Safety/Efficacy Study of Retigabine vs. Placebo in Post-Herpetic Neuralgia (PHN)

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the efficacy of retigabine vs. placebo in reducing pain associated with post-herpetic neuralgia.

Detailed Description
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This is a Phase 2a proof of concept study evaluating the safety/efficacy of retigabine vs. placebo in patients with post-herpetic neuralgia. After screening, patients will enter a maximum 6 week titration period followed by a 4 week maintenance period and a 3 week taper phase.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Proof-of-Concept Study to Evaluate the Efficacy of Maximally Tolerated Doses of Retigabine vs. Placebo in Reducing the Pain Associated With Post-Herpetic Neuralgia

Conditions
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Postherpetic Neuralgia

Intervention / Treatment
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* Drug: Retigabine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to provide informed consent Male or female subjects 18-85 years of age PHN for more than 6 months after the healing of herpes zoster skin rash Has a pain score at screening and randomization that qualifies Exclusion Criteria: Other significant pain that may potentially confound PHN pain assessment Previous neurolytic or neurosurgical therapy for PHN Subject has evidence of a progressive central nervous system (CNS) disease (e.g. CNS lupus, tumors, multiple sclerosis, Alzheimer's), lesion, or encephalopathy Significant psychiatric or neuropsychiatric disorders including but not limited to severe depression, bipolar disorder or schizophrenia spectrum disorder, history of suicide attempt, or recent history of suicidal ideation Has clinically significant abnormalities on physical examination, vital signs, ECG, or laboratory tests at the screening visit

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Retigabine | Drug: Retigabine<br>* 150mg/day up to 900mg/day<br>|
| Placebo Comparator: 2<br>Placebo | Drug: Placebo<br>* daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Endpoint Will be the Change From Baseline in Average Pain Score Over the Last 7 Days of the Maintenance Phase. | Change from Baseline (BL) was calculated as the value of the average diary pain score for the last 7 days of the MP minus the value of the average pain score at BL (post wash-out period, including the average of the last 7 available entries prior to/including the diary pain measurement on Titration Day 0). Based on their pain experienced during the previous 24 hours, participants assessed their pain every evening at bedtime in an electronic diary by choosing the appropriate number on an 11-point Numerical Rating Scale (NRS): 0, no pain; 1 to 3, mild; 4 to 6, moderate; 7 to 10, severe pain. | Baseline and Week 4 (Maintenance Phase-MP) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Weeks 2 and 4 of the Maintenance Phase in Mean In-clinic Pain Assessment | Participants rated their pain during the previous 24 hours at all clinic visits using an 11-point Numerical Rating Scale (NRS): 0, no pain; 1 to 3, mild; 4 to 6, moderate; 7 to 10, severe pain (10=worst possible pain). Change in In-clinic Pain Assessment was calculated by subtracting the average score on the NRS at Week 2 and Week 4 (values for each week were observed cases) of the MP from the average score on the NRS at Baseline (the last non-missing measurement prior to taking study drug). | Baseline and Weeks 2 and 4 (Maintenance Phase - MP) | 
| Number of Rescue Medication Tablets Taken Per Day During the Maintenance Phase (MP) | Participants recorded the number of acetaminophen tablets taken during the previous 24 hours in a participant diary. Rescue medication was summarized as the mean number of doses taken per day during each week of the Maintenance Phase (MP) and the mean number of doses taken during all MP weeks. | Weeks 1, 2, 3, and 4 Maintenance Phase | 
