Painful Diabetic Peripheral Neuropathy
Conditions
Brief summary
This study is to test the effectiveness of pregabalin in treating nerve pain caused by diabetes. The suitable subjects will be patients who also use an non-steroid anti-inflammatory drug for another pain which is not related to the diabetic nerve pain.
Interventions
DRUGpregabalin
150 - 300 mg/day in divided dose (3 time a day) for 6 weeks
DRUGplacebo
matching placebo 3 time a day
Sponsors
Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Type 1 or 2 diabetes with painful neuropathy * Currently treated with one NSAID (including COX 2 inhibitors) for a co morbid pain condition with a regular dose * Meet pre-defined level of pain severity at entrance
Exclusion criteria
* History of failed pregabalin treatment due to lack of efficacy at therapeutic dose * Participated in a previous or ongoing pregabalin clinical trial * Neurologic disorders unrelated to diabetic neuropathy that may confound the assessment of distal neuropathic pain
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | End of Period (includes both Visits 5 and 9) | 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 in the evening before bedtime on a telephone via interactive voice recognition system (IVRS) (time window for completion between 6.00 pm to midnight). The endpoint mean pain score was defined as the mean of the last 7 daily diary pain ratings while taking study drug 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | End of Period (includes both Visits 5 and 9) | 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 in the evening before bedtime on a telephone via IVRS (time window for completion between 6.00 pm to midnight). The endpoint mean pain score was defined as the mean of the last 7 daily diary pain ratings while taking study drug 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. |
| 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) | End of Period (includes both Visits 5 and 9) | 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. Four 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 - 10 with higher scores indicating greater pain severity. |
| BPI-sf Score for Pain-Interference Domain at the End of Each Treatment Period (Week 6 of Each Treatment Period) | End of Period (includes both Visits 5 and 9) | 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. Seven 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 an 11-point scale (0: does not interfere; 10: completely interferes). Scores range from 0 - 10 with higher scores indicating greater interference. |
| Mean Sleep Interference Rating Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | End of Period (includes both Visits 5 and 9) | 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. |
| Hospital Anxiety and Depression Scale - Anxiety (HADS-A) Total Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | End of Period (includes both Visits 5 and 9) | 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. |
| HADS-D Total Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | End of Period (includes both Visits 5 and 9) | 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. |
| Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) Total Quality of Life (TQOL) Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | End of Period (includes both Visits 5 and 9) | Norfolk QOL-DN is a 35-item participant-rated questionnaire used to assess impact of diabetic neuropathy on 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 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 (sub)scales are calculated without weighting of any kind, and reported as the integer sum of listed questionnaire items (range: -4 - 136). The QOL-DN version that was administered in this study was modified with a 2-week recall period. |
| Norfolk QOL-DN Symptoms Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | End of Period (includes both Visits 5 and 9) | Norfolk QOL-DN is a 35-item participant-rated questionnaire used to assess the impact of diabetic neuropathy on 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. Item 9 is scored according to the 5-point Likert Scale (0 - 4, no problem to severe problem). 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 (range: 0 - 32). The QOL-DN version that was administered in this study was modified with a 2-week recall period. |
| Norfolk QOL-DN Activities of Daily Living Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | End of Period (includes both Visits 5 and 9) | Norfolk QOL-DN is a 35-item participant-rated questionnaire used to assess the impact of diabetic neuropathy on quality of life of participants with diabetic neuropathy. The items are scored according to the 5-point Likert Scale (0 - 4, no problem to severe problem). Activities of the daily living domain score should be summed as follow: Σ (12, 22, 23, 25, 26). Scales and subscales are calculated without weighting of any kind, and reported as integer sum of listed questionnaire items (range: 0 - 20). The QOL-DN version that was administered in the study was modified with a 2-week recall period. |
| Norfolk QOL-DN Physical Functioning / Large Fiber Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | End of Period (includes both Visits 5 and 9) | Norfolk QOL-DN is a 35-item participant-rated questionnaire used to assess the impact of diabetic neuropathy on quality of life of participants with diabetic neuropathy. With exception of questions 31 and 32, items are scored according to the 5-point Likert Scale (0 - 4, no problem to severe problem). In question 31, good, 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, middle item, is scored as 0, somewhat better as -1, much better as -2, somewhat worse as 1, and much worse as 2. Physical functioning / large fiber domain score should be summed as follow: Σ (8, 11, 13 - 15, 24, 27 - 35). Scales and subscales are calculated without weighting of any kind, and reported as integer sum of listed questionnaire items (range: -4 - 56). QOL-DN version that was administered in the study was modified with a 2-week recall period. |
| 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) | End of Period (includes both Visits 5 and 9) | 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 in the evening before bedtime on a telephone via IVRS (time window for completion between 6.00 pm to midnight). The endpoint mean pain score was defined as the mean of the last 7 daily diary pain ratings while taking study drug 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. |
