A Clinical Study in Subjects With Neuropathic Pain From PHN Who Have Had an Inadequate Response to Gabapentin Treatment

Phase 2

Completed

Conditions: Neuralgia, Postherpetic

Interventions: Drug: GEn 1200mg/day
Drug: GEn 3600mg/day

Registration Number: NCT00617461

Lead Sponsor: XenoPort, Inc.

Brief Summary: The purpose of this study is evaluate the difference between two doses of gabapentin enacarbil (XP13512/GSK1838262), hereafter referred to as GEn, on pain associated with post-herpetic neuralgia.

Detailed Description: The primary purpose of study PXN110527 was to investigate the efficacy of a high (3600mg/day) dose versus a low (1200mg/day) dose of GEn in subjects with post-herpetic neuralgia (PHN) who have a history of an inadequate response to gabapentin treatment. The study is a cross-over design. Prior to screening subjects are required to have a demonstrated history of an inadequate response (as determined by the investigator) to at least 1800 mg/day of gabapentin. Prior history of treatment with gabapentin includes current treatment at 1800mg/day (2 weeks) or prior treatment with ≥1800mg/day (4 weeks). Subjects could also have been treated with pregabalin monotherapy (150-300mg/day, ≥4 weeks) and had an inadequate response.

Subjects are treated with gabapentin 1800mg/day during the Baseline Period and are randomized if during the Basleline Period they are compliant with gabapentin treatment and have a 24-hour average pain intensity score ≥4.0 based on an 11-point pain intensity numerical rating scale (PI-NRS). Subjects are then randomized to receive gabapentin enacarbil (either 1200mg/day or 3600mg/day in a 1:1 ratio) for Treatment Period 1 (28 days). Followed by a dose of 2400mg/day for 4 days and the alternate fixed dose (either 3600 mg/day or 1200 mg/day) for Treatment Period 2 (28 days).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 96

Inclusion Criteria

18 years or older
Documented medical diagnosis of PHN with pain present for at least 3 months from the healing of a herpes zoster rash
Female subjects are eligible if of non-childbearing potential or not lactating, has a negative pregnancy, and agrees to use one a specified highly effective method for avoiding pregnancy.
Currently on a stable dose of 1800 mg/day of gabapentin for ≥2 weeks with inadequate response OR
Not currently treated with gabapentin, but previously treated with ≥1800 mg/day of gabapentin for 4 weeks or more with inadequate response.
Baseline 24-hour average pain intensity score ≥ 4.0 based on an 11-point PI-NRS
Provides written informed consent in accordance with all applicable regulatory requirements

Exclusion Criteria

Other chronic pain conditions not associated with PHN. However, the subject will not be excluded if:
The pain is located at a different region of the body; and
The pain intensity is not greater than the pain intensity of the PHN; and
The subject can assess PHN pain independently of other pain
Is unable to discontinue prohibited medications or non-drug therapies or procedures throughout the duration of the study
Hepatic impairment defined as ALT or AST > 2x upper limit of normal (ULN), or alkaline phosphatase or bilirubin > 1.5x ULN
Chronic hepatitis B or C
Impaired renal function defined as creatinine clearance <60 mL/min or requiring hemodialysis
Corrected QT (QTc) interval ≥ 450 msec or QTc interval ≥480 msec for patients with Bundle Branch Block
Uncontrolled hypertension at screen (sitting systolic >160 mmHg and/or sitting diastolic >90 mmHg)
Current diagnosis of active epilepsy or any active seizure disorder requiring chronic therapy with antiepileptic drugs
Medical condition or disorder that would interfere with the action, absorption, distribution, metabolism, or excretion of GEn, or, in the investigator's judgment
Is considered to be clinically significant and may pose a safety concern, or,
Could interfere with the accurate assessment of safety or efficacy, or,
Could potentially affect a subject's safety or study outcome
Current or chronic history of liver disease (including acute viral hepatitis), or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
Meets criteria defined by the DSM-IV-TR for a major depressive episode or for active significant psychiatric disorders within last year
Depression in remission, with or without antidepressant treatment, may participate, unless stable antidepressant regimen is a prohibited medication
Antidepressant medication may not be changed or discontinued to meet entry criteria and must be stable for at least three months prior to enrollment
History of clinically significant drug or alcohol abuse (DSM-IV-TR) or is unable to refrain from substance abuse throughout the study. Benzodiazepines or atypical benzodiazepines as hypnotic sleep agents permitted.
Currently participating in another clinical study in which the subject is, or will be exposed to an investigational or non-investigational drug or device
Has participated in a clinical study and was exposed to investigational or non-investigational drug or device:
Within preceding month for studies unrelated to PHN, or
Within preceding six months for studies related to PHN
Treated previously with GEn
History of allergic or medically significant adverse reaction to investigational products (including gabapentin) or their excipients, acetaminophen or related compounds