| Change From Baseline in Pain Intensity Score at Each Week During the Maintenance Phase (MP) | Least square mean (LSM) of pain intensity was calculated from the NRS score entered by the participants in their diaries at each week during the MP. Participants rated their pain during the previous 24 hours at all clinic visits using an NRS: 0, no pain; 1-3, mild; 4-6, moderate; 7-10 (worst possible pain), severe pain. Change from Baseline was calculated by subtracting the value of the average of the LSM of the NRS score at each week during the MP (the last 7 available diary entries in the MP were used, provided at least 3 existed) from the average Baseline value of the LSM of the NRS score. | Baseline and Weeks 1, 2, 3, and 4 (MP) | 
| Number of Participants Classified as Responders, With a 50% and 30% Pain Reduction From Baseline to the Last 7 Days of the Maintenance Phase | Responders were defined as participants achieving a mean >=50% or >=30% pain reduction based on the NRS score from Baseline to the last 7 days of the MP. Those participants who did not have at least 3 diary entries in the MP, those who withdrew during the Titration Phase (TP), and non-completers (NC: who did not complete the study) were classified as non-responders. The number of responders and responders including non-completers from Baseline to the last 7 days of the MP were reported. | Baseline and Week 4 Maintenance Phase (MP) | 
| Change From Baseline to the End of the MP (Included All Participants Who Completed Week 4 of the MP and Who Terminated Early During the MP) in Medical Outcomes Study (MOS) Sleep Scale Scores | Change from BL (average value of MOS Sleep Scale score including Overall Sleep Problem [OSP] Index at end of MP minus average BL value) to the end of the MP was summarized for the OSP Index, in addition to the following subscales of the MOS Sleep Scale: Sleep Disturbance; Sleep Adequacy; Snoring; Awakening with Shortness of Breath or with a Headache; Somnolence; and Optimal Sleep. Each item was transformed to a scale with a range of 0-100. For each subscale, except Optimal Sleep, higher scores indicate a greater level of what was being measured (i.e., more snoring, more sleep adequacy, etc.). | Baseline and End of Maintenance Phase (MP) (Week 4). | 
| Change From Baseline to the End of the MP (Included All Participants Who Completed Week 4 of the MP and Who Terminated Early During the MP) in Sleep Quantity | Change from Baseline in sleep quantity was calculated by subtracting the average value of sleep quantity, calculated in hours, at the end of the MP from the average Baseline value. | Baseline and End of Maintenance Phase (MP) (Week 4). | 
| Number of Participants With the Indicated Change From Baseline to the End of the Maintenance Phase in Optimal Sleep Based on the Sleep Quantity Domain of the MOS Sleep Scale | Optimal Sleep was based on the Sleep Quantity domain of the MOS Sleep Scale and included the options of Yes if sleep quantity was 7-8 hours, and No otherwise. Improved indicated a change in response of no at baseline to yes at the end of the MP, Same indicated no change in response, and Worse indicated a change in response from yes at baseline to no at the end of the MP. | Baseline and End of Maintenance Phase (MP) (Week 4). | 
| Number of Participants With the Indicated Overall Patient Global Impression of Change (PGIC) | For the PGIC assessment, participants were asked to assess their overall status since they initiated the study drug to the end of the Maintenance Phase using a 7-point categorical scale: 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very much worse. All participants who completed Week 4 of the Maintenance Phase and participants who terminated early during the Maintenance Phase were assessed. | Baseline to the end of Maintenance Phase (MP) (Week 4) | 
| Mean Score on the Treatment Satisfaction Questionnaire for Medication (TSQM) at the End of the Maintenance Phase | The TSQM assessed the participant's overall satisfaction with treatment, including subscales to assess effectiveness, side effects, convenience, and global satisfaction. Raw scores from the scale were transformed into a numeric scale ranging from 0 to 100, where higher scores indicated greater satisfaction with treatment. TSQM was reported at the end of the MP. Participants who completed Week 4 of the MP and who terminated early during the MP were assessed. | End of Maintenance Phase (MP) (Week 4) | 
