095 ( 1.9626 )
Platelet count; visit 1 (Screening); n= 84	-1.7 ( 34.31 )
Platelet count; visit 2 (Week 13); n= 88	3.7 ( 38.83 )
Platelet count; visit 3 (Week 26); n= 73	5.1 ( 44.34 )
Platelet count; visit 4 (Week 39); n= 68	2.9 ( 45.75 )
Platelet count; visit 5 (Week 52); n= 63	4.1 ( 37.72 )
Platelet count; visit 6 (Week 69); n= 62	6.9 ( 39.48 )
Platelet count; visit 7 (Week 86); n= 55	1.5 ( 50.29 )
Platelet count; visit 8 (Week 104); n= 41	4.5 ( 43.95 )
Platelet count; visit 9 (Week 121); n= 35	8.7 ( 45.39 )
Platelet count; visit 10 (Week 138); n= 36	6.8 ( 42.37 )
Platelet count; visit 11 (Week 156); n= 31	1.9 ( 37.92 )
Platelet count; visit 12 (Week 173); n= 24	9.7 ( 37.95 )
Platelet count; visit 13 (Week 190); n= 18	7.0 ( 37.15 )
Platelet count; visit 14 (Week 208); n= 10	18.9 ( 69.95 )
Platelet count; visit 15 (Week 225); n= 4	-31.3 ( 11.15 )
Platelet count; visit 16 (Week 242); n= 4	-9.0 ( 63.92 )
Platelet count; visit 17 (Week 260); n= 4	-10.0 ( 61.60 )
Platelet count; visit 18 (Week 277); n= 2	-19.0 ( 100.41 )
Platelet count; withdrawal visit; n= 79	8.9 ( 43.88 )
Platelet count; follow up visit; n= 58	8.9 ( 54.58 )
WBC count; visit 1 (Screening); n= 84	0.30 ( 6.496 )
WBC count; visit 2 (Week 13); n= 78	-0.46 ( 1.512 )
WBC count; visit 3 (Week 26); n= 66	-0.24 ( 1.354 )
WBC count; visit 4 (Week 39); n= 59	-0.84 ( 1.627 )
WBC count; visit 5 (Week 52); n= 54	-0.05 ( 1.989 )
WBC count; visit 6 (Week 69); n= 54	-0.41 ( 1.637 )
WBC count; visit 7 (Week 86); n= 50	-0.12 ( 2.059 )
WBC count; visit 8 (Week 104); n= 33	-0.51 ( 1.666 )
WBC count; visit 9 (Week 121); n= 32	0.58 ( 1.968 )
WBC count; visit 10 (Week 138); n= 32	0.22 ( 2.106 )
WBC count; visit 11 (Week 156); n= 27	0.09 ( 1.805 )
WBC count; visit 12 (Week 173); n= 22	-0.15 ( 1.971 )
WBC count; visit 13 (Week 190); n= 15	0.43 ( 2.804 )
WBC count; visit 14 (Week 208); n= 10	-0.49 ( 2.247 )
WBC count; visit 15 (Week 225); n= 4	-2.00 ( 2.608 )
WBC count; visit 16 (Week 242); n= 4	-2.10 ( 2.825 )
WBC count; visit 17 (Week 260); n= 4	-2.03 ( 2.941 )
WBC count; visit 18 (Week 277); n= 2	-3.60 ( 3.394 )
WBC count; withdrawal visit; n= 70	0.13 ( 1.757 )
WBC count; follow up visit; n= 50	-0.05 ( 1.905 )

Notes
[38] - Safety Population

No statistical analyses for this end point

Primary: Change from Baseline in hemoglobin and mean corpuscle hemoglobin concentration (MCHC) levels

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End point title

Change from Baseline in hemoglobin and mean corpuscle hemoglobin concentration (MCHC) levels ^[39]

End point description

Blood samples were collected from participants for evaluation of change from Baseline in clinical hematology parameters including hemoglobin and MCHC. Baseline was defined by and taken directly from the Baseline assessments in the parent study NCT01336621. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

End point type

Primary

End point timeframe

Baseline and up to 5.8 years

Notes
[39] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[40]
Units: G/L
arithmetic mean (standard deviation)
Hemoglobin; visit 1 (Screening); n= 85	-3.5 ( 6.75 )
Hemoglobin; visit 2 (Week 13); n= 89	-2.4 ( 7.87 )
Hemoglobin; visit 3 (Week 26); n= 74	-2.7 ( 7.59 )
Hemoglobin; visit 4 (Week 39); n= 69	-2.9 ( 9.09 )
Hemoglobin; visit 5 (Week 52); n= 64	-2.9 ( 9.51 )
Hemoglobin; visit 6 (Week 69); n= 62	-2.5 ( 9.83 )
Hemoglobin; visit 7 (Week 86); n= 55	-0.4 ( 8.75 )
Hemoglobin; visit 8 (Week 104); n= 41	-0.7 ( 8.35 )
Hemoglobin; visit 9 (Week 121); n= 36	-1.4 ( 8.68 )
Hemoglobin; visit 10 (Week 138); n= 36	0.1 ( 12.38 )
Hemoglobin; visit 11 (Week 156); n= 31	-3.4 ( 9.73 )
Hemoglobin; visit 12 (Week 173); n= 24	-2.2 ( 9.46 )
Hemoglobin; visit 13 (Week 190); n= 18	-4.3 ( 9.11 )
Hemoglobin; visit 14 (Week 208); n= 10	-8.0 ( 10.02 )
Hemoglobin; visit 15 (Week 225); n= 4	-6.0 ( 4.76 )
Hemoglobin; visit 16 (Week 242); n= 4	-9.5 ( 6.66 )
Hemoglobin; visit 17 (Week 260); n= 4	-8.0 ( 6.16 )
Hemoglobin; visit 18 (Week 277); n= 2	-10.5 ( 7.78 )
Hemoglobin; withdrawal visit; n= 79	-1.7 ( 9.69 )
Hemoglobin; follow up visit; n= 59	-2.3 ( 11.53 )
MCHC; visit 1 (Screening); n= 85	-2.1 ( 12.61 )
MCHC; visit 2 (Week 13); n= 89	1.4 ( 12.22 )
MCHC; visit 3 (Week 26); n= 74	-1.1 ( 11.50 )
MCHC; visit 4 (Week 39); n= 69	-4.6 ( 12.75 )
MCHC; visit 5 (Week 52); n= 64	-5.4 ( 13.35 )
MCHC; visit 6 (Week 69); n= 62	-4.8 ( 11.64 )
MCHC; visit 7 (Week 86); n= 55	-5.8 ( 9.79 )
MCHC; visit 8 (Week 104); n= 41	-9.1 ( 10.62 )
MCHC; visit 9 (Week 121); n= 36	-6.9 ( 11.74 )
MCHC; visit 10 (Week 138); n= 36	-9.6 ( 9.87 )
MCHC; visit 11 (Week 156); n= 31	-10.1 ( 11.76 )
MCHC; visit 12 (Week 173); n= 24	-10.7 ( 9.45 )
MCHC; visit 13 (Week 190); n= 18	-15.2 ( 9.24 )
MCHC; visit 14 (Week 208); n= 10	-21.5 ( 10.48 )
MCHC; visit 15 (Week 225); n= 4	-16.3 ( 7.59 )
MCHC; visit 16 (Week 242); n= 4	-14.5 ( 5.51 )
MCHC; visit 17 (Week 260); n= 4	-16.0 ( 8.25 )
MCHC; visit 18 (Week 277); n= 2	-4.5 ( 9.19 )
MCHC; withdrawal visit; n= 79	-6.8 ( 9.61 )
MCHC; follow up visit; n= 59	-8.6 ( 10.18 )