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
GEn 1200mg/day	GEn 1200mg/day	gabapentin enacarbil 1200mg/day, 4 weeks treatment in either the first or second treatment period
GEn 3600mg/day	GEn 3600mg/day	gabapentin enacarbil 3600mg/day, 4 weeks treatment in either the first or second treatment period

Primary Outcome Measures

Name	Time	Method
Change From Baseline in the Mean 24-hour Average Pain Intensity (API) Score at the Last Week of Each Treatment Period Using Last Observation Carried Forward (LOCF) Data	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	Baseline and end of treatment values are the calculated means of the daily 24-hour API scores for each participant during the last 7 days prior to randomization (baseline) and the last 7 days on treatment within each period (end of treatment). Participants rated their API over the preceding 24 hours, using an 11-point PI-Numerical Rating Scale (0=no pain, 10=pain as bad as you can imagine). LOCF was used if less than 4 days of diary data were provided. Change from baseline was calculated as end of treatment minus baseline. Data are summarized by dose, independent of treatment period.
Change From Baseline in the Mean 24-hour Average Pain Intensity (API) Score at the Last Week of Each Treatment Period Using LOCF Data for Each Treatment Period	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	Baseline and end of treatment values are the calculated means of the daily 24-hour API scores for each participant during the last 7 days prior to randomization (baseline) and the last 7 days on treatment within each period (end of treatment). Participants used a hand-held diary to rate their average pain intensity over the preceding 24 hours, using an 11-point PI-NRS (0=no pain, 10=pain as bad as you can imagine). LOCF was used if less than 4 days of diary data were provided. The by period summary is provided as a sensitivity analysis for the primary analysis.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in the Mean Day-time Worst Pain Intensity Score at the Last Week of Each Treatment Period Using LOCF Data	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	Day-time worst pain is defined as the participant's assessment of their worst pain intensity between rising in the morning and going to bed at night. Day-time worst pain was recorded in the evening before bedtime using an 11-point PI-NRS (0=no pain, 10=pain as bad as you can imagine). Baseline and end of treatment scores are as defined for the primary endpoint. Change from baseline is calculated as the end of treatment score minus the baseline score. An ANCOVA with baseline value, BMI, grouped center as covariates was used. Data are summarized by dose, independent of treatment period.
Change From Baseline in the Mean Day-time Average Pain Intensity (API) Score at the Last Week of Each Treatment Period Using LOCF Data	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	Day-time is defined as the time between rising in the morning and going to bed at night. Participants recorded day-time API on a daily basis in the evening before bedtime using an 11-point PI-NRS (0=no pain, 10=pain as bad as you can imagine). Baseline and end of treatment scores are as defined for the primary endpoint. Change from baseline is calculated as the end of treatment score minus the baseline score. An ANCOVA with baseline value, BMI, grouped center as covariates was used. Data are summarized by dose, independent of treatment period.
Change From Baseline in the Mean Current (Evening) Pain Intensity Score at the Last Week of Each Treatment Period Using LOCF Data	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	Current pain is defined as the participant's assessment of pain intensity "right now." Participants recorded their current evening pain intensity in the evening before bedtime using an 11-point PI-NRS (0=no pain, 10=pain as bad as you can imagine). Baseline and end of treatment scores are as defined for the primary endpoint. Change from baseline is calculated as the end of treatment score minus the baseline score. An ANCOVA with baseline value, BMI, grouped center as covariates was used. Data are summarized by dose, independent of treatment period.