| Norfolk QOL-DN Autonomic Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | End of Period (includes both Visits 5 and 9) | Norfolk QOL-DN is a 35-item participant-rated questionnaire used to assess the impact of diabetic neuropathy on quality of life of participants with diabetic neuropathy. The items are scored according to the 5-point Likert Scale (0 - 4, no problem to severe problem). 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 (range: 0 - 12). The QOL-DN version that was administered in this study was modified with a 2-week recall period. |
| Euro QoL-5 Dimensions (EQ-5D) Mobility Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | End of Period (includes both Visits 5 and 9) | EQ-5D is a participant-completed 5-item questionnaire designed to assess health related quality of life in terms of a single index value or utility score. There are 5 dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension is rated on a 3-point response scale (no problems, some/moderate problems, extreme problems) and the scores are combined to form a single index utility value between 0 and 1 with higher scores indicating better health. |
| EQ-5D Self-Care Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | End of Period (includes both Visits 5 and 9) | EQ-5D is a participant-completed 5-item questionnaire designed to assess health related quality of life in terms of a single index value or utility score. There are 5 dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension is rated on a 3-point response scale \[1 = no problems, 2 = some/moderate problems, 3 = extreme problems\] and the scores are combined to form a single index utility value between 0 and 1 with higher scores indicating better health. |
| EQ-5D Usual Activities Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | End of Period (includes both Visits 5 and 9) | EQ-5D is a participant-completed 5-item questionnaire designed to assess health related quality of life in terms of a single index value or utility score. There are 5 dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension is rated on a 3-point response scale \[1 = no problems, 2 = some/moderate problems, 3 = extreme problems\] and the scores are combined to form a single index utility value between 0 and 1 with higher scores indicating better health. |
| EQ-5D Pain / Discomfort Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | End of Period (includes both Visits 5 and 9) | EQ-5D is a participant-completed 5-item questionnaire designed to assess health related quality of life in terms of a single index value or utility score. There are 5 dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension is rated on a 3-point response scale \[1 = no problems, 2 = some/moderate problems, 3 = extreme problems\] and the scores are combined to form a single index utility value between 0 and 1 with higher scores indicating better health. |
| EQ-5D Anxiety / Depression Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | End of Period (includes both Visits 5 and 9) | EQ-5D is a participant-completed 5-item questionnaire designed to assess health related quality of life in terms of a single index value or utility score. There are 5 dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension is rated on a 3-point response scale \[1 = no problems, 2 = some/moderate problems, 3 = extreme problems\] and the scores are combined to form a single index utility value between 0 and 1 with higher scores indicating better health. |
| EQ-5D Dolan 1997 Index Summary Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | End of Period (includes both Visits 5 and 9) | EQ-5D is a participant-completed 5-item questionnaire designed to assess health related quality of life in terms of a single index value or utility score. There are 5 dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension is rated on a 3-point response scale \[1 = no problems, 2 = some/moderate problems, 3 = extreme problems\] and the scores are combined to form a single index utility value between 0 and 1 with higher scores indicating better health. The utility score is calculated using the Dolan 1997 algorithm and the revised version which was provided to the EuroQol Group by Dolan in 2001 - but later published in medical care in 2002. |
| EQ-5D Dolan 2002 Index Summary Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | End of Period (includes both Visits 5 and 9) | EQ-5D is a participant-completed 5-item questionnaire designed to assess health related quality of life in terms of a single index value or utility score. There are 5 dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension is rated on a 3-point response scale \[1 = no problems, 2 = some/moderate problems, 3 = extreme problems\] and the scores are combined to form a single index utility value between 0 and 1 with higher scores indicating better health. The utility score is calculated using the Dolan 1997 algorithm and the revised version which was provided to the EuroQol Group by Dolan in 2001 - but later published in medical care in 2002. |
| Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores | End of Period 1 (V5) | 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). Due to the crossover design, PGIC was analyzed at the end of period 1 (V5). |
| PGIC Score at the End of Period 1 (Week 6) - Categorized Scores | End of Period 1 (V5) | 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 (7 different scores) and categorized scores (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 (V5). |
| Norfolk QOL-DN Small Fiber Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | End of Period (includes both Visits 5 and 9) | Norfolk QOL-DN is a 35-item participant-rated questionnaire used to assess impact of diabetic neuropathy on quality of life of participants with diabetic neuropathy. The items are scored according to the 5-point Likert Scale (0 - 4, no problem to severe problem). The small fiber domain score should be summed as follow: Σ (10, 16, 17, 18). Scales and subscales are calculated without weighting of any kind, and reported as integer sum of the listed questionnaire items (range: 0 - 16). The QOL-DN version that was administered in this study was modified with a 2-week recall period. |
Countries
Czechia, Italy, Sweden, United States
Participant flow
Recruitment details
501 participants were screened, of whom 197 were withdrawn before randomization. 304 were randomized, of whom 3 discontinued before being treated. Participants were randomized at 47 centers in 3 countries: US (43), Czech Republic (3), and Italy (1). 4 centers received study drug but did not randomize participants.
