An Open Label Study to Evaluate the Effects of Ezogabine/Retigabine Added to Existing Anti-epileptic Drug(s) on Urinary Voiding Function in Subjects With Partial Onset Seizures

NCT01607346 | Terminated Phase 4 Results

• 2 other identifiers: 1161582012-002260-26
• Study Type: interventional
• Target: 10
• Locations: 3 countries
• Sites: 7

Brief Summary

This is a multicentre, open label study to examine the effect of ezogabine/retigabine on the voiding function of adult subjects with drug-resistant partial onset seizures (POS). Subjects fulfilling the study entry criteria at Screening and at Baseline including a comprehensive eye examination by an ophthalmologist or retina specialist and a skin assessment by the investigator will receive ezogabine/retigabine. The starting dose of ezogabine/retigabine will be 300 mg/day. Subjects will be up titrated by 150 mg/day weekly up to the maximum ezogabine/retigabine daily dose of 1200 mg (or the highest tolerated dose). During the 49 days of the treatment phase, subjects will undergo three repeat non-invasive assessments of voiding function. In addition, subjects who meet pre-determined criteria for voiding dysfunction will undergo multichannel cystometry in order to characterise bladder hypocontractility, bladder outlet obstruction or a combination of events which clinically is manifest with difficulty emptying the bladder or acute urinary retention. At the end of the Treatment Phase, all subjects will enter the Taper Phase, a 3-week down titration period. Subjects who have new findings of abnormal pigmentation of the retina, unexplained vision loss, pigmentation of non-retinal ocular tissue or discoloration of skin, lip, nail, or mucosa since baseline will be asked to enter the Safety Follow-Up / Continuation Phase. All subjects will undergo 6-monthly comprehensive eye examinations during the Safety Follow-Up / Continuation Phase. Subjects who have not developed abnormal discoloration of the skin, lips, nails or mucosa will continue to undergo skin assessments by the investigator. Any subject who has developed abnormal discoloration of the skin, lips, nails or mucosa since baseline will be referred to a dermatologist for evaluation and 6-monthly follow up assessments. All subjects will continue to be followed until the pigmentation and/or discoloration has resolved or stabilised, as defined by no change over 2 consecutive 6-monthly assessments conducted over at least 12 months after discontinuation of ezogabine/retigabine.

Conditions

Epilepsy

Keywords

Urinary Retention

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in Maximum Flow Rate (Qmax) at Visit 5.

  Maximum urine flow rate was measured by uroflowmetry test. It is a non-invasive diagnostic test that measures the speed of urinary flow. Uroflowmetry was assessed at Baseline visit 2 (Day -1) and on visits 3, 4 and 5 (Days 21, 35 and 49 respectively). Measurement at visit 2 (Day -1) was considered as Baseline value. Change from Baseline was calculated by subtracting the Baseline value from the post-baseline value at Visit 5. Safety Population was defined as all participants who received more than or equal to one dose of study medication.

  Baseline (Day -1) and on Day 49 (Visit 5)

Secondary Outcomes (12)

• Change From Baseline in Maximum Flow Rate (Qmax) at Visits 3, 4 and 6

  Baseline (Day -1) and up to Day 80 (Visit 6)

• Percent Change From Baseline in Qmax at Visits 3, 4, 5 and 6

  Baseline (Day -1) and up to Day 80 (Visit 6)

• Change From Baseline in Percentage Residual Urinary Volume (RUV) at Visits 3, 4, 5 and 6

  Baseline (Day -1) and up to Day 80 (Visit 6)

• Change From Baseline in Voided Volume (VV) at Visits 3, 4, 5 and 6

  Baseline (Day -1) and up to Day 80 (Visit 6)

• Change From Baseline in Time to Maximum Flow at Visits 3, 4, 5 and 6

  Baseline (Day -1) and up to Day 80 (Visit 6)

