Efficacy and Safety Study of Pregabalin in the Treatment of Pain on Walking in Patients With Diabetic Peripheral Neuropathy (DPN)

Study Overview
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Brief Summary
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The intent of this study is to treat subjects with painful Diabetic Peripheral Neuropathy (DPN) who also have pain on walking and to determine whether or not pregabalin demonstrates improvement relative to placebo on the following: reducing DPN pain, reducing pain on walking, and providing other benefits associated with daily activities and quality of life.

Official Title
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A Phase 3b Multicenter, Double-blind, Randomized, Placebo-controlled Cross-over Efficacy And Safety Study Of Pregabalin In The Treatment Of Patients With Painful Diabetic Peripheral Neuropathy And Pain On Walking

Conditions
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Diabetic Peripheral Neuropathy

Intervention / Treatment
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* Drug: Pregabalin
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women who are at least 18 years old. Diagnosis of painful diabetic peripheral neuropathy. Pain on walking. Exclusion Criteria: Inability to walk 50 feet on a flat surface. Pain on walking due to conditions other than diabetic peripheral neuropathy.

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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pregabain<br> | Drug: Pregabalin<br>* 150-300 mg/day given in 3 divided doses as capsules<br>* Other names: Lyrica;|
| Placebo Comparator: Placebo<br> | Other: placebo<br>* matching placebo capsules given in 3 divided doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Diabetic Peripheral Neuropathy (DPN) Pain Based on a Numeric Rating Scale (NRS) Over the Last 7 Days of Each Treatment Period (Week 6 of Each Treatment Period) | The daily pain diary consisted of an 11-point numeric scale ranging from 0 (no pain) to 10 (worst possible pain). Participants described their pain during the past 24 hours by having chosen the appropriate number between 0 and 10. Self-assessment was performed daily each evening before bedtime (6.00 pm to midnight) on the telephone via Interactive Voice Recognition System (IVRS). The endpoint mean pain score was defined as the mean of the last 7 daily diary pain ratings while taking study medication in each treatment period - Period 1 and Period 2, respectively. A rating of 1 - 3 was considered as mild pain; 4 - 6 as moderate pain; and 7 - 10 as severe pain. | End of Period (includes both Visits 6 and 11) | 
| DPN Pain on Walking Based on a 11-point NRS of Each Treatment Period (Week 6 of Each Treatment Period) | The post-test DPN pain on walking NRS consisted of an 11-point numeric scale ranging from 0 (no pain) to 10 (worst possible pain). Participants described their DPN pain in their legs and/or feet while walking during the 50-foot walk test by choosing the appropriate number between 0 and 10. The post-test DPN pain on walking NRS was completed by the participant using paper-pen administration immediately after completing the 50-foot walk test at the end of each treatment period - Period 1 and Period 2, respectively. A rating of 1 - 3 was considered as mild pain; 4 - 6 as moderate pain; and 7 - 10 as severe pain. | End of Period (includes both Visits 6 and 11) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving 30% Reduction in Mean DPN Pain Score From Baseline at the End of Each Treatment Period (Week 6 of Each Treatment Period) | The daily pain diary consisted of an 11-point numeric scale ranging from 0 (no pain) to 10 (worst possible pain). Participants described their pain during the past 24 hours by having chosen the appropriate number between 0 and 10. Self-assessment was performed daily each evening before bedtime (6.00 pm to midnight) on the telephone via IVRS. The endpoint mean pain score was defined as the mean of the last 7 daily diary pain ratings while taking study medication in each treatment period - Period 1 and Period 2, respectively. A rating of 1 - 3 was considered as mild pain; 4 - 6 as moderate pain; and 7 - 10 as severe pain. | End of Period (includes both Visits 6 and 11) | 
| Percentage of Participants Achieving 50% Reduction in Mean DPN Pain Score From Baseline at the End of Each Treatment Period (Week 6 of Each Treatment Period) | The daily pain diary consisted of an 11-point numeric scale ranging from 0 (no pain) to 10 (worst possible pain). Participants described their pain during the past 24 hours by having chosen the appropriate number between 0 and 10. Self-assessment was performed daily each evening before bedtime (6.00 pm to midnight) on the telephone via IVRS. The endpoint mean pain score was defined as the mean of the last 7 daily diary pain ratings while taking study medication in each treatment period - Period 1 and Period 2, respectively. A rating of 1 - 3 was considered as mild pain; 4 - 6 as moderate pain; and 7 - 10 as severe pain. | End of Period (includes both Visits 6 and 11) | 