Notes
[40] - Safety Population

No statistical analyses for this end point

Primary: Change from Baseline in hematocrit levels

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End point title

Change from Baseline in hematocrit levels ^[41]

End point description

Blood samples were collected from participants for evaluation of change from Baseline in clinical hematology parameters including hematocrit. Baseline was defined by and taken directly from the Baseline assessments in the parent study NCT01336621. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

End point type

Primary

End point timeframe

Baseline and up to 5.8 years

Notes
[41] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[42]
Units: Proportion of red blood cells in blood
arithmetic mean (standard deviation)
Visit 1 (Screening); n= 85	-0.0080 ( 0.02259 )
Visit 2 (Week 13); n= 89	-0.0087 ( 0.02508 )
Visit 3 (Week 26); n= 74	-0.0066 ( 0.02651 )
Visit 4 (Week 39); n= 69	-0.0030 ( 0.02861 )
Visit 5 (Week 52); n= 64	-0.0020 ( 0.02985 )
Visit 6 (Week 69); n= 62	-0.0020 ( 0.02821 )
Visit 7 (Week 86); n= 55	0.0063 ( 0.02627 )
Visit 8 (Week 104); n= 41	0.0103 ( 0.02839 )
Visit 9 (Week 121); n= 36	0.0053 ( 0.02819 )
Visit 10 (Week 138); n= 36	0.0129 ( 0.04091 )
Visit 11 (Week 156); n= 31	0.0025 ( 0.02755 )
Visit 12 (Week 173); n= 24	0.0070 ( 0.03167 )
Visit 13 (Week 190); n= 18	0.0061 ( 0.02857 )
Visit 14 (Week 208); n= 10	0.0015 ( 0.03213 )
Visit 15 (Week 225); n= 4	0.0050 ( 0.01857 )
Visit 16 (Week 242); n= 4	-0.0097 ( 0.02017 )
Visit 17 (Week 260); n= 4	-0.0040 ( 0.00841 )
Visit 18 (Week 277); n= 2	-0.0270 ( 0.03677 )
Withdrawal visit; n= 79	0.0034 ( 0.02926 )
Follow up visit; n= 59	0.0039 ( 0.03501 )

Notes
[42] - Safety Population

No statistical analyses for this end point

Primary: Change from Baseline in mean corpuscle hemoglobin (MCH) levels

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End point title

Change from Baseline in mean corpuscle hemoglobin (MCH) levels ^[43]

End point description

Blood samples were collected from participants for evaluation of change from Baseline in clinical hematology parameters including MCH. Baseline was defined by and taken directly from the Baseline assessments in the parent study NCT01336621. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

End point type

Primary

End point timeframe

Baseline and up to 5.8 years

Notes
[43] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[44]
Units: Picograms (Pg)
arithmetic mean (standard deviation)
Visit 1 (Screening); n= 85	-0.17 ( 0.910 )
Visit 2 (Week 13); n= 89	-0.33 ( 1.058 )
Visit 3 (Week 26); n= 74	-0.47 ( 0.809 )
Visit 4 (Week 39); n= 69	-0.83 ( 1.238 )
Visit 5 (Week 52); n= 64	-0.77 ( 1.087 )
Visit 6 (Week 69); n= 62	-0.91 ( 1.317 )
Visit 7 (Week 86); n= 55	-0.99 ( 1.227 )
Visit 8 (Week 104); n= 41	-1.17 ( 1.503 )
Visit 9 (Week 121); n= 36	-1.11 ( 1.551 )
Visit 10 (Week 138); n= 36	-1.28 ( 1.282 )
Visit 11 (Week 156); n= 31	-1.44 ( 1.065 )
Visit 12 (Week 173); n= 24	-1.78 ( 1.380 )
Visit 13 (Week 190); n= 18	-1.90 ( 1.251 )
Visit 14 (Week 208); n= 10	-2.19 ( 1.883 )
Visit 15 (Week 225); n= 4	-2.00 ( 1.291 )
Visit 16 (Week 242); n= 4	-2.50 ( 1.669 )
Visit 17 (Week 260); n= 4	-1.83 ( 1.382 )
Visit 18 (Week 277); n= 2	-2.65 ( 0.354 )
Withdrawal visit; n= 79	-1.11 ( 1.305 )
Follow up visit; n= 59	-1.08 ( 1.437 )

Notes
[44] - Safety Population

No statistical analyses for this end point

Primary: Change from Baseline in mean corpuscle volume (MCV) and mean platelet volume (MPV) levels

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End point title

Change from Baseline in mean corpuscle volume (MCV) and mean platelet volume (MPV) levels ^[45]

End point description

Blood samples were collected from participants for evaluation of change from Baseline in clinical hematology parameters including MCV and MPV. Baseline was defined by and taken directly from the Baseline assessments in the parent study NCT01336621. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

