NCT01494584

Study in Pediatric Subjects With Epilepsy

Terminated Phase 2 Results posted Last updated 30 November 2020

What this trial tests

Phase 2 trial testing ezogabine/retigabine in Epilepsy in 5 participants. Terminated before completion.

Timeline

25 July 2012

Primary endpoint
29 April 2013

29 April 2013

Quick facts

Lead sponsor	GlaxoSmithKline
Phase	Phase 2
Status	Terminated
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	5
Start date	25 July 2012
Primary completion	29 April 2013
Estimated completion	29 April 2013
Sites	4 locations across United States

Drugs / interventions tested

• ezogabine/retigabine — full drug profile →

Conditions studied

• Epilepsy — all drugs for Epilepsy →

Sponsor

GlaxoSmithKline — full company profile →

Who can join

Adults 12 to 17, any sex, with Epilepsy. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

The Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUC[0-tau]) Following Oral Administration of Ezogabine/Retigabine Primary · Pre-dose and 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35

The steady state pharmacokinetic profile following oral administration of ezogabine/retigabine included determining the area under the curve over the dosing interval (AUC\[0-tau\]). The area under the plasma concentration-time curve over the dosing interval (AUC\[0-tau\]) was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. Blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35 to estimate AUC(0-tau).

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	1680.0	1162.4 – 2428.2
Regimen A: E/R 300/450 mg Then 600 mg	2558.8	1873.4 – 3494.8
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	3783.8	1059.6 – 13512.0

Apparent Clearance (CL/F) Following Oral Administration of Ezogabine/Retigabine Primary · Pre-dose and 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35

Clearance (CL/F) is defined as dose/AUC(0-tau). Blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35 to estimate CL/F.

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	178.6	123.5 – 258.1
Regimen A: E/R 300/450 mg Then 600 mg	234.5	171.7 – 320.3
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	237.9	66.6 – 849.4

Maximum Observed Concentration (Cmax) and Pre-dose (Trough) Concentration at the End of the Dosing Interval (Ctau) Following Oral Administration of Ezogabine/Retigabine Primary · Pre-dose and 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35

Cmax is defined as the first occurrence of the maximum observed plasma concentration. Ctau refers to the pre-dose (trough) concentration after the dosing interval which is equal to the minimum observed concentration (Cmin) at Steady State. Blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35 to estimate Cmax and Ctau.

Cmax

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	370.0	260.9 – 524.7
Regimen A: E/R 300/450 mg Then 600 mg	535.9	344.4 – 833.8
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	750.9	289.8 – 1945.3

Ctau

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	105.32	58.70 – 188.98
Regimen A: E/R 300/450 mg Then 600 mg	199.77	140.67 – 283.72
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	287.48	44.38 – 1862.12

Apparent Volume of Distribution (Vd/F) Following Oral Administration of Ezogabine/Retigabine Primary · Pre-dose and 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35

The volume of distribution (Vd/F) is defined as MRT\*CL/F, where MRT is the mean residence time (calculated as AUMC\[0-tau\]/AUC\[0-tau\], where AUMC\[0-tau\] is the area under the first moment curve determined as the area under the concentration\*time versus time curve). Blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 4, 6, and 8 hours post-dose on Day 7, Day 21, and Day 35 to estimate the apparent volume of distribution.

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	1130.9	511.1 – 2502.1
Regimen A: E/R 300/450 mg Then 600 mg	2118.0	539.4 – 8315.8
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	1934.3	NA – NA

Number of Participants With Any Adverse Event (AE) Secondary · From the start of the first titration until follow-up (assessed up to 46 days)

An AE is defined as 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product.

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine 300 mg	1
Regimen A: Ezogabine/Retigabine 300 mg, Then 450 mg	1
Regimen A: Ezogabine/Retigabine 300/450 mg, Then 600 mg	1
Regimen A: Ezogabine/Retigabine 300/450/600 mg, Then 750 mg	0
Regimen A: Ezogabine/Retigabine 300/450/600/750, Then 900 mg	0

Change From Baseline in Albumin and Total Protein at Day 7 Post Each Up-titration Secondary · Baseline (Screening), Day 7, Day 21, and Day 35

Change from baseline was calculated 7 days after each up-titration (Day 7 for 300 mg/day dose; Day 21 for up-titration to 600 mg/day dose; Day 35 for up-titration to 900 mg/day dose) by subtracting the baseline value from the individual post-dose values. Baseline is defined as the Screening visit.

Albumin, n=4, 4, 3

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	-3.8	± 0.96
Regimen A: E/R 300/450 mg Then 600 mg	-3.0	± 3.46
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	-0.7	± 3.06

Total protein, n=4, 4, 3

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	-4.0	± 2.94
Regimen A: E/R 300/450 mg Then 600 mg	-3.5	± 3.79
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	-0.7	± 5.03

Change From Baseline in Alkaline Phosphatase, Alanine Amino Transferase, Aspartate Amino Transferase, and Gamma Glutamyl Transferase at Day 7 Post Each Up-titration Secondary · Baseline (Screening), Day 7, Day 21, and Day 35

Change from baseline was calculated 7 days after each up-titration (Day 7 for 300 mg/day dose; Day 21 for up-titration to 600 mg/day dose; Day 35 for up-titration to 900 mg/day dose) by subtracting the baseline value from the individual post-dose values. Baseline is defined as the Screening visit.