Pre-assignment details
Participants completed daily pain and sleep diary from Visit 1 (Screening) to Visit 9. Participants with a mean pain score ≥ 4 (moderate to severe pain) and those having completed ≥ 4 daily pain dairies over past 7 days and having a mean score of ≥ 4 at Visit 2 (Baseline) were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Pregabalin/Placebo Participants were randomized to double-blind treatment with pregabalin for 6 weeks (150 - 300 mg/day) in period 1 followed by placebo in period 2. There was a 2-week single-blind washout (blinded to participant) between the treatment periods. A 1-week taper was administered at the end of the second treatment period, followed by a final follow-up visit. | 154 |
| Placebo/Pregablin Participants were randomized to double-blind treatment with placebo for 6 weeks in period 1 followed by pregabalin in period 2 (150 - 300 mg/day). There was a 2-week single-blind washout (blinded to participant) between the treatment periods. A 1-week taper was administered at the end of the second treatment period, followed by a final follow-up visit. | 147 |
| Total | 301 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Follow-up | AE Related to Study Drug | 0 | 1 |
| Follow-up | Lack of Efficacy | 0 | 1 |
| Follow-up | Unspecified Reason | 1 | 0 |
| Follow-up | Withdrawal by Subject | 2 | 0 |
| Period 1 | Adverse Event (AE) Related to Study Drug | 9 | 6 |
| Period 1 | AE Not Related to Study Drug | 2 | 6 |
| Period 1 | Drug Error not Associated to AE | 0 | 1 |
| Period 1 | Lost To Follow-up Related to Study Drug | 3 | 3 |
| Period 1 | Protocol Violation | 0 | 2 |
| Period 1 | Unspecified Reason | 1 | 1 |
| Period 1 | Withdrawal by Subject | 4 | 5 |
| Period 2 | AE Not Related to Study Drug | 2 | 1 |
| Period 2 | AE Related to Study Drug | 1 | 2 |
| Period 2 | Lack of Efficacy | 2 | 0 |
| Period 2 | Lost to Follow-up | 2 | 1 |
| Period 2 | Protocol Violation | 2 | 0 |
| Period 2 | Unspecified Reason | 2 | 3 |
| Period 2 | Withdrawal by Subject | 2 | 3 |
| Washout | AE Not Related to Study Drug | 2 | 3 |
| Washout | AE Related to Study Drug | 2 | 0 |
| Washout | Drug Error not Associated to AE | 2 | 1 |
| Washout | Lost to Follow-up | 1 | 0 |
| Washout | Protocol Violation | 0 | 1 |
| Washout | Unspecified Reason | 1 | 2 |
Baseline characteristics
| Characteristic | Pregabalin/Placebo | Placebo/Pregablin | Total |
|---|---|---|---|
| Age, Continuous | 59.4 years STANDARD_DEVIATION 9.8 | 58.4 years STANDARD_DEVIATION 9.5 | 58.9 years STANDARD_DEVIATION 9.7 |
| Sex: Female, Male Female | 65 Participants | 72 Participants | 137 Participants |
| Sex: Female, Male Male | 89 Participants | 75 Participants | 164 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 84 / 272 | 45 / 276 |
| serious Total, serious adverse events | 5 / 272 | 7 / 276 |
Outcome results
Primary
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 in the evening before bedtime on a telephone via interactive voice recognition system (IVRS) (time window for completion between 6.00 pm to midnight). The endpoint mean pain score was defined as the mean of the last 7 daily diary pain ratings while taking study drug 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.