End point type

Primary

End point timeframe

Baseline and up to 5.8 years

Notes
[45] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[46]
Units: Femtoliter (fL)
arithmetic mean (standard deviation)
MCV (Screening); Visit 1; n= 85	0.0 ( 3.55 )
MCV; Visit 2 (Week 13); n= 89	-1.5 ( 3.63 )
MCV; Visit 3 (Week 26); n= 74	-1.0 ( 3.32 )
MCV; Visit 4 (Week 39); n= 69	-1.2 ( 3.62 )
MCV; Visit 5 (Week 52); n= 64	-0.8 ( 3.71 )
MCV; Visit 6 (Week 69); n= 62	-1.4 ( 4.29 )
MCV; Visit 7 (Week 86); n= 55	-1.2 ( 3.56 )
MCV; Visit 8 (Week 104); n= 41	-0.9 ( 4.75 )
MCV; Visit 9 (Week 121); n= 36	-1.4 ( 4.00 )
MCV; Visit 10 (Week 138); n= 36	-1.1 ( 4.30 )
MCV; Visit 11 (Week 156); n= 31	-1.5 ( 4.18 )
MCV; Visit 12 (Week 173); n= 24	-2.5 ( 4.64 )
MCV; Visit 13 (Week 190); n= 18	-1.2 ( 4.40 )
MCV; Visit 14 (Week 208); n= 10	-0.9 ( 4.48 )
MCV; Visit 15 (Week 225); n= 4	-1.5 ( 1.73 )
MCV; Visit 16 (Week 242); n= 4	-4.0 ( 3.92 )
MCV; Visit 17 (Week 260); n= 4	-1.3 ( 2.63 )
MCV; Visit 18 (Week 277); n= 2	-7.0 ( 4.24 )
MCV; Withdrawal visit; n= 79	-1.4 ( 4.14 )
MCV; Follow up visit; n= 59	-0.9 ( 4.39 )
MPV; visit 1 (Screening); n= 84	-0.12 ( 0.715 )
MPV: visit 2 (Week 13); n= 86	-0.10 ( 0.756 )
MPV: visit 3 (Week 26); n= 71	-0.08 ( 0.612 )
MPV; visit 4 (Week 39); n= 67	-0.17 ( 0.823 )
MPV; visit 5 (Week 52); n= 61	-0.06 ( 0.746 )
MPV; visit 6 (Week 69); n= 58	-0.03 ( 0.654 )
MPV; visit 7 (Week 86); n= 53	0.12 ( 0.786 )
MPV; visit 8 (Week 104); n= 38	0.01 ( 0.902 )
MPV: visit 9 (Week 121); n= 35	0.13 ( 0.788 )
MPV; visit 10 (Week 138); n= 34	0.06 ( 0.773 )
MPV; visit 11 (Week 156); n= 29	0.14 ( 0.728 )
MPV: visit 12 (Week 173); n= 24	0.04 ( 0.944 )
MPV; visit 13 (Week 190); n= 17	-0.09 ( 0.766 )
MPV; visit 14 (Week 208); n= 10	-0.37 ( 0.455 )
MPV; visit 15 (Week 225); n= 4	-0.33 ( 1.053 )
MPV; visit 16 (Week 242); n= 4	-0.75 ( 0.802 )
MPV; visit 17 (Week 260); n= 4	-0.17 ( 0.670 )
MPV; visit 18 (Week 277); n= 2	-1.15 ( 0.071 )
MPV; withdrawal visit; n= 78	0.19 ( 0.902 )
MPV; follow up visit; n= 57	0.12 ( 0.859 )

Notes
[46] - Safety Population

No statistical analyses for this end point

Primary: Change from Baseline in RBC count

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End point title

Change from Baseline in RBC count ^[47]

End point description

Blood samples were collected from participants for evaluation of change from Baseline in clinical hematology parameters including RBC count. Baseline was defined by and taken directly from the Baseline assessments in the parent study NCT01336621. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

End point type

Primary

End point timeframe

Up to 5.8 years

Notes
[47] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[48]
Units: Tetra cells per liter (TI/L)
arithmetic mean (standard deviation)
Visit 1 (Screening); n= 85	-0.10 ( 0.212 )
Visit 2 (Week 13); n= 89	-0.03 ( 0.255 )
Visit 3 (Week 26); n= 74	-0.03 ( 0.240 )
Visit 4 (Week 39); n= 69	0.01 ( 0.272 )
Visit 5 (Week 52); n= 64	0.00 ( 0.311 )
Visit 6 (Week 69); n= 62	0.04 ( 0.300 )
Visit 7 (Week 86); n= 55	0.12 ( 0.260 )
Visit 8 (Week 104); n= 41	0.14 ( 0.280 )
Visit 9 (Week 121); n= 36	0.11 ( 0.299 )
Visit 10 (Week 138); n= 36	0.19 ( 0.445 )
Visit 11 (Week 156); n= 31	0.09 ( 0.344 )
Visit 12 (Week 173); n= 24	0.18 ( 0.385 )
Visit 13 (Week 190); n= 18	0.12 ( 0.343 )
Visit 14 (Week 208); n= 10	0.05 ( 0.366 )
Visit 15 (Week 225); n= 4	0.13 ( 0.206 )
Visit 16 (Week 242); n= 4	0.10 ( 0.216 )
Visit 17 (Week 260); n= 4	0.00 ( 0.082 )
Visit 18 (Week 277); n= 2	0.05 ( 0.212 )
Withdrawal visit; n= 79	0.10 ( 0.327 )
Follow up visit; n= 59	0.07 ( 0.409 )

Notes
[48] - Safety Population

No statistical analyses for this end point

Primary: Change from Baseline in percent basophils, percent eosinophils, percent lymphocytes, percent monocytes, percent neutrophils and RBC distribution width (RDW) levels

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End point title

Change from Baseline in percent basophils, percent eosinophils, percent lymphocytes, percent monocytes, percent neutrophils and RBC distribution width (RDW) levels ^[49]

End point description

Blood samples were collected from participants for evaluation of change from Baseline in clinical hematology parameters including percent basophils, eosinophils, lymphocytes, monocytes, neutrophils and RDW. Baseline was defined by and taken directly from the Baseline assessments in the parent study NCT01336621. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