Alkaline phosphatse, n=4, 4, 3

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	-5.8	± 16.17
Regimen A: E/R 300/450 mg Then 600 mg	10.3	± 35.93
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	5.0	± 6.93

Alanine amino transferase, n=4, 4, 3

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	-2.0	± 2.16
Regimen A: E/R 300/450 mg Then 600 mg	35.0	± 74.02
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	-1.0	± 2.00

Aspartate amino transferase, n=4, 4, 3

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	-0.8	± 2.50
Regimen A: E/R 300/450 mg Then 600 mg	10.8	± 17.75
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	1.7	± 3.21

Gamma glutamyl transferase, n=3, 3, 2

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	-1.3	± 0.58
Regimen A: E/R 300/450 mg Then 600 mg	111.0	± 181.06
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	50.5	± 47.38

Change From Baseline in Direct Bilirubin, Total Bilirubin, Creatinine, and Uric Acid at Day 7 Post Each Up-titration Secondary · Baseline (Screening), Day 7, Day 21, and Day 35

Change from baseline was calculated 7 days after each up-titration (Day 7 for 300 mg/day dose; Day 21 for up-titration to 600 mg/day dose; Day 35 for up-titration to 900 mg/day dose) by subtracting the baseline value from the individual post-dose values. Baseline is defined as the Screening visit.

Direct bilirubin, n=1, 2, 1

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	2.7360	± NA
Regimen A: E/R 300/450 mg Then 600 mg	2.7360	± 3.86929
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	-0.8550	± NA

Total bilirubin, n=4, 4, 3

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	0.855	± 2.2076
Regimen A: E/R 300/450 mg Then 600 mg	2.138	± 2.5650
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	4.560	± 0.9873

Creatinine, n=4, 4, 3

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	1.3260	± 1.14124
Regimen A: E/R 300/450 mg Then 600 mg	-4.1990	± 5.02015
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	0.5893	± 3.34677

Uric acid, n=4, 3, 1

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	16.3570	± 19.04289
Regimen A: E/R 300/450 mg Then 600 mg	15.8613	± 36.34288
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	23.7920	± NA

Change From Baseline in Calcium, Chloride, Carbon Dioxide Content/Bicarbonate, Glucose, Potassium, Sodium, Inorganic Phosphorus, and Urea/Blood Urea Nitrogen (BUN) at Day 7 Post Each Up-titration Secondary · Baseline (Screening), Day 7, Day 21, and Day 35

Change from baseline was calculated 7 days after each up-titration (Day 7 for 300 mg/day dose; Day 21 for up-titration to 600 mg/day dose; Day 35 for up-titration to 900 mg/day dose) by subtracting the baseline value from the individual post-dose values. Baseline is defined as the Screening visit.

Calcium, n=4, 4, 3

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	0.00624	± 0.062375
Regimen A: E/R 300/450 mg Then 600 mg	-0.04366	± 0.117689
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	0.02495	± 0.194866

Chloride, n=4, 4, 3

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	1.8	± 0.96
Regimen A: E/R 300/450 mg Then 600 mg	3.0	± 0.82
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	3.0	± 1.73

Carbon dioxide content/bicarbonate, n=4, 4, 3

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	0.8	± 3.50
Regimen A: E/R 300/450 mg Then 600 mg	-1.5	± 1.73
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	-2.7	± 2.08

Glucose, n=4, 4, 3

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	0.69388	± 1.184069
Regimen A: E/R 300/450 mg Then 600 mg	0.15265	± 0.821317
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	0.29605	± 0.279394

Potassium, n=4, 4, 3

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	0.08	± 0.206
Regimen A: E/R 300/450 mg Then 600 mg	0.17	± 0.574
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	0.20	± 0.624

Sodium, n=4, 4, 3

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	1.8	± 0.50
Regimen A: E/R 300/450 mg Then 600 mg	2.0	± 1.83
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	2.3	± 3.06

Inorganic phosphorus, n=4, 3, 1

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	-0.39555	± 0.727481
Regimen A: E/R 300/450 mg Then 600 mg	-0.04305	± 0.189202
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	0.09687	± NA

Urea/BUN, n=4, 4, 3

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	-0.3570	± 1.23668
Regimen A: E/R 300/450 mg Then 600 mg	0.7140	± 0.71400
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	1.3090	± 0.74315

Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils (Total ANC [Total Absolute Neutrophil Count]), Platelet Count, and White Blood Cell Count at Day 7 Post Each Up-titration Secondary · Baseline (Screening), Day 7, Day 21, and Day 35

Change from baseline was calculated 7 days after each up-titration (Day 7 for 300 mg/day dose; Day 21 for up-titration to 600 mg/day dose; Day 35 for up-titration to 900 mg/day dose) by subtracting the baseline value from the individual post-dose values. Baseline is defined as the Screening visit.