Study Arms (1)

ezogabine/retigabine

EXPERIMENTAL

Open-label

Drug: ezogabine/retigabine

Interventions

ezogabine/retigabine DRUG

Starting dose of 300mg/day, titrate up to a targeted maximum dose of 1200 mg/day. Dose can be reduced to a minimum of 600 mg/day if unable to tolerate higher doses

ezogabine/retigabine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Is ≥18 years of age (male or female).
• Has a confident diagnosis of epilepsy with partial onset seizures with or without secondary generalization (classified according to International League Against Epilepsy (ILAE) Guidelines, 1981) ≥ 2 years.
• Is currently being treated with a stable regimen of one to three AEDs during the 4 weeks prior to the Screening Visit.
• Following Amendment 03: must be considered drug resistant, consistent with the definition proposed by Kwan, et al 2010 \[Kwan\].
• Note: Vagus Nerve Stimulator (VNS), VNS will not be counted as a concurrent AED. Subjects with surgically implanted VNS will be allowed to enter the study provided that all of the following conditions are met:
• The VNS has been in place for at least 24 weeks prior to the Screening Visit
• The settings must remain the same for at least 4 weeks prior to the Screening Visit and throughout the study
• The battery is expected to last for the duration of the study
• Subject who are considering implantation of a VNS are excluded from participating in this study
• Note: The chronic use of benzodiazepines as a concurrent AED is permitted as long as the dose is kept constant for at least 4 weeks before the Screen Visit and throughout the study.
• Is able and willing to maintain an accurate and complete a two (2) day Voiding Diary at protocol specified time points.
• Is able and willing to maintain an accurate and complete daily written Seizure Calendar at specified time points or has a caregiver who is able and willing to maintain an accurate and complete daily written Seizure Calendar for the entire duration of the study.
• Has given written informed consent, prior to the performance of any study assessments.
• A female subject is eligible to enter and participate in the study if she is not pregnant or lactating or planning to become pregnant during the study and is of:
• Non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is pre-menarchal or post-menopausal).

You may not qualify if:

• Has generalized epilepsy (e.g., Lennox-Gastaut, Juvenile Myoclonic epilepsy, Absence, etc).
• Has had status epilepticus (other than simple partial status epilepticus) within the 12 months prior to Screening or during the Baseline Phase.
• Has a history of innumerable seizures within the 12 months prior to Screening where the individual seizures cannot be counted.
• Has a history of pseudo seizures, non-epilepsy events or any other type of psychogenic seizures that could be confused with seizures.
• Acute Urinary Retention (treated or untreated) within 6 months of screening or an episode of Acute Urinary Retention (treated) within the last two years with symptoms within the last 6 months.
• Screening AUA SI Score \>7 (\>11 for subject over 55 years old).
• Flowmetry Peak Flow \< 15mL/sec out of a urine volume void of 150mL (\<11 mL/sec for subject over 55 years old) at Screening.
• PVR \>125mL or \>40% functional residual volume at Screening.
• Prior history of administration of Botox® within genitourinary system.
• Prior history or any type of medical or surgical therapy for urinary incontinence.
• Prior history of treated or untreated, bladder, prostate, uterine or cervical cancer.
• Use of sildenafil, tadalafil, vardenafil or other PDE-5 inhibitors within 2 weeks of study start.
• Use of α-adrenoreceptor antagonists within 2 weeks of study start.
• Has had previous exposure to ezogabine/retigabine.
• Is currently or has been abusing substance(s) or any medications in the 12 months prior to Screening.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (7)

GSK Investigational Site

Bethesda, Maryland, 20817, United States

Location

GSK Investigational Site

Columbus, Ohio, 43210, United States

Location

GSK Investigational Site

Dallas, Texas, 75251, United States

Location

GSK Investigational Site

Madison, Wisconsin, 53715, United States

Location

GSK Investigational Site

Rennes, 35033, France

Location

GSK Investigational Site

Strasbourg, 67091, France

Location

GSK Investigational Site

Warsaw, 02-957, Poland

Location

MeSH Terms

Conditions

Epilepsy; Urinary Retention

Interventions

ezogabine

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Urination Disorders; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Limitations and Caveats

The study was terminated after 10 of 100 subjects had been enrolled. Statistical analyses were not performed as the sample size enrolled was too small to allow for these analyses to be meaningful. The data are presented as summary statistics only.

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 17, 2012
• First Posted: May 30, 2012
• Study Start: March 27, 2013
• Primary Completion: November 16, 2016
• Study Completion: November 16, 2016
• Last Updated: December 4, 2020
• Results First Posted: September 26, 2017

Record last verified: 2020-11

Locations

US (4); PL (1); FR (2)