Change From Baseline in the Mean Night-time Worst Pain Intensity Score at the Last Week of Each Treatment Period Using LOCF	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	Night-time worst pain is defined as the participant's assessment of their worst pain intensity between going to bed and rising in the morning. Participants recorded night-time worst pain in the morning upon wakening using an 11-point PI-NRS (0=no pain, 10=pain as bad as you can imagine). Baseline and end of treatment scores are as defined for primary endpoint. Change from baseline = the end of treatment score minus the baseline score. An ANCOVA with baseline value, BMI, grouped center as covariates was used. Data are summarized by dose, independent of treatment period.
Number of Participants Achieving Various Levels of Percent Reduction From Baseline in the Mean 24-hour Average Pain Intensity Score at the Last Week of Each Treatment Period Using LOCF Data by Period	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	Baseline and end of treatment scores are the calculated means of the 24-hour average pain scores for each participant during the last 7 days prior to randomization (Baseline) and the 7 days prior to the last on-treatment completed diary (end of treatment). Percent reduction from baseline was calculated as the \[(end of treatment score minus the baseline score) divided by the baseline score\], multiplied by 100. The PI-NRS is an 11-point scale (0=no pain, 10=pain as bad as you can imagine) by which a participant assesses their 24-hour average pain intensity. Data are summarized by period.
Change From Baseline in the Mean Night-time Average Pain Intensity (API) Score at the Last Week of Each Treatment Period Using LOCF	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	Night-time is defined as the time between going to bed in the evening and rising in the morning. Participants recorded night-time API on a daily basis in the morning upon wakening using an 11-point PI-NRS (0=no pain, 10=pain as bad as you can imagine). Baseline and end of treatment scores are as defined for the primary endpoint. Change from baseline is calculated as the end of treatment score minus the baseline score. An ANCOVA with baseline value, BMI, grouped center as covariates was used. Data are summarized by dose, independent of treatment period.
Change From Baseline in the Mean Current Morning Pain Intensity Score at the Last Week of Each Treatment Period Using LOCF	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	Current pain is defined as the participant's assessment of pain intensity "right now." Participants recorded their current morning pain intensity in the morning upon wakening using an 11-point PI-NRS (0=no pain, 10=pain as bad as you can imagine). Baseline and end of treatment scores are as defined for the primary endpoint. Change from baseline is calculated as the end of treatment score minus the baseline score. An ANCOVA with baseline value, BMI, grouped center as covariates was used. Data are summarized by dose, independent of treatment period.
Number of Participants Achieving Various Levels of Percent Reduction From Baseline in the Mean 24-hour Average Pain Intensity Score at the Last Week of Each Treatment Period Using LOCF Data	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	Baseline and end of treatment (EOT) scores are the calculated means of the 24-hour average pain scores for each participant during the last 7 days prior to randomization (Baseline) and the 7 days prior to the last on-treatment completed diary (EOT). Percent reduction from baseline was calculated as the \[(EOT score minus baseline score) divided by the baseline score\], multiplied by 100. The PI-NRS is an 11-point scale (0=no pain, 10=pain as bad as you can imagine) by which a participant assesses their 24-hour average pain intensity. Data are summarized by dose, independent of treatment period.
Change From Baseline in the Mean Daily Dose in Milligrams of Rescue Medication at the Last Week of Each Treatment Period	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	Mean daily use of rescue medication (milligrams of acetaminophen) was calculated by determining the average number of tablets taken per day of rescue medication (Commercial Tylenol) during treatment and multiplying that by 500 mg. Baseline and end of treatment scores are as defined for the primary endpoint. Change from baseline is calculated as the end of treatment score minus the baseline score. An ANCOVA with baseline value, BMI, grouped center as covariates was used. Data are summarized by dose, independent of treatment period.
