Pregabalin Versus Placebo In The Treatment Of Neuropathic Pain Associated With HIV Neuropathy

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy of pregabalin compared to placebo in reducing neuropathic pain associated with HIV neuropathy.

Detailed Description
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Based on DMC interim efficacy analysis results indicating a low probability for success the study was terminated on April 2, 2012; the termination was unrelated to any safety findings that could impact patient health.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Trial Of Pregabalin Versus Placebo In The Treatment Of Neuropathic Pain Associated With HIV Neuropathy (Pregabalin A0081244)

Conditions
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Neuropathy

Intervention / Treatment
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* Drug: pregabalin
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women, ages of 18 or greater Documented evidence of HIV-1 infection Documented diagnosis of HIV-associated Distal Symmetrical Polyneuropathy (DSP) with subjective sensory symptom of pain Pain starts in the feet Exclusion Criteria: Subject has untreated vitamin B12 deficiency (serum B12 level <200 pg/ml) or if treated B12 deficiency -treatment is less than 6 months of B12 supplementation (injection or intranasal B12) prior to screening Diabetes mellitus requiring regular medical treatment (other than diet and exercise) or HbA1C >6.9 Subjects with peripheral neuropathic pain that is not associated with HIV infection; including subjects with conditions such as: Post Herpetic Neuralgia (PHN), Diabetic Peripheral Neuropathy (DPN), familial neuropathies; compression related neuropathy, radicular pain, other infection related neuropathies (eg, leprosy); neuropathy related to: metabolic abnormalities; nutritional factors; vascular insults; inflammation; autoimmune disease; and malignancy