End point type

Primary

End point timeframe

Baseline and up to 5.8 years

Notes
[49] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[50]
Units: Percent of blood components
arithmetic mean (standard deviation)
Percent basophils; visit 1 (Screening); n= 84	0.00 ( 0.312 )
Percent basophils; visit 2 (Week 13); n= 85	-0.06 ( 0.243 )
Percent basophils; visit 3 (Week 26); n= 71	-0.03 ( 0.305 )
Percent basophils; visit 4 (Week 39); n= 65	0.07 ( 0.393 )
Percent basophils; visit 5 (Week 52); n= 60	0.04 ( 0.279 )
Percent basophils; visit 6 (Week 69); n= 58	-0.02 ( 0.315 )
Percent basophils; visit 7 (Week 86); n= 53	-0.02 ( 0.302 )
Percent basophils; visit 8 (Week 104); n= 36	0.11 ( 0.271 )
Percent basophils; visit 9 (Week 121); n= 35	-0.06 ( 0.239 )
Percent basophils; visit 10 (Week 138); n= 33	-0.02 ( 0.255 )
Percent basophils; visit 11 (Week 156); n= 29	0.00 ( 0.267 )
Percent basophils; visit 12 (Week 173); n= 24	-0.06 ( 0.253 )
Percent basophils; visit 13 (Week 190); n= 17	-0.01 ( 0.339 )
Percent basophils; visit 14 (Week 208); n= 10	-0.03 ( 0.283 )
Percent basophils; visit 15 (Week 225); n= 4	0.00 ( 0.216 )
Percent basophils; visit 16 (Week 242); n= 4	0.03 ( 0.126 )
Percent basophils; visit 17 (Week 260); n= 4	0.03 ( 0.050 )
Percent basophils; visit 18 (Week 277); n= 2	0.25 ( 0.212 )
Percent basophils; withdrawal visit; n= 78	0.01 ( 0.291 )
Percent basophils; follow up visit; n= 56	-0.13 ( 0.304 )
Percent eosinophils; visit 1 (Screening); n= 84	-0.06 ( 1.745 )
Percent eosinophils; visit 2 (Week 13); n= 85	0.00 ( 3.214 )
Percent eosinophils; visit 3 (Week 26); n= 71	-0.29 ( 2.773 )
Percent eosinophils; visit 4 (Week 39); n= 65	-0.44 ( 3.339 )
Percent eosinophils; visit 5 (Week 52); n= 60	-0.77 ( 4.046 )
Percent eosinophils; visit 6 (Week 69); n= 58	-0.26 ( 2.630 )
Percent eosinophils; visit 7 (Week 86); n= 53	-0.30 ( 2.634 )
Percent eosinophils; visit 8 (Week 104); n= 36	-0.04 ( 3.003 )
Percent eosinophils; visit 9 (Week 121); n= 35	-0.47 ( 2.653 )
Percent eosinophils; visit 10 (Week 138); n= 33	-0.92 ( 2.942 )
Percent eosinophils; visit 11 (Week 156); n= 29	-0.79 ( 2.484 )
Percent eosinophils; visit 12 (Week 173); n= 24	-0.70 ( 5.548 )
Percent eosinophils; visit 13 (Week 190); n= 17	-1.38 ( 5.539 )
Percent eosinophils; visit 14 (Week 208); n= 10	-2.49 ( 2.975 )
Percent eosinophils; visit 15 (Week 225); n= 4	-1.53 ( 1.565 )
Percent eosinophils; visit 16 (Week 242); n= 4	-0.43 ( 1.628 )
Percent eosinophils; visit 17 (Week 260); n= 4	0.00 ( 1.359 )
Percent eosinophils; visit 18 (Week 277); n= 2	1.65 ( 0.636 )
Percent eosinophils; withdrawal visit; n= 78	-0.83 ( 3.466 )
Percent eosinophils; follow up visit; n= 56	-1.30 ( 3.804 )
Percent lymphocytes; visit 1 (Screening); n= 84	-2.21 ( 8.440 )
Percent lymphocytes; visit 2 (Week 13); n= 85	-0.40 ( 9.550 )
Percent lymphocytes; visit 3 (Week 26); n= 71	-1.14 ( 10.820 )
Percent lymphocytes; visit 4 (Week 39); n= 65	0.27 ( 9.306 )
Percent lymphocytes; visit 5 (Week 52); n= 60	-2.58 ( 11.216 )
Percent lymphocytes; visit 6 (Week 69); n= 58	-1.26 ( 8.119 )
Percent lymphocytes; visit 7 (Week 86); n= 53	-0.53 ( 11.226 )
Percent lymphocytes; visit 8 (Week 104); n= 36	0.69 ( 9.013 )
Percent lymphocytes; visit 9 (Week 121); n= 35	-2.27 ( 11.733 )
Percent lymphocytes; visit 10 (Week 138); n= 33	-3.91 ( 8.960 )
Percent lymphocytes; visit 11 (Week 156); n= 29	-4.52 ( 9.015 )
Percent lymphocytes; visit 12 (Week 173); n= 24	-3.19 ( 9.398 )
Percent lymphocytes; visit 13 (Week 190); n= 17	-4.73 ( 12.168 )
Percent lymphocytes; visit 14 (Week 208); n= 10	-3.72 ( 5.911 )
Percent lymphocytes; visit 15 (Week 225); n= 4	-6.58 ( 3.848 )
Percent lymphocytes; visit 16 (Week 242); n= 4	-3.88 ( 10.160 )
Percent lymphocytes; visit 17 (Week 260); n= 4	-5.85 ( 4.886 )
Percent lymphocytes; visit 18 (Week 277); n= 2	-8.10 ( 3.818 )
Percent lymphocytes; withdrawal visit; n= 78	-2.60 ( 10.978 )
Percent lymphocytes; follow up visit; n= 56	-0.81 ( 12.709 )
Percent monocytes; visit 1 (Screening); n= 84	-0.33 ( 3.048 )
Percent monocytes; visit 2 (Week 13); n= 85	0.27 ( 2.720 )
Percent monocytes; visit 3 (Week 26); n= 71	0.86 ( 3.274 )
Percent monocytes; visit 4 (Week 39); n= 65	0.76 ( 3.286 )
Percent monocytes; visit 5 (Week 52); n= 60	-0.01 ( 3.058 )
Percent monocytes; visit 6 (Week 69); n= 58	0.64 ( 2.834 )
Percent monocytes; visit 7 (Week 86); n= 53	0.94 ( 3.148 )
Percent monocytes; visit 8 (Week 104); n= 36	0.04 ( 3.458 )
Percent monocytes; visit 9 (Week 121); n= 35	-0.11 ( 2.895 )
Percent monocytes; visit 10 (Week 138); n= 33	0.15 ( 3.160 )
Percent monocytes; visit 11 (Week 156); n= 29	-0.27 ( 3.007 )
Percent monocytes; visit 12 (Week 173); n= 24	-0.44 ( 2.687 )
Percent monocytes; visit 13 (Week 190); n= 17	-1.43 ( 2.909 )
Percent monocytes; visit 14 (Week 208); n= 10	-0.71 ( 5.153 )
Percent monocytes; visit 15 (Week 225); n= 4	1.08 ( 1.090 )
Percent monocytes; visit 16 (Week 242); n= 4	1.25 ( 1.686 )
Percent monocytes; visit 17 (Week 260); n= 4	2.03 ( 2.219 )
Percent monocytes; visit 18 (Week 277); n= 2	4.20 ( 2.687 )
Percent monocytes; withdrawal visit; n= 78	0.48 ( 3.355 )
Percent monocytes; follow up visit; n= 56	-0.35 ( 3.293 )
Percent neutrophils; visit 1 (Screening); n= 84	2.60 ( 11.021 )
Percent neutrophils; visit 2 (Week 13); n= 85	0.19 ( 11.584 )
Percent neutrophils; visit 3 (Week 26); n= 71	0.60 ( 12.994 )
Percent neutrophils; visit 4 (Week 39); n= 65	-0.66 ( 11.810 )
Percent neutrophils; visit 5 (Week 52); n= 60	3.31 ( 14.222 )
Percent neutrophils; visit 6 (Week 69); n= 58	0.90 ( 10.552 )
Percent neutrophils; visit 7 (Week 86); n= 53	-0.09 ( 14.427 )
Percent neutrophils; visit 8 (Week 104); n= 37	-0.81 ( 11.595 )
Percent neutrophils; visit 9 (Week 121); n= 35	2.91 ( 14.604 )
Percent neutrophils; visit 10 (Week 138); n= 33	4.70 ( 12.464 )
Percent neutrophils; visit 11 (Week 156); n= 29	5.58 ( 10.691 )
Percent neutrophils; visit 12 (Week 173); n= 24	4.39 ( 13.509 )
Percent neutrophils; visit 13 (Week 190); n= 17	7.55 ( 16.056 )
Percent neutrophils; visit 14 (Week 208); n= 10	6.95 ( 7.643 )
Percent neutrophils; visit 15 (Week 225); n= 4	7.03 ( 5.900 )
Percent neutrophils; visit 16 (Week 242); n= 4	3.03 ( 10.460 )
Percent neutrophils; visit 17 (Week 260); n= 4	3.80 ( 3.990 )
Percent neutrophils; visit 18 (Week 277); n= 2	2.00 ( 7.354 )
Percent neutrophils; withdrawal visit; n= 78	2.94 ( 13.146 )
Percent neutrophils; follow up visit; n= 56	2.58 ( 14.680 )
RDW; visit 1 (Screening); n= 85	0.41 ( 1.398 )
RDW; visit 2 (Week 13); n= 89	-0.07 ( 1.532 )
RDW; visit 3 (Week 26); n= 74	0.05 ( 0.924 )
RDW; visit 4 (Week 39); n= 69	0.47 ( 1.637 )
RDW; visit 5 (Week 52); n= 64	0.35 ( 1.598 )
RDW; visit 6 (Week 69); n= 62	0.05 ( 1.437 )
RDW; visit 7 (Week 86); n= 55	0.05 ( 1.109 )
RDW; visit 8 (Week 104); n= 41	0.32 ( 1.386 )
RDW; visit 9 (Week 121); n= 36	-0.19 ( 1.084 )
RDW; visit 10 (Week 138); n= 36	0.22 ( 0.885 )
RDW; visit 11 (Week 156); n= 31	0.94 ( 1.760 )
RDW; visit 12 (Week 173); n= 24	0.41 ( 1.292 )
RDW; visit 13 (Week 190); n= 18	0.88 ( 0.919 )
RDW; visit 14 (Week 208); n= 10	1.98 ( 1.605 )
RDW; visit 15 (Week 225); n= 4	0.28 ( 0.550 )
RDW; visit 16 (Week 242); n= 4	3.95 ( 6.855 )
RDW; visit 17 (Week 260); n= 4	2.50 ( 2.202 )
RDW; visit 18 (Week 277); n= 2	2.05 ( 0.495 )
RDW; withdrawal visit; n= 79	0.10 ( 1.097 )
RDW; follow up visit; n= 59	0.27 ( 1.235 )