Time frame: End of Period (includes both Visits 5 and 9)
Population: The ITT population included all randomized participants with at least one dose of study drug. The ITT population was analyzed according to what the randomization schedule intended for the participants to take in each period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | 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) | 4.980 units on a scale | Standard Error 0.127 |
| Placebo | 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) | 5.018 units on a scale | Standard Error 0.126 |
Comparison: A longitudinal analysis was done using a repeated measure linear mixed effects model including visit, treatment, an indicator variable for Week 6, and treatment by visit and by the indicator variable interaction as fixed effect factors and participant within sequence and within-participant error (estimated by using an unstructured covariance structure) as random factors. The treatment differences were tested using within-participant variability as the error term.p-value: 0.717495% CI: [-0.248, 0.171]Repeated measure mixed effects model
Secondary
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. Seven 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 an 11-point scale (0: does not interfere; 10: completely interferes). Scores range from 0 - 10 with higher scores indicating greater interference.
Time frame: End of Period (includes both Visits 5 and 9)
Population: The ITT population included all randomized participants with at least one dose of study drug. The ITT population was analyzed according to what the randomization schedule intended for the participants to take in each period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | BPI-sf Score for Pain-Interference Domain at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 3.50 units on a scale | Standard Error 0.12 |
| Placebo | BPI-sf Score for Pain-Interference Domain at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 3.59 units on a scale | Standard Error 0.11 |
Comparison: Analysis was done using a linear mixed effects model which included baseline interference score, sequence, period, and treatment as fixed effect factors and participant within sequence and within-participant error as random factors. The treatment difference (pregabalin - placebo) has been tested using within-participant variability as error term.p-value: 0.454895% CI: [-0.32, 0.14]Mixed Models Analysis
Secondary
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. Four 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 - 10 with higher scores indicating greater pain severity.
Time frame: End of Period (includes both Visits 5 and 9)
Population: The ITT population included all randomized participants with at least one dose of study drug. The ITT population was analyzed according to what the randomization schedule intended for the participants to take in each period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | 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) | 4.49 units on a scale | Standard Error 0.11 |
| Placebo | 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) | 4.48 units on a scale | Standard Error 0.11 |
Comparison: Analysis was done using a linear mixed effects model which included baseline pain severity, sequence, period, and treatment as fixed effect factors and participant within sequence and within-participant error as random factors. The treatment difference (pregabalin - placebo) has been tested using within-participant variability as error term.p-value: 0.944895% CI: [-0.21, 0.22]Mixed Models Analysis
Secondary
EQ-5D Anxiety / Depression Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period)
EQ-5D is a participant-completed 5-item questionnaire designed to assess health related quality of life in terms of a single index value or utility score. There are 5 dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension is rated on a 3-point response scale \[1 = no problems, 2 = some/moderate problems, 3 = extreme problems\] and the scores are combined to form a single index utility value between 0 and 1 with higher scores indicating better health.
Time frame: End of Period (includes both Visits 5 and 9)
Population: The ITT population included all randomized participants with at least one dose of study drug. The ITT population was analyzed according to what the randomization schedule intended for the participants to take in each period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | EQ-5D Anxiety / Depression Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 1.30 units on a scale | Standard Error 0.03 |
| Placebo | EQ-5D Anxiety / Depression Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 1.35 units on a scale | Standard Error 0.03 |
Comparison: Analysis was done using a linear mixed effects model which included baseline anxiety / depression domain score, sequence, period, and treatment as fixed effect factors and participant within sequence and within-participant error as random factors. The treatment difference (pregabalin - placebo) has been tested using within-participant variability as error term.p-value: 0.129795% CI: [-0.11, 0.01]Mixed Models Analysis
Secondary
EQ-5D Dolan 1997 Index Summary Score at the End of Each Treatment Period (Week 6 of Each Treatment Period)
EQ-5D is a participant-completed 5-item questionnaire designed to assess health related quality of life in terms of a single index value or utility score. There are 5 dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension is rated on a 3-point response scale \[1 = no problems, 2 = some/moderate problems, 3 = extreme problems\] and the scores are combined to form a single index utility value between 0 and 1 with higher scores indicating better health. The utility score is calculated using the Dolan 1997 algorithm and the revised version which was provided to the EuroQol Group by Dolan in 2001 - but later published in medical care in 2002.
