A Study In Patients With Neuropathic Pain From Diabetic Peripheral Neuropathy (DPN)

Study Overview
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Brief Summary
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The purpose of this study is to determine whether gabapentin enacarbil (XP13512/GSK1838262), hereafter referred to as GEn is effective in the treatment of neuropathic pain associated with diabetic peripheral neuropathy(DPN)

Detailed Description
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This is a dose-response study of XP13512 compared with concurrent placebo control and LYRICA (pregabalin), in subjects with neuropathic pain associated with DPN. Three doses of XP13512 (1200 mg/day, 2400 mg/day and 3600 mg/day) are being evaluated for the management of neuropathic pain associated with DPN. Approximately 392 subjects from 70 to 80 participating sites in the US will be randomized to receive either XP13512 at the above mentioned doses, placebo or pregabalin (300mg/day).

Official Title
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Study PXN110448: A Dose-response Study of XP13512, Compared With Concurrent Placebo Control and LYRICA(Pregabalin), in Subjects With Neuropathic Pain Associated Withdiabetic Peripheral Neuropathy (DPN)

Conditions
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Neuropathy, Diabetic

Intervention / Treatment
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* Drug: Placebo
* Drug: GEn 1200mg/day
* Drug: GEn 2400mg/day
* Drug: GEn 3600mg/day
* Drug: Pregabalin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 18 years or older Female subjects are eligible to enter if of non-childbearing potential or not lactating, has a negative pregnancy test and agrees to use a specified highly effective method for avoiding pregnancy Documented medical diagnosis of Type 1 or 2 diabetes including: Stable glycemic control for 3 months defined as <25% change of routine insulin, <50% change of routine oral anti-diabetic agent dose and HbA1c < 8%. (HbA1c of 8 to 11% eligible if attempts to improve diabetic control failed) DPN defined by: Bilateral reduced or absent reflexes at the ankles, or Bilateral impaired vibration, pinprick, fine touch or temperature perception in the distal lower extremities And Persistent distal burning or dull pain in the feet, or Persistent proximal aching pain in the legs, or Paroxysmal electric, shooting, stabbing pain, or Dysasthesias, or Evoked pain And history of pain for at least six months and no greater than five years attributed to DPN (refers to duration of pain) Baseline 24-hour average daily pain intensity score >4.0 as measured on an 11 point pain intensity numerical rating scale Provides written informed consent in accordance with all applicable regulatory requirements Exclusion criteria: Other chronic pain conditions not associated with DPN. However, the subject will not be excluded if: The pain condition is located at a different region of the body, and The pain intensity of this condition is not greater than the pain intensity of the DPN, and The subject can assess their DPN independently of other pain condition. Other causes of neuropathy or lower extremity 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 either 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 drug(s) Medical condition or disorder that would interfere with the action, absorption, distribution, metabolism, or excretion of GEn or pregabalin, or, in the investigator's judgment: Is considered to be clinically significant and could 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 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 met entry criteria and must be stable for at least 3 months prior to enrollment History of clinically significant drug or alcohol abuse (DSM-IV-TR). 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 DPN, or Within six months for studies related to DPN Treated previously with GEn History of allergic or medically significant adverse reaction to investigational products (including gabapentin or pregabalin) or their excipients, acetaminophen or related compounds