| Brief Pain Inventory-Short Form (BPI-sf) Score for Pain-Severity Domain at the End of Each Treatment Period (Week 6 of Each Treatment Period) | The BPI-sf is a self-administered questionnaire developed to assess the severity of pain and the impact of pain on daily functions during a 24 hour period prior to evaluation. The BPI-sf consists of 5 questions: 4 items measure pain (0: no pain; 10: worst pain possible) at its worst, least, average, and now (current pain) on an 11-point scale. Scores range from 0 - 40 with higher scores indicating greater pain severity. Another item, containing 7 sub-questions, evaluates the level of interference of pain on daily functioning (general activity, walking, work ability, mood, enjoyment of life, relations with other people, and sleep) on 11-point scales (0: does not interfere; 10: completely interferes). Scores range from 0 - 70 with higher scores indicating greater interference. | End of Period (includes both Visits 6 and 11) | 
| BPI-sf Score for Pain-Interference Domain at the End of Each Treatment Period (Week 6 of Each Treatment Period) | The BPI-sf is a self-administered questionnaire developed to assess the severity of pain and the impact of pain on daily functions during a 24 hour period prior to evaluation. The BPI-sf consists of 5 questions: 4 items measure pain (0: no pain; 10: worst pain possible) at its worst, least, average, and now (current pain) on an 11-point scale. Scores range from 0 - 40 with higher scores indicating greater pain severity. Another item, containing 7 sub-questions, evaluates the level of interference of pain on daily functioning (general activity, walking, work ability, mood, enjoyment of life, relations with other people, and sleep) on 11-point scales (0: does not interfere; 10: completely interferes). Scores range from 0 - 70 with higher scores indicating greater interference. | End of Period (includes both Visits 6 and 11) | 
| BPI-sf Score for Pain-Interference With Walking Ability at the End of Each Treatment Period (Week 6 of Each Treatment Period) | The BPI-sf is a self-administered questionnaire developed to assess the severity of pain and the impact of pain on daily functions during a 24 hour period prior to evaluation. The BPI-sf consists of 5 questions: 4 items measure pain on an 11-point scale. Scores range from 0 - 40 with higher scores indicating greater pain severity. Another item, containing 7 sub-questions, evaluates the level of interference of pain on daily functioning (general activity, walking, work ability, mood, enjoyment of life, relations with other people, and sleep) on 11-point scales (0: does not interfere; 10: completely interferes). Scores range from 0 - 70 with higher scores indicating greater interference. The sub-score pain interference with walking ability was evaluated, as it was considered to be the most relevant in the context of this study. | End of Period (includes both Visits 6 and 11) | 
| Daytime Total Activity Counts Per Day Measured by Actigraphy Over the Last 7 Days of Each Treatment Period (Week 6 of Each Treatment Period) | Actigraphy data which measured steps and daytime activity during waking hours were assessed for the last 7 days at Baseline, Visit 6, and Visit 11. 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). Actigraphy was performed with an accelerometer that was worn on the hip during the waking hours. It was programmed to record movements while the device was being worn. | End of Period (includes both Visits 6 and 11) | 
| Steps Per Day Measured by Actigraphy Over the Last 7 Days of Each Treatment Period (Week 6 of Each Treatment Period) | Actigraphy data which measured steps and daytime activity during waking hours were assessed for the last 7 days at Baseline, Visit 6, and Visit 11. The participants were instructed to wear the device on their hip during the waking hours. | End of Period (includes both Visits 6 and 11) | 
| Walk 12 Questionnaire Over the Last 2 Weeks of Each Treatment Period (Week 6 of Each Treatment Period) | The Walk-12 is a self-administered questionnaire that assesses the impact of the participant's diabetic neuropathy over the past 2 weeks on parameters associated with walking (12 questions) based on a 5-point scale (from not at all to extremely). The total score is the sum of scores from the 12 questions, which then gets transferred to a 0-100 scale with higher scores indicating greater impairment | End of Period (includes both Visits 6 and 11) | 
| Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) Total Quality of Life (TQOL) Score Measured Over the Last 2 Weeks of Each Treatment Period (Week 6 of Each Treatment Period) | Norfolk QOL-DN is a 35-item participant-rated questionnaire used to assess impact of diabetic neuropathy on the quality of life of participants with diabetic neuropathy. All symptoms (1 - 7) are scored as either 1 or 0, indicating presence or absence of the symptom. With the exception of questions 31 and 32, the other items are scored according to the 5-point Likert Scale (0 - 4, no problem to severe problem). In question 31, good, the middle item, is scored as 0, very good as -1, excellent as -2, fair as 1, and poor as 2. In question 32, about the same, the middle item, is scored as 0, somewhat better as -1, much better as -2, somewhat worse as 1, and much worse as 2. TQOL score should be summed as follow: sum (Σ) (1 - 7, 8 - 35). The scales and subscales are calculated without weighting of any kind, and reported as the integer sum of the listed questionnaire items. | End of Period (includes both Visits 6 and 11) | 
| Norfolk QOL-DN Symptoms Domain Score Measured Over the Last 2 Weeks of Each Treatment Period (Week 6 of Each Treatment Period) | Norfolk QOL-DN is a 35-item participant-rated questionnaire used to assess impact of diabetic neuropathy on the quality of life of participants with diabetic neuropathy. All symptoms (1 - 7) are scored as either 1 or 0, indicating presence or absence of the symptom. With the exception of questions 31 and 32, the other items are scored according to the 5-point Likert Scale (0 - 4, no problem to severe problem). In question 31, good, the middle item, is scored as 0, very good as -1, excellent as -2, fair as 1, and poor as 2. In question 32, about the same, the middle item, is scored as 0, somewhat better as -1, much better as -2, somewhat worse as 1, and much worse as 2. The symptoms domain score should be summed as follow: Σ(1 - 7, 9). The scales and subscales are calculated without weighting of any kind, and reported as the integer sum of the listed questionnaire items. | End of Period (includes both Visits 6 and 11) | 
| Norfolk QOL-DN Activities of Daily Living Domain Score Measured Over the Last 2 Weeks of Each Treatment Period (Week 6 of Each Treatment Period) | Norfolk QOL-DN is a 35-item participant-rated questionnaire used to assess impact of diabetic neuropathy on the quality of life of participants with diabetic neuropathy. All symptoms (1 - 7) are scored as either 1 or 0, indicating presence or absence of the symptom. With the exception of questions 31 and 32, the other items are scored according to the 5-point Likert Scale (0 - 4, no problem to severe problem). In question 31, good, the middle item, is scored as 0, very good as -1, excellent as -2, fair as 1, and poor as 2. In question 32, about the same, the middle item, is scored as 0, somewhat better as -1, much better as -2, somewhat worse as 1, and much worse as 2. The activities of daily living domain score should be summed as follow: Σ(12, 22, 23, 25, 26). The scales and subscales are calculated without weighting of any kind, and reported as the integer sum of the listed questionnaire items. | End of Period (includes both Visits 6 and 11) | 
| Norfolk QOL-DN Physical Functioning / Large Fiber Domain Score Measured Over the Last 2 Weeks of Each Treatment Period (Week 6 of Each Treatment Period) | Norfolk QOL-DN is a 35-item participant-rated questionnaire used to assess impact of diabetic neuropathy on the quality of life of participants with diabetic neuropathy. All symptoms (1 - 7) are scored as either 1 or 0, indicating presence or absence of the symptom. With the exception of questions 31 and 32, the other items are scored according to the 5-point Likert Scale (0 - 4, no problem to severe problem). In question 31, good, the middle item, is scored as 0, very good as -1, excellent as -2, fair as 1, and poor as 2. In question 32, about the same, the middle item, is scored as 0, somewhat better as -1, much better as -2, somewhat worse as 1, and much worse as 2. The physical functioning / large fiber domain score should be summed as follow: Σ(8, 11, 13 - 15, 24, 27 - 35). The scales and subscales are calculated without weighting of any kind, and reported as the integer sum of the listed questionnaire items. | End of Period (includes both Visits 6 and 11) | 
| Norfolk QOL-DN Small Fiber Domain Score Measured Over the Last 2 Weeks of Each Treatment Period (Week 6 of Each Treatment Period) | Norfolk QOL-DN is a 35-item participant-rated questionnaire used to assess impact of diabetic neuropathy on the quality of life of participants with diabetic neuropathy. All symptoms (1 - 7) are scored as either 1 or 0, indicating presence or absence of the symptom. With the exception of questions 31 and 32, the other items are scored according to the 5-point Likert Scale (0 - 4, no problem to severe problem). In question 31, good, the middle item, is scored as 0, very good as -1, excellent as -2, fair as 1, and poor as 2. In question 32, about the same, the middle item, is scored as 0, somewhat better as -1, much better as -2, somewhat worse as 1, and much worse as 2. The small fiber domain score should be summed as follow: Σ(10, 16, 17, 18). The scales and subscales are calculated without weighting of any kind, and reported as the integer sum of the listed questionnaire items. | End of Period (includes both Visits 6 and 11) | 