Time frame: End of Period (includes both Visits 5 and 9)
Population: The ITT population included all randomized participants with at least one dose of study drug. The ITT population was analyzed according to what the randomization schedule intended for the participants to take in each period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | EQ-5D Dolan 1997 Index Summary Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 0.63 units on a scale | Standard Error 0.01 |
| Placebo | EQ-5D Dolan 1997 Index Summary Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 0.65 units on a scale | Standard Error 0.01 |
Comparison: Analysis was done using a linear mixed effects model which included baseline Dolan 1997 index summary score, sequence, period, and treatment as fixed effect factors and participant within sequence and within-participant error as random factors. The treatment difference (pregabalin - placebo) has been tested using within-participant variability as error term.p-value: 0.427995% CI: [-0.04, 0.02]Mixed Models Analysis
Secondary
EQ-5D Dolan 2002 Index Summary Score at the End of Each Treatment Period (Week 6 of Each Treatment Period)
EQ-5D is a participant-completed 5-item questionnaire designed to assess health related quality of life in terms of a single index value or utility score. There are 5 dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension is rated on a 3-point response scale \[1 = no problems, 2 = some/moderate problems, 3 = extreme problems\] and the scores are combined to form a single index utility value between 0 and 1 with higher scores indicating better health. The utility score is calculated using the Dolan 1997 algorithm and the revised version which was provided to the EuroQol Group by Dolan in 2001 - but later published in medical care in 2002.
Time frame: End of Period (includes both Visits 5 and 9)
Population: The ITT population included all randomized participants with at least one dose of study drug. The ITT population was analyzed according to what the randomization schedule intended for the participants to take in each period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | EQ-5D Dolan 2002 Index Summary Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 0.63 units on a scale | Standard Error 0.01 |
| Placebo | EQ-5D Dolan 2002 Index Summary Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 0.64 units on a scale | Standard Error 0.01 |
Comparison: Analysis was done using a linear mixed effects model which included baseline Dolan 2001 index summary score, sequence, period, and treatment as fixed effect factors and participant within sequence and within-participant error as random factors. The treatment difference (pregabalin - placebo) has been tested using within-participant variability as error term.p-value: 0.550595% CI: [-0.04, 0.02]Mixed Models Analysis
Secondary
EQ-5D Pain / Discomfort Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period)
EQ-5D is a participant-completed 5-item questionnaire designed to assess health related quality of life in terms of a single index value or utility score. There are 5 dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension is rated on a 3-point response scale \[1 = no problems, 2 = some/moderate problems, 3 = extreme problems\] and the scores are combined to form a single index utility value between 0 and 1 with higher scores indicating better health.
Time frame: End of Period (includes both Visits 5 and 9)
Population: The ITT population included all randomized participants with at least one dose of study drug. The ITT population was analyzed according to what the randomization schedule intended for the participants to take in each period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | EQ-5D Pain / Discomfort Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 2.03 units on a scale | Standard Error 0.03 |
| Placebo | EQ-5D Pain / Discomfort Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 1.98 units on a scale | Standard Error 0.02 |
Comparison: Analysis was done using a linear mixed effects model which included baseline pain / discomfort domain score, sequence, period, and treatment as fixed effect factors and participant within sequence and within-participant error as random factors. The treatment difference (pregabalin - placebo) has been tested using within-participant variability as error term.p-value: 0.149595% CI: [-0.02, 0.11]Mixed Models Analysis
Secondary
EQ-5D Self-Care Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period)
EQ-5D is a participant-completed 5-item questionnaire designed to assess health related quality of life in terms of a single index value or utility score. There are 5 dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension is rated on a 3-point response scale \[1 = no problems, 2 = some/moderate problems, 3 = extreme problems\] and the scores are combined to form a single index utility value between 0 and 1 with higher scores indicating better health.