Number of Participants Who Are Responders on the Patient Global Impression of Change (PGIC) at the Last Week of Each Treatment Period Using LOCF Data	End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	The PGIC is a single-item questionnaire designed to provide an overall assessment of treatment from the participant's perspective since the start of the study. It is measured on a 7-point scale, where 1=very much improved and 7=very much worse. A participant is considered a responder if they have a response of "very much improved" or "much improved" Data are summarized by dose, independent of treatment period.
Number of Participants Who Are Responders on the Patient Global Impression of Change (PGIC) Questionnaire at the Last Week of Each Treatment Period Presented by Period Using LOCF Data	End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	The PGIC is a single-item questionnaire designed to provide an overall assessment of treatment from the participant's perspective since the start of the study. It is measured on a 7-point scale, where 1=very much improved and 7=very much worse. A participant is considered a responder if they have a response of "very much improved" or "much improved". Data are summarized by dose within each treatment period.
Number of Participants Who Are Responders on the Clinical Global Impression of Change (CGIC) Questionnaire at the Last Week of Each Treatment Period Using LOCF Data	End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	The CGIC is a single-item questionnaire designed to provide an overall assessment of treatment from the clinician's perspective since the start of the study. It is measured on a 7-point scale, where 1=very much improved and 7=very much worse. A participant is considered a responder if they have a response of "very much improved" or "much improved." Data are summarized by dose, independent of treatment period.
Number of Participants Who Are Responders on the Clinical Global Impression of Change (CGIC) Questionnaire at the Last Week of Each Treatment Period Presented by Period Using LOCF Data	End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	The CGIC is a single-item questionnaire designed to provide an overall assessment of treatment from the clinician's perspective since the start of the study. It is measured on a 7-point scale, where 1=very much improved and 7=very much worse. A participant is considered a responder if they have a response of "very much improved" or "much improved." Data are summarized by dose within each treatment period.
Change From Baseline in the Severity of Pain and the Impact of Pain as Assessed by the Brief Pain Inventory (BPI) at the Last Week of Each Treatment Period Using LOCF	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of treatment)	The BPI assesses the severity and interference of pain; and consists of 6 items assessed on an 11-point NRS (0=no impact to 10=greatest impact). 2 summary scores are calculated: BPI Severity Score (average of first 4 items) and BPI Interference Score (average of 7 responses to item 6); where scores range from 0 to 10 (0=no impact to 10=greatest impact). Analysis of this endpoint is based on the change from baseline (BL) (EOMT score minus the BL score) using an ANCOVA model with BL value, BMI, grouped center as covariates. Data are summarized by dose, independent of treatment period.
Mean Gabapentin Steady-State (ss) Average, Minimum and Maximum Concentrations	A total of 10 blood samples (2 samples at each visit) were collected per participant at Baseline, and the Week 1 and Week 4 visits for each period	Steady-state average (Cave, ss), maximum (Cmax, ss), and minimum (Cmin,ss) plasma concentration of gabapentin in each participant were estimated using the gabapentin plasma concentration data and with the aid of a population pharmacokinetic model. Dispersion is represented by the fifth to ninety-fifth percentile, though labeled as "Full Range." A total of 10 blood samples were collected per participant over the Baseline, Period 1, and Period 2 at various timepoints during the dosing interval. Plasma concentration of gabapentin in these samples was measured.
Change From Baseline in the Mean Sleep Interference Score at the Last Week of Each Treatment Period Using LOCF Data	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	Participants assessed sleep interference due to pain on a daily basis using the 11-point NRS (0=pain does not interfere with sleep, 10=pain completely interferes with sleep). Baseline and end of treatment scores are as defined for the primary endpoint. Change from baseline is calculated as the end of treatment score minus the baseline score. An ANCOVA with baseline value, BMI, grouped center as covariates was used. Data are summarized by dose, independent of treatment period.