Notes
[50] - Safety Population

No statistical analyses for this end point

Primary: Change from Baseline in urine albumin creatinine ratio

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End point title

Change from Baseline in urine albumin creatinine ratio ^[51]

End point description

Urine samples were collected from participants for evaluation of change from Baseline in urinalysis parameters including albumin creatinine ratio. Baseline was defined by and taken directly from the Baseline assessments in the parent study NCT01336621. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

End point type

Primary

End point timeframe

Baseline and up to 5.8 years

Notes
[51] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[52]
Units: Mg of urine albumin/ mmol of creatinine
arithmetic mean (standard deviation)
Visit 1 (Screening); n= 39	-0.57 ( 3.573 )
Visit 2 (Week 13); n= 72	-0.07 ( 3.172 )
Visit 3 (Week 26); n= 54	0.15 ( 3.678 )
Visit 4 (Week 39); n= 53	-0.64 ( 3.241 )
Visit 5 (Week 52); n= 52	-0.69 ( 3.065 )
Visit 6 (Week 69); n= 46	-0.53 ( 3.489 )
Visit 7 (Week 86); n= 47	0.07 ( 6.062 )
Visit 8 (Week 104); n= 32	-0.75 ( 4.508 )
Visit 9 (Week 121); n= 30	-0.89 ( 5.421 )
Visit 10 (Week 138); n= 26	-1.05 ( 4.236 )
Visit 11 (Week 156); n= 22	-0.65 ( 2.494 )
Visit 12 (Week 173); n= 19	-1.81 ( 5.060 )
Visit 13 (Week 190); n= 10	-0.59 ( 1.748 )
Visit 14 (Week 208); n= 8	-1.70 ( 4.032 )
Visit 15 (Week 225); n= 4	0.13 ( 0.981 )
Visit 16 (Week 242); n= 3	-0.33 ( 0.153 )
Visit 17 (Week 260); n= 3	-0.33 ( 0.321 )
Visit 18 (Week 277); n= 2	-0.50 ( 0.990 )
Withdrawal visit; n= 63	-0.35 ( 3.874 )
Follow up visit; n= 48	-0.62 ( 3.515 )

Notes
[52] - Safety Population

No statistical analyses for this end point

Primary: Change from Baseline in urine albumin levels

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End point title

Change from Baseline in urine albumin levels ^[53]

End point description

Urine samples were collected from participants for evaluation of change from Baseline in urinalysis parameters including albumin levels. Baseline was defined by and taken directly from the Baseline assessments in the parent study NCT01336621. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

End point type

Primary

End point timeframe

Baseline and up to 5.8 years

Notes
[53] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[54]
Units: Milligrams per liter (mg/L)
arithmetic mean (standard deviation)
Visit 1 (Screening); n= 39	-5.2 ( 57.64 )
Visit 2 (Week 13); n= 72	-1.8 ( 48.39 )
Visit 3 (Week 26); n= 54	-17.1 ( 92.34 )
Visit 4 (Week 39); n= 53	-21.0 ( 94.25 )
Visit 5 (Week 52); n= 52	-21.6 ( 94.87 )
Visit 6 (Week 69); n= 46	-15.7 ( 56.98 )
Visit 7 (Week 86); n= 47	7.7 ( 131.03 )
Visit 8 (Week 104); n= 32	-8.1 ( 59.50 )
Visit 9 (Week 121); n= 30	-14.7 ( 61.73 )
Visit 10 (Week 138); n= 26	-16.0 ( 66.79 )
Visit 11 (Week 156); n= 22	-7.4 ( 35.40 )
Visit 12 (Week 173); n= 19	-27.2 ( 80.24 )
Visit 13 (Week 190); n= 10	-2.8 ( 27.95 )
Visit 14 (Week 208); n= 8	-15.9 ( 45.76 )
Visit 15 (Week 225); n= 4	-1.8 ( 11.53 )
Visit 16 (Week 242); n= 3	-8.7 ( 9.61 )
Visit 17 (Week 260); n= 3	-3.3 ( 12.86 )
Visit 18 (Week 277); n= 2	-7.5 ( 0.71 )
Withdrawal visit; n= 63	-6.5 ( 51.69 )
Follow up visit; n= 48	-19.9 ( 99.24 )