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 |
| --- | --- |
| Experimental: Active drug<br> | Drug: pregabalin<br>* Pregabalin 75 mg-300mg twice daily during the course of the study.<br>|
| Placebo Comparator: Control<br> | Drug: placebo<br>* Subjects may be assigned to placebo during this study. The study duration is approximately 19 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Pain Score at Endpoint (up to Week 16) | Mean pain score was defined as the mean of the last 7 daily diary pain ratings. Participants rated their Human Immunodeficiency Virus (HIV) neuropathy pain over the past 24 hours on an 11-point numeric rating scale ranging from 0 = no pain to 10 = worst possible pain. A rating of 1-3 was considered as mild pain; 4-6 = moderate pain; and 7-10 = severe pain. Endpoint was the last observation for a participant assessed using specified imputation method, modified Baseline Observation Carried Forward (mBOCF). | Baseline, Endpoint (up to Week 16) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Categorical Scores on Patient Global Impression of Change (PGIC) | PGIC: participant rated instrument to measure participant's change in overall status on a 7-point scale; range from 1 (very much improved) to 7 (very much worse). Number of participants in each category is reported. | Week 16 | 
| Number of Participants With Categorical Scores on Clinician Global Impression of Change (CGIC) | The CGIC scale measures a physician's global impression of a participant's clinical condition at final visit in terms of change relative to the start of treatment (CGIC). At final visit, the participants CGIC will be categorized into a three point scale as: improvement: CGI response of very much improved, much improved or minimally improved; no change: CGI response of no change; worsening: CGI response of very much worse, much worse or minimally worse. Number of participants in each category is reported. | Week 16 | 
| Change From Baseline in Numeric Rating Scale (NRS)-Sleep Interference Score at Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 and Endpoint (up to Week 16) | Weekly mean sleep interference score was defined as the mean of the daily sleep interference diary ratings split into 7 day intervals. Participants rated how HIV neuropathy pain has interfered with their sleep during the past 24 hours on an 11-point NRS ranging from 0 = does not interfere with sleep to 10 = completely interferes (unable to sleep due to pain). Endpoint was the last observation for a participant assessed using specified imputation method. | Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, Endpoint (up to Week 16) | 
| Change From Baseline in Numeric Rating Scale (NRS)-Current Pain Score at Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 and Endpoint (up to Week 16) | Weekly current pain score was defined as the mean of the daily current pain diary ratings split into 7 day intervals. Participants rated current (right now) HIV neuropathy pain an 11-point NRS ranging from 0 = no pain to 10 = worst possible pain. A rating of 1-3 was considered as mild pain; 4-6 = moderate pain; and 7-10 = severe pain. Endpoint was the last observation for a participant assessed using specified imputation method. | Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, Endpoint (up to Week 16) | 
| Change From Baseline in Brief Pain Inventory-Short Form (BPI-sf) Score at Week 4, 8, 12, 16 and Endpoint (up to Week 16) | BPI-sf:5-item self-administered questionnaire to assess severity,impact of pain on daily functions. Pain Severity Index (PSI):average of Question 1-4 each measured severity of pain over past 24-hours on 11-point scale (0=no pain to 10=worst possible pain). Pain Interference Index (PII):average of 7 pain interference items of Question 5 that measured level of interference of pain on daily function on 11-point scale (0=does not interfere to 10=completely interferes). For PSI, PII range:0-10 higher score=higher pain/interference. Endpoint=last observation for participant as per imputation method. | Baseline, Week 4, 8, 12, 16, Endpoint (up to Week 16) | 
| Change From Baseline in Neuropathic Pain Symptom Inventory (NPSI) Item Scores at Endpoint (up to Week 16) | NPSI: participant-rated questionnaire to evaluate different symptoms of neuropathic pain. It includes 10 descriptors and 2 temporal items. Results reported for the 10 descriptors (burning, squeezing, pressure, electric shocks, stabbing, light touching of area, pressure of area, cold of area, pins and needles, tingling) quantified on a 0 (no symptoms) to 10 (worst symptoms imaginable) scale. Endpoint was the last observation for a participant assessed using specified imputation method. | Baseline, Endpoint (up to Week 16) | 
| Neuropathic Pain Symptom Inventory (NPSI): Change From Baseline in Number of Participants With Duration of Spontaneous Pain and Number of Pain Attacks at Endpoint (up to Week 16) | NPSI: participant-rated questionnaire to evaluate different symptoms of neuropathic pain. It includes 10 descriptors, and 2 temporal items. Results reported for categorical change in temporal items assessed on 5-point scale for duration of spontaneous pain (1=continuously, 2=8-12 hours [hrs], 3=4-7 hrs, 4=1-3 hrs, 5=less than 1 hr), numbers of pain attacks (1=more than 20, 2=11-20 attacks, 3=6-10 attacks, 4=1-5 attacks, 5=no attack). Change data categorized as worsened (negative change), unchanged (no change), and improved (positive change). Endpoint=last observation as per imputation method. | Baseline, Endpoint (up to Week 16) | 
| Change From Baseline in Neuropathic Pain Symptom Inventory (NPSI) Subscales and Total Intensity Score at Endpoint (up to Week 16) | NPSI: participant rated questionnaire to evaluate different symptoms of neuropathic pain (subscales: burning [superficial] spontaneous pain, pressing [deep] spontaneous pain, paroxysmal pain, evoked pain, and paresthesia/dyesthesia [P/D]). Includes 10 descriptors quantified on a 0 (no symptoms) to 10 (worst symptoms imaginable) and 2 temporal items assessing duration of spontaneous ongoing and paroxysmal pain. The relevant subscales and total score were transformed to 0-1, higher score indicates a greater intensity of pain. Endpoint=last observation for participant as per imputation method. | Baseline, Endpoint (up to Week 16) | 
| Total Sleep Time (TST) and Minutes of Interrupted Sleep (MIS) | Total sleep time is the number of minutes asleep between time of sleep onset to morning awakening and MIS is the number of minutes spent awake after sleep onset to final awakening. TST and MIS were determined by actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to record movements while the device was being worn. Endpoint was the last observation for a participant assessed using specified imputation method. | Baseline (Day -14 to 1), Week 1 through Week 4, Week 12 through Week 16, Endpoint (up to Week 16) | 