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* placebo<br>|
| Other: Pregabalin<br>Pregabalin 300mg/day (positive control), maintenance treatment 14 weeks | Drug: Pregabalin<br>* pregabalin 300mg/day<br>|
| Experimental: GEn 1200mg/day<br>gabapentin enacarbil 1200mg/day, maintenance treatment 14 weeks | Drug: GEn 1200mg/day<br>* gabapentin enacarbil 1200mg/day<br>* Other names: gabapentin enacarbil;|
| Experimental: GEn 2400mg/day<br>gabapentin enacarbil 2400mg/day, maintenance treatment 14 weeks | Drug: GEn 2400mg/day<br>* gabapentin enacarbil 2400mg/day<br>* Other names: XP13512;|
| Experimental: GEn 3600mg/day<br>gabapentin enacarbil 3600mg/day, maintanance treatment 14 weeks | Drug: GEn 3600mg/day<br>* gabapentin enacarbil 3600mg/day<br>* Other names: gabapentin enacarbil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Mean 24-hour Average Pain Intensity (API) Score at End of Maintenance Treatment (EOMT) Using Last Observation Carried Forward (LOCF) Data | Baseline and EOMT 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 earliest date of Week 13 visit/Withdrawal visit/last dose of study drug (EOMT). Participants used a hand-held diary to rate their API over the preceding 24 hours, using an 11-point Pain Intensity Numerical Rating Scale (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. Change from baseline was calculated as the EOMT score minus the Baseline score. | Baseline and EOMT (representing the earliest date of Week 13 visit/withdrawal visit) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Mean Day-time Average Pain Intensity (API) Score at EOMT 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 EOMT are as defined for the primary endpoint. Change from baseline was calculated as the EOMT score minus the baseline score. An ANCOVA model with baseline value, BMI, grouped center as covariates was used. | Baseline and EOMT (representing the earliest date of Week 13 visit/withdrawal visit) | 
| Change From Baseline in the Mean Night-time Average Pain Intensity (API) Score at EOMT Using LOCF Data | Night-time is defined as the time between going to bed at night and rising in the morning. Participants recorded night-time API on a daily basis in the morning upon awakening using an 11-point PI-NRS (0=no pain, 10=pain as bad as you can imagine). Baseline and EOMT are as defined for the primary endpoint. Change from baseline was calculated as the EOMT score minus the baseline score. An ANCOVA model with baseline value, BMI, grouped center as covariates was used. | Baseline and EOMT (representing the earliest date of Week 13 visit/withdrawal visit) | 
| Change From Baseline in the Mean Current (Morning) Pain Intensity Score at EOMT Using LOCF Data | 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 EOMT are as defined for the primary endpoint. Change from baseline was calculated as the EOMT score minus the baseline score. An ANCOVA model with baseline value, BMI, grouped center as covariates was used. | Baseline and EOMT (representing the earliest date of Week 13 visit/withdrawal visit) | 
| Change From Baseline in the Mean Current (Evening) Pain Intensity Score at EOMT 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 EOMT are as defined for the primary endpoint. Change from baseline was calculated as the EOMT score minus the baseline score. An ANCOVA model with baseline value, BMI, grouped center as covariates was used. | Baseline and EOMT (representing the earliest date of Week 13 visit/withdrawal visit) | 
| Change From Baseline in the Mean Day-time Worst Pain Intensity Score at EOMT Using LOCF Data | Day-time worst pain is defined as the partipant's assessment of their worst pain between rising in the morning and going to bed at night. Participants recorded day-time worst pain in the evening before bedtime using an 11-point PI-NRS (0=no pain, 10=pain as bad as you can imagine). Baseline and EOMT are as defined for the primary endpoint. Change from baseline was calculated as the EOMT score minus the baseline score. An ANCOVA model with baseline value, BMI, grouped center as covariates was used. | Baseline and EOMT (representing the earliest date of Week 13 visit/withdrawal visit) | 
| Change From Baseline in the Mean Night-time Worst Pain Intensity Score at EOMT Using LOCF Data | Night-time worst pain is defined as the partipant's assessment of their worst pain between going to bed at night and rising in the morning. Participants recorded night-time worst pain in the morning upon awakening using an 11-point PI-NRS (0=no pain, 10=pain as bad as you can imagine). Baseline and EOMT are as defined for the primary endpoint. Change from baseline was calculated as the EOMT score minus the baseline score. An ANCOVA model with baseline value, BMI, grouped center as covariates was used. | Baseline and EOMT (representing the earliest date of Week 13 visit/withdrawal visit) | 
| Change From Baseline in the Mean Sleep Interference Score at EOMT Using LOCF Data | Participants assessed sleep interference due to pain on a daily basis in the morning upon awakening using an 11-point NRS (0=pain does not interfere with sleep, 10=pain completely interferes with sleep). Baseline and EOMT are as defined for the primary endpoint. Change from baseline was calculated as the EOMT score minus the baseline score. An ANCOVA model with baseline value, BMI, grouped center as covariates was used. | Baseline and EOMT (representing the earliest date of Week 13 visit/withdrawal visit) | 
| Change From Baseline in the Mean Daily Dose of Rescue Medication at EOMT Using LOCF Data | Mean daily use of rescue medication (milligrams of acetaminophen) was calculated by determining the average number of tablets taken per day of rescue medication (Commerical Tylenol) during treatment and multiplying that by 500 mg. Baseline and EOMT are as defined for the primary endpoint. Change from baseline was calculated as the EOMT score minus the baseline score. An ANCOVA model with baseline value, BMI, grouped center as covariates was used. | Baseline and EOMT (representing the earliest date of Week 13 visit/withdrawal visit) | 