Notes
[54] - Safety Population

No statistical analyses for this end point

Primary: Change from baseline in urine creatinine levels

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End point title

Change from baseline in urine creatinine levels ^[55]

End point description

Urine samples were collected from participants for evaluation of change from Baseline in urinalysis parameters including creatinine levels. Baseline was defined by and taken directly from the Baseline assessments in the parent study NCT01336621. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

End point type

Primary

End point timeframe

Baseline and up to 5.8 years

Notes
[55] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[56]
Units: µmol/L
arithmetic mean (standard deviation)
Visit 1 (Screening); n= 52	-2019.6 ( 10153.70 )
Visit 2 (Week 13); n= 89	-1846.2 ( 8206.65 )
Visit 3 (Week 26); n= 75	-3023.7 ( 9197.50 )
Visit 4 (Week 39); n= 66	-2849.6 ( 7810.79 )
Visit 5 (Week 52); n= 63	-1626.5 ( 10205.13 )
Visit 6 (Week 69); n= 59	-3534.2 ( 8657.09 )
Visit 7 (Week 86); n= 55	-2664.4 ( 7900.30 )
Visit 8 (Week 104); n= 42	-2645.1 ( 8368.43 )
Visit 9 (Week 121); n= 37	-1727.3 ( 10330.75 )
Visit 10 (Week 138); n= 35	-1712.6 ( 11352.03 )
Visit 11 (Week 156); n= 30	-1400.0 ( 13151.92 )
Visit 12 (Week 173); n= 23	-1008.3 ( 9395.56 )
Visit 13 (Week 190); n= 19	-3604.1 ( 10215.20 )
Visit 14 (Week 208); n= 10	3238.3 ( 12290.24 )
Visit 15 (Week 225); n= 5	-675.0 ( 16785.90 )
Visit 16 (Week 242); n= 4	-5426.3 ( 13280.49 )
Visit 17 (Week 260); n= 4	148.8 ( 15164.36 )
Visit 18 (Week 277); n= 2	-7337.5 ( 10850.55 )
Withdrawal visit; n= 80	-3570.3 ( 8244.65 )
Follow up visit; n= 60	-515.8 ( 9359.74 )

Notes
[56] - Safety Population

No statistical analyses for this end point

Primary: Changes from Baseline in American Urological Association Symptom Scale (AUA SS) score

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End point title

Changes from Baseline in American Urological Association Symptom Scale (AUA SS) score ^[57]

End point description

The effect of retigabine on bladder function was assessed using AUA symptom index. It is a 7-item Likert-scored scale ranging from 0 (no symptom at all) to 5 (almost always symptoms present) with a total possible score of 35. AUA SS score is the sum of the responses to these seven questions. The total score for all questions was classified as mild (0 to 7), moderate (8 to 19), or severe (>19). Baseline was defined by and taken directly from the Baseline assessments in the parent study NCT01336621. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

End point type

Primary

End point timeframe

Baseline and up to 5.8 years

Notes
[57] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[58]
Units: Score on AUA SS scale
arithmetic mean (standard deviation)
Visit 3 (Week 26); n= 82	-0.7 ( 3.50 )
Visit 5 (Week 52); n= 68	-0.9 ( 4.67 )
Visit 8 (Week 104); n= 42	-1.0 ( 3.79 )
Visit 11 (Week 156); n= 31	-1.0 ( 4.18 )
Visit 14 (Week 208); n= 10	-2.3 ( 5.54 )
Visit 17 (Week 260); n= 4	-6.5 ( 7.72 )
Withdrawal visit; n= 85	-1.0 ( 3.99 )

Notes
[58] - Safety Population

No statistical analyses for this end point

Primary: Change from Baseline in Post-Void Residual (PVR) bladder ultrasound urine volume

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End point title

Change from Baseline in Post-Void Residual (PVR) bladder ultrasound urine volume ^[59]

End point description

The PVR bladder ultrasound was used to assess urinary retention. Baseline was defined by and taken directly from the Baseline assessments in the parent study NCT01336621. Change from Baseline was defined as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

End point type

Primary

End point timeframe

Baseline and up to 5.8 years

Notes
[59] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[60]
Units: Milliliter (mL)
arithmetic mean (standard deviation)
Visit 3 (Week 26); n= 77	-6.0 ( 24.73 )
Visit 5 (Week 52); n= 64	2.7 ( 49.20 )
Visit 8 (Week 104); n= 40	3.9 ( 49.03 )
Visit 11 (Week 156); n= 25	2.0 ( 18.40 )
Visit 14 (Week 208); n= 10	-16.0 ( 21.33 )
Visit 17 (Week 260); n= 4	-23.3 ( 25.00 )
Withdrawal visit; n= 67	-7.6 ( 30.39 )

Notes
[60] - Safety Population

No statistical analyses for this end point

Primary: Number of participants with suicidal ideation or behavior assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) score

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End point title

Number of participants with suicidal ideation or behavior assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) score ^[61]

End point description

Number of participants with suicidal ideation or behavior during treatment were assessed using the C-SSRS score scale. It is a brief questionnaire designed to assess severity and change in suicidality by integrating both behavior and ideation using a semi-structured interview to probe participant responses. Participants are classified with respect to extent of suicidal ideation, extent of suicidal behavior, and with respect to self-injurious behavior.

End point type

Primary

End point timeframe

Up to 5.8 years

Notes
[61] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	95 ^[62]
Units: Participants
Suicidal ideation	1
Suicidal behavior	0
Self-injurious behavior, no suicidal attempt	0

Notes
[62] - Safety Population

No statistical analyses for this end point

Primary: Number of participants experiencing new seizure types

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End point title

Number of participants experiencing new seizure types ^[63]

End point description

Number of participants experiencing new seizure type that is seizure not experienced before were summarized. New seizure types were classified into 5 classes including type A (simple partial seizure), type B (complex partial seizure), type C (Partials, evolving to Secondary Generalized Seizures), type D (Generalized, excluding Myoclonic Seizures), type D2 (Myoclonic Seizures) and type E (Unclassified Seizures).

End point type

Primary

End point timeframe

Up to 5.8 years

Notes
[63] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[64]
Units: Participants
Type A; Simple Partial Seizures	5
Type B; Complex Partial Seizures	2
Type C; Partials, evolving to Sec. Gen. Seizures	0
Type D; Generalized, excl. Myoclonic Seizures	0
Type D2; Myoclonic Seizures	0
Type E; Unclassified seizures	0

Notes
[64] - Safety Population

No statistical analyses for this end point

Primary: Number of participants experiencing worsening of seizures

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End point title

Number of participants experiencing worsening of seizures ^[65]

End point description

Worsening of seizures was defined as an increase in seizure frequency or the occurrence of a new, more severe seizure type, or status epilepticus occurring in a participant without a history of status epilepticus. An increase in seizure frequency was defined as doubling of the 28-day seizure frequency compared to the 28-day Baseline seizure frequency established in the parent study. Number of participants experiencing worsening of seizure during study period are presented.