| Sleep Fragmentation Index (SFI) | SFI is a measure to quantify sleep restlessness. SFI calculated from analysis of the periods that participant was not moving (immobile bouts). It is number of immobile bouts that were exactly 1 minute long divided by total number of immobile bouts. Value ranges from 0-100 percent, with low number representing more restful sleep. SFI determined by actigraphy. Actigraphy was performed with an accelerometer that was worn on wrist like a watch. It was programmed to record movements while device was being worn. Endpoint was the last observation for a participant assessed using imputation method. | Baseline (Day -14 to 1), Week 1 through Week 4, Week 12 through Week 16, Endpoint (up to Week 16) | 
| Sleep Efficiency | Sleep efficiency is the time spent asleep divided by total time between sleep onset and sleep end, multiplied by 100. Sleep efficiency was determined by actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to record movements while the device was being worn. Endpoint was the last observation for a participant assessed using specified imputation method. | Baseline (Day -14 to 1), Week 1 through Week 4, Week 12 through Week 16, Endpoint (up to Week 16) | 
| Total Activity Counts | Activity counts are the units of motion. It is equal to the sum of peak accelerations each second during the epoch (60 seconds). Total activity counts per day is the sum of the activity counts for each epoch (60 seconds) during the day (non sleep period). A total activity count was determined by actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to record movements while the device was being worn. Endpoint was the last observation for a participant assessed using specified imputation method. | Baseline (Day -14 to 1), Week 1 through Week 4, Week 12 through Week 16, Endpoint (up to Week 16) | 
| Percentage Day Time Above Sedentary Level | Percentage of time above sedentary level is number of epochs (60 seconds) with greater than (>) 200 activity counts per minute divided by total number of epochs during the day (non sleep period) multiplied by 100. This was determined by actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to record movements while the device was being worn. Endpoint was the last observation for a participant assessed using specified imputation method. | Baseline (Day -14 to 1), Week 1 through Week 4, Week 12 through Week 16, Endpoint (up to Week 16) | 
| Change From Baseline in Medical Outcomes Study-Sleep Scale (MOS-SS) at Endpoint (up to Week 16) | Participant-rated 12-item questionnaire to assess constructs of sleep over past week; 7 subscales: sleep disturbance (range 0-100), snoring (range 0-100), awaken short of breath (SOB) or with headache (range 0-100), sleep adequacy (range 0-100), somnolence (range: 0-100); sleep quantity (range: 0-24), optimal sleep (yes/no), and 9 item index measures of sleep disturbance provide composite scores: sleep problems index (range 0-100). Except adequacy, optimal sleep and quantity, higher scores=more impairment. Endpoint was the last observation for a participant assessed using imputation method. | Baseline, Endpoint (up to Week 16) | 
| Medical Outcomes Study-Sleep Scale (MOS-SS): Number of Participants With Optimal Sleep | MOS-SS: participant-rated 12 item questionnaire to assess constructs of sleep over past week. It included 7 subscales: sleep disturbance, snoring, awaken short of breath or with headache, sleep adequacy, somnolence, sleep quantity, optimal sleep, and 9 item index measures of sleep disturbance provide composite scores: sleep problems index. Participants responded whether their sleep was optimal or not optimal by choosing yes or no. Endpoint was the last observation for a participant assessed using imputation method. | Baseline, Endpoint (up to Week 16) | 
| Change From Baseline in Hospital Anxiety and Depression Scales (HADS) at Endpoint (up to Week 16) | HADS: participant rated questionnaire with 2 subscales. HADS-A assesses state of generalized anxiety (anxious mood, restlessness, anxious thoughts, panic attacks); HADS-D assesses state of lost interest and diminished pleasure response (lowering of hedonic tone). Each subscale comprised of 7 items with range 0 (no presence of anxiety or depression) to 3 (severe feeling of anxiety or depression). Total score 0 to 21 for each subscale; higher score indicates greater severity of anxiety and depression symptoms. Endpoint was the last observation for a participant assessed using imputation method. | Baseline, Endpoint (up to Week 16) | 
| Change From Baseline in 36-Item Short-Form Health Survey (SF-36) at Endpoint (up to Week 16) | SF-36 is a standardized survey evaluating 8 domains of functional health and well being: physical and social (So) functioning (Fn), physical and emotional role (role-physical [R-P], role-emotional [R-E]) limitations, bodily pain (BP), general health (GH), vitality (Vit), mental health (MnH). Two summary scores include Physical Component (Ph C) and Mental Component (Mn C). The score for a section is an average of the individual question scores. Score range for domain scores and summary scores: 0-100 (100=highest level of functioning). | Baseline, Endpoint (up to Week 16) | 
| Number of Participants Who Were Employed or Unemployed Assessed by Work Productivity and Activity Impairment: Specific Health Problem (WPAI: SHP) Questionnaire | WPAI: 6-question participant rated questionnaire to determine the degree to which specific health problem (SHP) affected work productivity while at work and affected activities outside of work. It assesses amount of absenteeism, presenteeism and daily activity impairment attributable to a HIV neuropathy pain. Number of participants who responded Yes/No to Question 1: Are you currently employed (working for pay)? are reported. | Baseline, Week 16, 17 | 
| Absenteeism and Presenteeism Assessed by Work Productivity and Activity Impairment: Specific Health Problem (WPAI: SHP) Questionnaire | WPAI: 6-question participant rated questionnaire to determine the degree to which SHP affected work productivity while at work and affected activities outside of work. It assesses amount of absenteeism, presenteeism and daily activity impairment attributable to a HIV neuropathy pain. Question 2 and 3 assesses absenteeism as: Hours of work missed in past 7 days due to leg/foot pain or other reason, respectively. Question 4 assesses presenteeism as: Hours of work performed in past 7 days. A participant who had responded 'no' to question 1 regarding employment status reported hours of work and as this was a self-reported questionnaire the source data were included. | Baseline, Week 16, 17 | 
| Productivity and Activity Impairment Assessed by Work Productivity and Activity Impairment: Specific Health Problem (WPAI: SHP) Questionnaire | WPAI: 6-question participant rated questionnaire to determine the degree to which SHP affected work productivity while at work and affected activities outside of work. It assesses amount of absenteeism, presenteeism and daily activity impairment attributable to a HIV neuropathy pain. Question 5 and 6 assesses: How much leg/foot pain affect productivity and daily activity, respectively in past 7 days? on 11-point scale, where 0 (not affected/no impairment) to 10 (completely affected/impaired). | Baseline, Week 16, 17 | 
| Diagnostic Neuropathy Assessment |  | Screening | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neuropathy, pain, HIV-1, HIV Infections