| Change From Baseline in Pain Quality as Assessed by the Neuropathic Pain Scale (NPS) Summary Scores at EOMT Using LOCF Data | The NPS assesses pain qualities and consists of 11-items, 10 assessed on an 11-point NRS (0=no impact to 10=greatest impact); and 1 open-ended question not used in score calculation. 4 summary scores are calculated: NPS 10 (items 1-7, 9-11), NPS 8 (8 pain descriptor items), NPS Non-Allodynic (NA) (8 NA items), and NPS 4 (4 pain quality items); and range from 0 to 100 (0=no impact and 100=greatest impact). The analysis 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. | Baseline and EOMT (representing the earliest date of Week 13 visit/withdrawal visit) | 
| Change From Baseline in Pain Characteristics and Intensity as Assessed by the Short Form-McGill Pain Questionnaire (SF-MPQ) at EOMT Using LOCF Data | The SF-MPQ, a general pain instrument, assesses the characteristics and intensity of pain and consists of 15-items assessed on a 4-point scale (0=none, 1=mild, 2=moderate, and 3=severe). 3 summary scores are calculated: sensory score (sum of items 1-11, range 0-33), affective score (sum of items 12-15, range 0-12), total score (sum of items 1-15, range 0-45), where lower scores = lower pain/impact. Analysis 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. | Baseline and EOMT (representing the earliest date of Week 13 visit/withdrawal visit) | 
| Change From Baseline in Pain Score After Taking a 50-foot Walk at EOMT | Baseline and EOMT scores are the pain scores each participant reported after taking a 50-foot walk at the randomization and Week 13/Withdrawal visits, respectively, using an 11-point PI-NRS (0=no pain, 10=pain as bad as you can imagine). Change from baseline was calculated as the EOMT score minus the baseline score. An ANCOVA model with BMI, baseline pain intensity after 50-foot walk, pain intensity prior to 50-foot walk at the visit being assessed, and grouped center as covariates was used. | Baseline and EOMT (representing the earliest date of Week 13 visit/withdrawal visit) | 
| Number of Participants Who Are Responders on the Patient Global Impression of Change (PGIC) Questionnaire at EOMT 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. EOMT response is defined as the score recorded at the Week 13/Withdrawal visit. | EOMT (representing the earliest date of Week 13 visit/withdrawal visit) | 
| Number of Participants Who Are Responders on the Clinician Global Impression of Change (CGIC) Questionnaire at EOMT 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. EOMT response is defined as the score recorded at the Week 13/Withdrawal visit. | EOMT (representing the earliest date of Week 13 visit/withdrawal visit) | 
| Number of Participants Achieving Various Levels of Percent Reduction From Baseline in the Mean 24-hour Average Pain Intensity Score at EOMT Using LOCF Data | Baseline and EOMT scores are the calculated means of the 24-hour average pain scores for each participant during the last 7 days prior to randomization and EOMT, respectively. Percent reduction from baseline was calculated as the [(EOMT 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. | Baseline and EOMT (representing the earliest date of Week 13 visit/withdrawal visit) | 
| Time to Onset of Sustained Improvement in the 24-hour Average Pain Intensity Score | Sustained improvement in the 24-hour average pain intensity score is defined as at least 2 consecutive days on which the 24-hour average pain intensity score is >=2 points less than the mean 24-hour average pain intensity score at baseline. Time to onset is measured from baseline and was calculated as first day of event minus last day of baseline and is expressed in days. Baseline score is the calculated mean of the 24-hour average pain score for each participant during the last 7 days prior to randomization. | Any time post-baseline until date of last dose of study medication (up to Week 13) | 
| Change From Baseline in Severity of Pain and the Impact of Pain as Assessed by the Brief Pain Inventory (BPI) at EOMT Using LOCF Data | The BPI, a general pain instrument, assesses the severity and interference of pain; and consists of 6 items assessed on an 11-point NRS (0=no impact and 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 each summary score ranges from 0 to 10 (0=no impact and 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. | Baseline and EOMT | 
| Change From Baseline in Quality of Life as Assessed by the 36-Item Short Form Health Survey (SF-36) at EOMT Using LOCF Data | The SF-36 is a general health-related quality of life instrument consisting of 36 items with various response options (Yes/No, 5- to 6-point Likert scale). Summary scores are calculated for 8 domains and 2 components (physical and mental); where scores range from 0 to 100 (higher scores = better quality of life). 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. | Baseline and EOMT (representing the earliest date of Week 13 visit/withdrawal visit) | 
| Change From Baseline in Emotional Functioning as Assessed by the Profile of Mood States-Brief Form (POMS-B) at EOMT Using LOCF Data | The POMS-B, an emotional functioning instrument, assesses mood, tension, and other psychological symptoms and consists of 30-items assessed on a 5-point scale (0=not at all to 4=extremely). 6 summary scores are calculated: Tension/Anxiety, Depression/Rejection, Anger/Hostility, Vigor/Activity, Fatigue/Inertia, and Confusion/Bewilderment; and range from 0-20 (higher scores = more negative mood state). 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. | Baseline and EOMT (representing the earliest date of Week 13 visit/withdrawal visit) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Peripheral Diabetic Neuropathy (PDN), Neuropathic Pain