| Scores on the Brief Pain Inventory-Short Form (BPI-SF) at the End of the MP for All Participants Who Completed Week-4 of the MP and Who Terminated Early During the MP | The BPI-SF assessed pain intensity, pain relief from medication, and pain interference with function over the previous 24 hours. Pain intensity was assessed by the mean of 4 intensity items rated on a 0-10 categorical scale: 0=no pain, 10=pain as bad as you can imagine. Pain interference was assessed by determining the mean of the 7 interference items on a 0-10 categorical scale ranging from 0=does not interfere to 10=completely interferes. The level of pain relief provided by treatment was assessed on an 11-point categorical scale ranging from 0% to 100% | End of Maintenance Phase (MP) (Week 4) | 
| Scores on the Medical Outcomes Short Form-36 (SF-36) at the End of the MP for All Participants Who Completed Week 4 of the MP and Who Terminated Early During the MP | Least square (LS) mean calculated based on participant's assessment of SF-36,a quality of life questionnaire consisting of 36 items grouped into 8 domains. These 8 domains further grouped into 2 overall summary measures,physical health and mental health. Higher scores on SF-36 represented better state of health. Physical/mental components summarized the data of all the physical/mental domains of SF-36 and higher scores represented better state of health. | End of Maintenance Phase (MP) (Week 4) | 
| Scores for Reported Health Transition at the End of the MP for All Participants Who Completed Week 4 of the MP and Who Terminated Early During the MP | The least square (LS) mean score for reported health transition was calculated based on the scores (ranging from 1 to 5) given by the participant in answer to the following question: Compared to 1 year ago, how would you rate your health in general now?. Lower numbers represent a better state of health. | End of maintenance Phase (MP) (Week 4) | 
| Number of Participants With the Indicated Responses at Baseline to the Question: How Painful Was the Affected Side Compared to the Opposite Side? in an Assessment of Tactile Allodynia | At Baseline, the investigator conducted the Neuropathic Pain Physical Examination (NPPE) to examine hyperalgesia and allodynia (tactile and cold). Tactile allodynia was assessed with a foam brush, based on the question:How painful was the affected side compared to the opposite side?. | Baseline Phase (Day -7 to Randomization Day 0) | 
| Number of Participants With the Indicated Responses at Baseline to the Questions of Is it Cool? and Is it Painful? in an Assessment of Cold Threshold and Allodynia | At Baseline the investigator conducted the NPPE to examine hyperalgesia and allodynia (tactile and cold). Cold threshold and allodynia was assessed to determine if a metal bar felt cool and if it felt painful, based on the questions:Is it cool? and Is it painful? | Timeframe: Baseline Phase (Day -7 to Randomization Day 0) | 
| Number of Subjects With the Indicated Responses at Baseline to the Questions: How Sharp Was the Affected Side Compared to the Opposite Side? and How Painfule Was the Affected Side Compared to the Opposite Side? in an Assessment of Hyperalgesia | At Baseline the investigator conducted the NPPE to examine hyperalgesia and allodynia (tactile and cold). Hyperalgesia is defined as increased sensitivity to pain, which may be caused by damage to peripheral nerves. It was assessed with a pinprick brush, based on the questions: How sharp was the affected side compared to the opposite side? and How painfule was the affected side compared to the opposite side? | Baseline Phase (Day -7 to Randomization Day 0) | 
| Number of Participants With the Indicated Responses at the End of the MP to the Question: How Painful Was the Affected Side Compared to the Opposite Side? in an Assessment of Tactile Allodynia | At the end of the MP, the investigator conducted the NPPE (an examination of the effect of retigabine on sensory abnormalities) to examine hyperalgesia and allodynia (tactile and cold). Tactile allodynia was assessed with a foam brush, based on the question:How painful was the affected side compared to the opposite side? End of Maintenance Phase includes participants who completed Week 4 of the MP and who terminated early during the MP. | End of Maintenance Phase (MP) (Week 4) | 