End point type

Primary

End point timeframe

Up to 5.8 years

Notes
[65] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[66]
Units: Participants
Participants	1

Notes
[66] - Safety Population

No statistical analyses for this end point

Primary: Duration of retigabine exposure

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End point title

Duration of retigabine exposure ^[67]

End point description

Duration of exposure was calculated from the first dose through the last dose during study including the Taper Phase and presented using median and full range.

End point type

Primary

End point timeframe

Up to 5.8 years

Notes
[67] - 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: There are no statistical data to report.

End point values	Retigabine IR
Number of subjects analysed	98 ^[68]
Units: Weeks
median (full range (min-max))
Weeks	103.7 (0.5 to 284)

Notes
[68] - Safety Population

No statistical analyses for this end point

Secondary: Number of participants experiencing a 0 to <25, 25 to <50, 50 to <75 and 75 to 100 percent reduction in 28 day POS frequency from Baseline

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End point title

Number of participants experiencing a 0 to <25, 25 to <50, 50 to <75 and 75 to 100 percent reduction in 28 day POS frequency from Baseline

End point description

The seizure frequency was recorded in daily seizure calendar by participants during the treatment period. Baseline assessments in this OLE study are defined by and taken directly from the Baseline assessments in the parent study NCT01336621.

End point type

Secondary

End point timeframe

Baseline and up to 5.8 years

End point values	Retigabine IR
Number of subjects analysed	98 ^[69]
Units: Participants
0 to <25 percent reduction	7
25 to <50 percent reduction	13
50 to <75 percent reduction	26
75 to 100 percent reduction	42

Notes
[69] - Safety Population

No statistical analyses for this end point

Secondary: Percent change from Baseline in 28-day partial-onset seizure frequency

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End point title

Percent change from Baseline in 28-day partial-onset seizure frequency

End point description

The seizure frequency was recorded in daily seizure calendar by participants during the treatment period. Percent change from Baseline in 28-day partial onset seizure frequency was presented as mean and standard deviation (SD). Baseline assessments in this OLE study are defined by and taken directly from the Baseline assessments in the parent study NCT01336621. Percent change from Baseline was calculated as post-Baseline value minus Baseline value divided by Baseline value into 100.

End point type

Secondary

End point timeframe

Baseline and up to 5.8 years

End point values	Retigabine IR
Number of subjects analysed	98 ^[70]
Units: Percent change
arithmetic mean (standard deviation)
Category title 1	-56.9 ( 52.46 )

Notes
[70] - Safety Population

No statistical analyses for this end point

Secondary: Number of participants experiencing an increase in 28-day partial-onset seizure frequency from Baseline

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End point title

Number of participants experiencing an increase in 28-day partial-onset seizure frequency from Baseline

End point description

End point type

Secondary

End point timeframe

Baseline and up to 5.8 years

End point values	Retigabine IR
Number of subjects analysed	98 ^[71]
Units: Participants
Participants	10

Notes
[71] - Safety Population

No statistical analyses for this end point

Secondary: Number of participants who remained seizure-free

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End point title

Number of participants who remained seizure-free

End point description

The seizure frequency was recorded in daily seizure calendar by participants during the treatment period. Number of participants who were treated retigabine for at least 6 months and who remained seizure free for any 6 continuous months as well as number of participants who were treated with retigabine for at least 12 months and who remained seizure free for any 12 continuous months are presented.

End point type

Secondary

End point timeframe

Up to 5.8 years

End point values	Retigabine IR
Number of subjects analysed	98 ^[72]
Units: Participants
Seizure free for 6 months; n= 85	27
Seizure free for 12 months; n= 71	13

Notes
[72] - Safety Population

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment until the Follow up (Up to 5.8 years)

Adverse event reporting additional description

AEs and SAEs were collected in Safety Population which comprised all the participants who took at least 1 dose of study medication after they have enrolled into this OLE study.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

Retigabine IR

Reporting group description

Serious adverse events	Retigabine IR
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 98 (4.08%)
number of deaths (all causes)	0
number of deaths resulting from adverse events
Investigations
Hemoglobin decreased
subjects affected / exposed	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant melanoma stage II
subjects affected / exposed	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Injury, poisoning and procedural complications
Scar
subjects affected / exposed	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Nervous system disorders
Cerebrovascular disorder
subjects affected / exposed	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 2
deaths causally related to treatment / all	0 / 0
Generalised tonic-clonic seizure
subjects affected / exposed	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Seizure
subjects affected / exposed	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Psychiatric disorders
Agitation
subjects affected / exposed	1 / 98 (1.02%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Epileptic psychosis
subjects affected / exposed	1 / 98 (1.02%)
occurrences causally related to treatment / all	1 / 1
deaths causally related to treatment / all	0 / 0

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

Non-serious adverse events	Retigabine IR
Total subjects affected by non serious adverse events
subjects affected / exposed	38 / 98 (38.78%)
Investigations
Weight increased
subjects affected / exposed	7 / 98 (7.14%)
occurrences all number	7
Nervous system disorders
Dizziness
subjects affected / exposed	14 / 98 (14.29%)
occurrences all number	18
Headache
subjects affected / exposed	10 / 98 (10.20%)
occurrences all number	23
General disorders and administration site conditions
Asthenia
subjects affected / exposed	11 / 98 (11.22%)
occurrences all number	20
Respiratory, thoracic and mediastinal disorders
Respiratory disorder
subjects affected / exposed	6 / 98 (6.12%)
occurrences all number	7
Skin and subcutaneous tissue disorders
Nail pigmentation
subjects affected / exposed	6 / 98 (6.12%)
occurrences all number	6
Infections and infestations
Bacteriuria
subjects affected / exposed	6 / 98 (6.12%)
occurrences all number	7

More information

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Were there any global substantial amendments to the protocol? Yes

16 Oct 2013

To update the Sponsor Information page including change in Medical Monitor; to add the requirement to re-evaluate all ongoing participants at each clinic visit with respect to the risk versus the benefit of continuing treatment with Retigabine; revision of study conclusion conditions under which participants will continue to receive retigabine treatment; to re-consent all ongoing participants with revised patient information materials detailing the risk of retinal pigmentation, possible vision loss, pigmentation of non retinal ocular tissue, and discolouration of skin, lips, nails or Mucosa; Addition of 6-monthly comprehensive eye assessments by an ophthalmologist/retina specialist to assess for retinal pigmentation and/or unexplained vision loss; Addition of a skin examination by the investigator at scheduled clinic visits; Addition of referral to a dermatologist for abnormal skin discolouration noted by the investigator or reported by the participant, and repeat 6-monthly assessments by the dermatologist for follow-up of confirmed abnormal skin discolouration; Addition of a Safety Follow-Up / Continuation Phase to provide follow-up of participants who are found to have retinal pigmentation, unexplained vision loss, pigmentation of non-retinal ocular tissue or abnormal discolouration of skin, lips, nails or mucosa and who have stopped taking retigabine; Addition of safety endpoints related to abnormal pigmentation of the eye and/or discolouration of the skin, lips, nails or mucosa; Addition of Pharmacogenetics (PGx) sample collection.

