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

Neuralgia, Postherpetic Clinical Trial

Official title:

Study PXN110527: The Investigation of the Efficacy and Pharmacokinetics of XP13512 in Subjects With Neuropathic Pain Associated With Post-herpetic Neuralgia (PHN) Who Have Had an Inadequate Response to Gabapentin Treatment.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00617461
• Other study ID #: 110527
• Status: Completed
• Phase: Phase 2
• First received: February 6, 2008
• Last updated: July 15, 2013
• Start date: March 2008
• Est. completion date: July 2009

Study information

• Verified date: January 2013
• Source: XenoPort, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 96
• Est. completion date: July 2009
• Est. primary completion date: July 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Neuralgia
• Neuralgia, Postherpetic

Intervention

Drug:
• GEn 1200mg/day
1200mg/day gabapentin enacarbil
• GEn 3600mg/day
3600mg/day gabapentin enacarbil

Locations

Country	Name	City	State
Germany	GSK Investigational Site	Achim	Niedersachsen
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Bochum	Nordrhein-Westfalen
Germany	GSK Investigational Site	Dresden	Sachsen
Germany	GSK Investigational Site	Hattingen	Nordrhein-Westfalen
Germany	GSK Investigational Site	Huettenberg	Hessen
Germany	GSK Investigational Site	Leipzg	Sachsen
Germany	GSK Investigational Site	Mainz	Rheinland-Pfalz
Germany	GSK Investigational Site	Schoenau	Baden-Wuerttemberg
Germany	GSK Investigational Site	Wiesbaden	Hessen
United States	GSK Investigational Site	Austin	Texas
United States	GSK Investigational Site	Bradenton	Florida
United States	GSK Investigational Site	Chicago	Illinois
United States	GSK Investigational Site	Chipley	Florida
United States	GSK Investigational Site	Daytona Beach	Florida
United States	GSK Investigational Site	Decatur	Georgia
United States	GSK Investigational Site	Fort Myers	Florida
United States	GSK Investigational Site	Gainesville	Florida
United States	GSK Investigational Site	Greensboro	North Carolina
United States	GSK Investigational Site	Greensburg	Pennsylvania
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Kansas City	Missouri
United States	GSK Investigational Site	Kingsport	Tennessee
United States	GSK Investigational Site	Lebanon	New Hampshire
United States	GSK Investigational Site	Longview	Texas
United States	GSK Investigational Site	Marianna	Florida
United States	GSK Investigational Site	Marietta	Georgia
United States	GSK Investigational Site	Medford	Oregon
United States	GSK Investigational Site	Miami Springs	Florida
United States	GSK Investigational Site	Missoula	Montana
United States	GSK Investigational Site	Naranja	Florida
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	Norman	Oklahoma
United States	GSK Investigational Site	Oklahoma City	Oklahoma
United States	GSK Investigational Site	Oxnard	California
United States	GSK Investigational Site	Phoenix	Arizona
United States	GSK Investigational Site	Roseville	California
United States	GSK Investigational Site	Salisbury	North Carolina
United States	GSK Investigational Site	San Antonio	Texas
United States	GSK Investigational Site	San Francisco	California
United States	GSK Investigational Site	South Miami	Florida
United States	GSK Investigational Site	St. Louis	Missouri
United States	GSK Investigational Site	Tacoma	Washington
United States	GSK Investigational Site	Tallahassee	Florida
United States	GSK Investigational Site	Tampa	Florida
United States	GSK Investigational Site	Tampa	Florida
United States	GSK Investigational Site	Terre Haute	Indiana
United States	GSK Investigational Site	Weber City	Virginia
United States	GSK Investigational Site	Winston-Salem	North Carolina
United States	GSK Investigational Site	Yakima	Washington

Sponsors (1)

Lead Sponsor	Collaborator
XenoPort, Inc.

Countries where clinical trial is conducted

United States,  Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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 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.	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	No
Primary	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 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.	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	No
Secondary	Change From Baseline in the Mean Day-time Average Pain Intensity (API) Score at the Last Week of Each Treatment Period Using LOCF Data	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.	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	No
Secondary	Change From Baseline in the Mean Day-time Worst Pain Intensity Score at the Last Week of Each Treatment Period Using LOCF Data	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.	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	No
Secondary	Change From Baseline in the Mean Current (Evening) Pain Intensity Score at the Last Week of Each Treatment Period Using LOCF Data	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.	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	No
Secondary	Change From Baseline in the Mean Night-time Average Pain Intensity (API) Score at the Last Week of Each Treatment Period Using LOCF	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.	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	No
Secondary	Change From Baseline in the Mean Night-time Worst Pain Intensity Score at the Last Week of Each Treatment Period Using LOCF	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.	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	No
Secondary	Change From Baseline in the Mean Current Morning Pain Intensity Score at the Last Week of Each Treatment Period Using LOCF	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.	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	No
Secondary	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 (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.	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	No
Secondary	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 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.	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	No
Secondary	Change From Baseline in the Mean Daily Dose in Milligrams of Rescue Medication at 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.	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	No
Secondary	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	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.	End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	No
Secondary	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	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.	End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	No
Secondary	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	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.	End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	No
Secondary	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	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.	End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	No
Secondary	Change From Baseline in the Mean Sleep Interference Score at the Last Week of Each Treatment Period Using LOCF Data	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.	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of each treatment period)	No
Secondary	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	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.	Baseline and End of Treatment (Weeks 4 and 9, representing the last week of treatment)	No
Secondary	Mean Gabapentin Steady-State (ss) Average, Minimum and Maximum Concentrations	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.	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	No