| Number of Participants With the Indicated Responses at the End of the MP to the Questions of Is it Cool? and Is it Painful? in an Assessment of Cold Threshold and Allodynia | At the end of the MP, the investigator conducted the NPPE (an examination of the effect of retigabine on sensory abnormalities) to examine hyperalgesia and allodynia (tactile and cold). Cold threshold and allodynia was assessed to determine if a metal bar felt cool and if it felt painful, based on the questions:Is it cool? and Is it painful? | End of Maintenance Phase (MP) (Week 4) | 
| Number of Participants With Indicated Responses at the End of the MP to the Questions: How Sharp Was the Affected Side Compared to the Opposite Side? and How Painful Was the Affected Side Compared to the Opposite Side? in an Assessment of Hyperalgesia | At the end of the MP, the investigator conducted the NPPE (an examination of the effect of retigabine on sensory abnormalities) to examine hyperalgesia and allodynia (tactile and cold). Hyperalgesia is defined as increased sensitivity to pain, which may be caused by damage to peripheral nerves. It was assessed with a pinprick brush, based on the questions:How sharp was the affected side compared to the opposite side? and How painful was the affected side compared to the opposite side? | End of Maintenance Phase (MP) (Week 4) | 
| Change From Baseline in the Average Diary Pain Score to the Last 7 Days of the Maintenance Phase by Post Herpetic Neuralgia (PHN) Subtype Irritable Nociceptors | Participants were stratified into four different PHN subtypes based on the NPPE. Participants with pain, abnormal sensitization of the specific receptor (irritable nociceptors), and with minimal sensory loss were stratified in theirritable nociceptors subtype. Based on their pain experienced during the previous 24 hours, participants assessed their pain every evening at bedtime in an electronic diary by choosing the appropriate number on an 11-point NRS: 0, no pain; 1 to 3, mild; 4 to 6, moderate; 7 to 10, severe pain. | Baseline and Week 4 Maintenance Phase (MP) | 
| Change From Baseline in the Average Diary Pain Score to the Last 7 Days of the Maintenance Phase by Post Herpetic Neuralgia (PHN) SubtypeDeafferentation Type 1 (D Type 1) | Participants stratified into 4 different PHN subtypes based on NPPE. Participants with marked sensory loss associated with severe burning pain upon slight mechanical stimuli (allodynia) were stratified in the deafferentation type 1 subtype. Based on their pain experienced during the previous 24 hours, participants assessed their pain every evening at bedtime in an electronic diary by choosing the appropriate number on an 11-point NRS: 0, no pain; 1 to 3, mild; 4 to 6, moderate; 7 to 10, severe pain. | Baseline and Week 4 Maintenance Phase (MP) | 
| Change From Baseline in the Average Diary Pain Score to the Last 7 Days of the Maintenance Phase by Post Herpetic Neuralgia (PHN) Subtype Deafferentation Type 2 (D Type 2) | Participants stratified into 4 different PHN subtypes based on NPPE. Participants with marked sensory loss and severe spontaneous burning pain without allodynia associated with reorganization of central nerve fibers were stratified in the deafferentation type 2 subtype. Based on their pain experienced during the previous 24 hours, participants assessed their pain every evening at bedtime in an electronic diary by choosing the appropriate number on an 11-point NRS: 0, no pain; 1 to 3, mild; 4 to 6, moderate; 7 to 10, severe pain. | Baseline and Week 4 Maintenance phase (MP) | 
| Change From Baseline in the Average Diary Pain Score to the Last 7 Days of the Maintenance Phase by Post Herpetic Neuralgia (PHN) Subtype Unclassifiable | Participants stratified into 4 different PHN subtypes based on NPPE. Participants who could not be specifically differentiated in any of the other three subtypes were stratified as unclassifiable meaning that the participants could not be classified into any of the predefined PHN subtypes. Based on their pain experienced during the previous 24 hours, participants assessed their pain every evening at bedtime in an electronic diary by choosing the appropriate number on an 11-point NRS: 0, no pain; 1 to 3, mild; 4 to 6, moderate; 7 to 10, severe pain. | Baseline and Week 4 Maintenance Phase (MP) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Postherpetic Neuralgia, PHN, Shingles,