Basophils, n=3, 3, 2

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	0.03	± 0.062
Regimen A: E/R 300/450 mg Then 600 mg	0.04	± 0.053
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	0.00	± 0.006

Eosinophils, n=3, 3, 2

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	0.07	± 0.059
Regimen A: E/R 300/450 mg Then 600 mg	0.09	± 0.200
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	0.10	± 0.005

Lymphocytes, n=3, 3, 2

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	14.77	± 26.358
Regimen A: E/R 300/450 mg Then 600 mg	-0.45	± 0.654
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	-0.65	± 0.918

Monocytes, n=3, 3, 2

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	-0.04	± 0.347
Regimen A: E/R 300/450 mg Then 600 mg	0.09	± 0.101
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	0.05	± 0.065

Total neutrophils, n=3, 3, 2

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	14.90	± 24.176
Regimen A: E/R 300/450 mg Then 600 mg	-0.11	± 0.370
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	0.61	± 0.263

Platelet count, n=4, 4, 3

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	-17.0	± 40.12
Regimen A: E/R 300/450 mg Then 600 mg	-15.8	± 34.32
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	-1.3	± 17.16

White blood cell count, n=4, 4, 3

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	0.393	± 1.2125
Regimen A: E/R 300/450 mg Then 600 mg	-0.600	± 0.6272
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	-0.583	± 1.3345

Change From Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration at Day 7 Post Each Up-titration Secondary · Baseline (Screening), Day 7, Day 21, and Day 35

Change from baseline was calculated 7 days after each up-titration (Day 7 for 300 mg/day dose; Day 21 for up-titration to 600 mg/day dose; Day 35 for up-titration to 900 mg/day dose) by subtracting the baseline value from the individual post-dose values. Baseline is defined as the Screening visit.

Hemoglobin, n=4, 4, 3

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	-3.0	± 4.90
Regimen A: E/R 300/450 mg Then 600 mg	-10.3	± 6.85
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	-2.0	± 4.36

Mean corpuscle hemoglobin concentration, n=4, 4, 3

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	-2.5	± 2.38
Regimen A: E/R 300/450 mg Then 600 mg	0.3	± 10.59
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	-6.7	± 4.93

Change From Baseline in Hematocrit at Day 7 Post Each Up-titration Secondary · Baseline (Screening), Day 7, Day 21, and Day 35

Change from baseline was calculated 7 days after each up-titration (Day 7 for 300 mg/day dose; Day 21 for up-titration to 600 mg/day dose; Day 35 for up-titration to 900 mg/day dose) by subtracting the baseline value from the individual post-dose values. Baseline is defined as the Screening visit. The International System of Units (SI) "Fraction of one unit (1)" is reported here.

Group	Value	95% CI
Regimen A: Ezogabine/Retigabine (E/R) 300 mg	-0.0057	± 0.01452
Regimen A: E/R 300/450 mg Then 600 mg	-0.0303	± 0.02198
Regimen A: E/R 300/450/ 600/750 mg Then 900 mg	0.0017	± 0.1201

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse event data, volunteered by the participant, discovered by the investigator, or detected by other means, were collected from the start of study treatment until the Follow-up contact (maximum of 46 days).. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Regimen A: Ezogabine/Retigabine 300 mg

Serious: 0/5 (0%)

Deaths: —

Regimen A: Ezogabine/Retigabine 300 mg, Then 450 mg

Serious: 0/5 (0%)

Deaths: —

Regimen A: Ezogabine/Retigabine 300/450 mg, Then 600 mg

Serious: 0/4 (0%)

Deaths: —

Regimen A: Ezogabine/Retigabine 300/450/600 mg, Then 750 mg

Serious: 0/4 (0%)

Deaths: —

Regimen A: Ezogabine/Retigabine 300/450/600/750, Then 900 mg

Serious: 0/3 (0%)

Deaths: —

Other adverse events (3 terms — click to expand)

Reaction	System	Regimen A: Ezogabine/Retig…	Regimen A: Ezogabine/Retig…	Regimen A: Ezogabine/Retig…	Regimen A: Ezogabine/Retig…	Regimen A: Ezogabine/Retig…
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—
Somnolence	Nervous system disorders	—	—	—	—	—
Urinary hesitation	Renal and urinary disorders	—	—	—	—	—

Data from ClinicalTrials.gov NCT01494584 adverse events section.

Sponsor's own description

This is an open-label study to evaluate the pharmacokinetics, safety and tolerability of ezogabine/retigabine in subjects aged 12 years to less than 18 years with uncontrolled partial onset seizures or Lennos-Gastaut syndrome.

Publications & conference data

1 peer-reviewed publication reference this trial (live from Europe PMC):

1. Adolescent Clinical Development of Ezogabine/Retigabine as Adjunctive Therapy for Partial-Onset Seizures: Pharmacokinetics and Tolerability.
   Tompson DJ, Buraglio M, Andrews SM, Wheless JW. · · 2016 · cited 6× · PMID 27877093 · DOI 10.5863/1551-6776-21.5.404