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.

17 parts. withdrew due to AE, however only 16 had a TEAE leading to withdrawal of RTG. 1 part. with a TEAE of seizure, withdrew due to lack of efficacy. 2 further parts. withdrew due to AE but had no TEAEs which led to withdrawal of RTG.

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Clinical trials

Clinical Trial Results: A Multicentre, Open-Label, Long-Term, Safety and Tolerability Study of Retigabine Immediate Release (IR) in Adults with Partial-Onset Seizures (Extension of Study RGB113905)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of participants with treatment emergent adverse events (TEAEs) and serious AEs (TESAEs)

Primary: Number of participants with treatment emergent adverse events (TEAEs) and serious AEs (TESAEs)

Primary: Number of participants withdrawn due to TEAEs

Primary: Number of participants withdrawn due to TEAEs

Primary: Number of participants with retinal pigmentary abnormalities

Primary: Number of participants with retinal pigmentary abnormalities

Primary: Number of participants with pigmentation of non-retinal ocular tissue(s)

Primary: Number of participants with pigmentation of non-retinal ocular tissue(s)

Primary: Number of participants with abnormal discoloration of skin

Primary: Number of participants with abnormal discoloration of skin

Primary: Number of participants with a clinically significant decrease in visual acuity from initial examination

Primary: Number of participants with a clinically significant decrease in visual acuity from initial examination

Primary: Number of participants with decrease in confrontational visual field from initial examination

Primary: Number of participants with decrease in confrontational visual field from initial examination

Primary: Number of participants with potential clinical concern (PCC) values of change from Baseline in vital signs and weight

Primary: Number of participants with potential clinical concern (PCC) values of change from Baseline in vital signs and weight

Primary: Change from Baseline in electrocardiogram (ECG) parameter including HR

Primary: Change from Baseline in electrocardiogram (ECG) parameter including HR

Primary: Change from Baseline in ECG parameter including PR interval, QRS duration, uncorrected QT interval, corrected QT by Bazett's formula (QTcB), corrected QT by Fridericia's formula (QTcF) and RR interval

Primary: Change from Baseline in ECG parameter including PR interval, QRS duration, uncorrected QT interval, corrected QT by Bazett's formula (QTcB), corrected QT by Fridericia's formula (QTcF) and RR interval

Primary: Number of participants with clinical chemistry parameters of PCC

Primary: Number of participants with clinical chemistry parameters of PCC

Primary: Number of participants with hematology parameters of PCC

Primary: Number of participants with hematology parameters of PCC

Primary: Number of participants with urinalysis parameters of PCC

Primary: Number of participants with urinalysis parameters of PCC

Primary: Change from Baseline in albumin and total protein

Primary: Change from Baseline in albumin and total protein

Primary: Change from Baseline in alk. phosphatase, ALT, AST, creatine kinase and LD levels

Primary: Change from Baseline in alk. phosphatase, ALT, AST, creatine kinase and LD levels

Primary: Change from Baseline in direct bilirubin, total bilirubin and creatinine

Primary: Change from Baseline in direct bilirubin, total bilirubin and creatinine

Primary: Change from Baseline in BUN/creatinine ratio

Primary: Change from Baseline in BUN/creatinine ratio

Primary: Change from Baseline in calcium, chloride, CO2, glucose, potassium, magnesium, sodium and BUN

Primary: Change from Baseline in calcium, chloride, CO2, glucose, potassium, magnesium, sodium and BUN

Primary: Change from Baseline in absolute basophils, absolute eosinophils, absolute lymphocytes, absolute monocytes, absolute total neutrophils, platelet count and WBC count

Primary: Change from Baseline in absolute basophils, absolute eosinophils, absolute lymphocytes, absolute monocytes, absolute total neutrophils, platelet count and WBC count

Primary: Change from Baseline in hemoglobin and mean corpuscle hemoglobin concentration (MCHC) levels

Primary: Change from Baseline in hemoglobin and mean corpuscle hemoglobin concentration (MCHC) levels

Primary: Change from Baseline in hematocrit levels

Primary: Change from Baseline in hematocrit levels

Primary: Change from Baseline in mean corpuscle hemoglobin (MCH) levels

Primary: Change from Baseline in mean corpuscle hemoglobin (MCH) levels

Primary: Change from Baseline in mean corpuscle volume (MCV) and mean platelet volume (MPV) levels

Primary: Change from Baseline in mean corpuscle volume (MCV) and mean platelet volume (MPV) levels

Primary: Change from Baseline in RBC count

Primary: Change from Baseline in RBC count

Primary: Change from Baseline in percent basophils, percent eosinophils, percent lymphocytes, percent monocytes, percent neutrophils and RBC distribution width (RDW) levels

Primary: Change from Baseline in percent basophils, percent eosinophils, percent lymphocytes, percent monocytes, percent neutrophils and RBC distribution width (RDW) levels

Primary: Change from Baseline in urine albumin creatinine ratio

Primary: Change from Baseline in urine albumin creatinine ratio

Primary: Change from Baseline in urine albumin levels

Primary: Change from Baseline in urine albumin levels

Primary: Change from baseline in urine creatinine levels

Primary: Change from baseline in urine creatinine levels

Primary: Changes from Baseline in American Urological Association Symptom Scale (AUA SS) score

Primary: Changes from Baseline in American Urological Association Symptom Scale (AUA SS) score

Primary: Change from Baseline in Post-Void Residual (PVR) bladder ultrasound urine volume

Primary: Change from Baseline in Post-Void Residual (PVR) bladder ultrasound urine volume

Primary: Number of participants with suicidal ideation or behavior assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) score

Primary: Number of participants with suicidal ideation or behavior assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) score

Primary: Number of participants experiencing new seizure types

Primary: Number of participants experiencing new seizure types

Primary: Number of participants experiencing worsening of seizures

Primary: Number of participants experiencing worsening of seizures

Primary: Duration of retigabine exposure

Primary: Duration of retigabine exposure

Secondary: Number of participants experiencing a 0 to <25, 25 to <50, 50 to <75 and 75 to 100 percent reduction in 28 day POS frequency from Baseline

Secondary: Number of participants experiencing a 0 to <25, 25 to <50, 50 to <75 and 75 to 100 percent reduction in 28 day POS frequency from Baseline

Clinical Trial Results:
A Multicentre, Open-Label, Long-Term, Safety and Tolerability Study of Retigabine Immediate Release (IR) in Adults with Partial-Onset Seizures (Extension of Study RGB113905)