| Norfolk QOL-DN Autonomic Domain Score Measured Over the Last 2 Weeks of Each Treatment Period (Week 6 of Each Treatment Period) | Norfolk QOL-DN is a 35-item participant-rated questionnaire used to assess impact of diabetic neuropathy on the quality of life of participants with diabetic neuropathy. All symptoms (1 - 7) are scored as either 1 or 0, indicating presence or absence of the symptom. With the exception of questions 31 and 32, the other items are scored according to the 5-point Likert Scale (0 - 4, no problem to severe problem). In question 31, good, the middle item, is scored as 0, very good as -1, excellent as -2, fair as 1, and poor as 2. In question 32, about the same, the middle item, is scored as 0, somewhat better as -1, much better as -2, somewhat worse as 1, and much worse as 2. The autonomic domain score should be summed as follow: Σ(19, 20, 21). The scales and subscales are calculated without weighting of any kind, and reported as the integer sum of the listed questionnaire items. | End of Period (includes both Visits 6 and 11) | 
| Percentage of Participants With Patient Global Impression of Change (PGIC) Score From Baseline at the End of Period 1 (Week 6) | The PGIC is a participant-rated instrument that measures the participant's assessment of change in his/her overall status on a scale ranging from 1 (very much improved) to 7 (very much worse). Original scores (OS; 7 different scores) and categorized scores (CS; 4 different scores) were provided. Categorized scores were very much improved (consisting of very much improved and much improved); any improvement (consisting of very much improved, much improved, and minimally improved); no change (consisting of no change); and any worsening (consisting of minimally worse, much worse, and very much worse). Due to the crossover design, PGIC was analyzed at the end of period 1 (V6). | End of Period 1 (V6) | 
| Mean Sleep Interference Rating Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | The daily sleep diary consists of an 11-point numeric rating scale with which the participant rates how painful DPN pain has interfered with their sleep during the past 24 hours. Zero indicates does not interfere with sleep and 10 indicates completely interferes (unable to sleep due to pain). Self-assessment was performed daily in the evening before bedtime on a telephone via IVRS (time window for completion between 6.00 pm to midnight) after completion of the daily pain diary. | End of Period (includes both Visits 6 and 11) | 
| Hospital Anxiety and Depression Scale - Anxiety (HADS-A) Total Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | The Hospital Anxiety and Depression Scale (HADS) is a 14-item self-administered questionnaire that consists of 2 scales, one measuring anxiety (HADS-A), and the other measuring depression (HADS-D). Each subscale consists of 7 statements and the participant responds as to how each item applies to him/her over the past week on 4-point response scale. Separate scores are calculated for anxiety and depression and a score (ranging from 0 to 21) is obtained for each subscale. The higher the score, the more severe the anxiety or depression. | End of Period (includes both Visits 6 and 11) | 
| Hospital Anxiety and Depression Scale - Depression (HADS-D) Total Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | The HADS is a 14-item self-administered questionnaire that consists of 2 scales, one measuring anxiety (HADS-A), and the other measuring depression (HADS-D). Each subscale consists of 7 statements and the participant responds as to how each item applies to him/her over the past week on 4-point response scale. Separate scores are calculated for anxiety and depression and a score (ranging from 0 to 21) is obtained for each subscale. The higher the score, the more severe the anxiety or depression. | End of Period (includes both Visits 6 and 11) | 
| Euro QoL-5 Dimensions (EQ-5D) - Health State Profile Utility Scores at the End of Each Treatment Period (Week 6 of Each Treatment Period) | The EQ-5D describes participant's health status based on 5 attributes producing an 5 digit index score. The 5 dimensions are: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Dolan 1997 advised how to transfer this index score to a single score for clinical trials, a revised single index was published in 2001. The index uses general population weighted estimates for various health states. In general, the range of the single index tends to vary between 0 = death and 1 = perfect health and there are some states that have been rated by the general population to be worse than death which may result in numbers below 0. | End of Period (includes both Visits 6 and 11) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetic Peripheral Neuropathy, Pain on Walking, Pregabalin