Time frame: End of Period (includes both Visits 5 and 9)
Population: The ITT population included all randomized participants with at least one dose of study drug. The ITT population was analyzed according to what the randomization schedule intended for the participants to take in each period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | EQ-5D Self-Care Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 1.18 units on a scale | Standard Error 0.02 |
| Placebo | EQ-5D Self-Care Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 1.18 units on a scale | Standard Error 0.02 |
Comparison: Analysis was done using a linear mixed effects model which included baseline self-care domain score, sequence, period, and treatment as fixed effect factors and participant within sequence and within-participant error as random factors. The treatment difference (pregabalin - placebo) has been tested using within-participant variability as error term.p-value: 0.972695% CI: [-0.05, 0.05]Mixed Models Analysis
Secondary
EQ-5D Usual Activities Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period)
EQ-5D is a participant-completed 5-item questionnaire designed to assess health related quality of life in terms of a single index value or utility score. There are 5 dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension is rated on a 3-point response scale \[1 = no problems, 2 = some/moderate problems, 3 = extreme problems\] and the scores are combined to form a single index utility value between 0 and 1 with higher scores indicating better health.
Time frame: End of Period (includes both Visits 5 and 9)
Population: The ITT population included all randomized participants with at least one dose of study drug. The ITT population was analyzed according to what the randomization schedule intended for the participants to take in each period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | EQ-5D Usual Activities Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 1.53 units on a scale | Standard Error 0.03 |
| Placebo | EQ-5D Usual Activities Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 1.51 units on a scale | Standard Error 0.03 |
Comparison: Analysis was done using a linear mixed effects model which included baseline usual activities domain score, sequence, period, and treatment as fixed effect factors and participant within sequence and within-participant error as random factors. The treatment difference (pregabalin - placebo) has been tested using within-participant variability as error term.p-value: 0.549795% CI: [-0.04, 0.08]Mixed Models Analysis
Secondary
Euro QoL-5 Dimensions (EQ-5D) Mobility Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period)
EQ-5D is a participant-completed 5-item questionnaire designed to assess health related quality of life in terms of a single index value or utility score. There are 5 dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension is rated on a 3-point response scale (no problems, some/moderate problems, extreme problems) and the scores are combined to form a single index utility value between 0 and 1 with higher scores indicating better health.
Time frame: End of Period (includes both Visits 5 and 9)
Population: The ITT population included all randomized participants with at least one dose of study drug. The ITT population was analyzed according to what the randomization schedule intended for the participants to take in each period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Euro QoL-5 Dimensions (EQ-5D) Mobility Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 1.65 units on a scale | Standard Error 0.03 |
| Placebo | Euro QoL-5 Dimensions (EQ-5D) Mobility Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 1.65 units on a scale | Standard Error 0.03 |
Comparison: Analysis was done using a linear mixed effects model which included baseline mobility domain score, sequence, period, and treatment as fixed effect factors and participant within sequence and within-participant error as random factors. The treatment difference (pregabalin - placebo) has been tested using within-participant variability as error term.p-value: 0.995195% CI: [-0.05, 0.05]Mixed Models Analysis
Secondary
HADS-D Total Score at the End of Each Treatment Period (Week 6 of Each Treatment Period)
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.
Time frame: End of Period (includes both Visits 5 and 9)
Population: The ITT population included all randomized participants with at least one dose of study drug. The ITT population was analyzed according to what the randomization schedule intended for the participants to take in each period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | HADS-D Total Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 4.42 units on a scale | Standard Error 0.17 |
| Placebo | HADS-D Total Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 4.50 units on a scale | Standard Error 0.17 |
Comparison: Analysis was done using a linear mixed effects model which included baseline HADS-D score, sequence, period, and treatment as fixed effect factors and participant within sequence and within-participant error as random factors. The treatment difference (pregabalin - placebo) has been tested using within-participant variability as error term.p-value: 0.600795% CI: [-0.42, 0.24]Mixed Models Analysis
Secondary
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.
Time frame: End of Period (includes both Visits 5 and 9)
Population: The ITT population included all randomized participants with at least one dose of study drug. The ITT population was analyzed according to what the randomization schedule intended for the participants to take in each period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Hospital Anxiety and Depression Scale - Anxiety (HADS-A) Total Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 4.90 units on a scale | Standard Error 0.18 |
| Placebo | Hospital Anxiety and Depression Scale - Anxiety (HADS-A) Total Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 4.96 units on a scale | Standard Error 0.18 |
Comparison: Analysis was done using a linear mixed effects model which included baseline HADS-A score, sequence, period, and treatment as fixed effect factors and participant within sequence and within-participant error as random factors. The treatment difference (pregabalin - placebo) has been tested using within-participant variability as error term.p-value: 0.734495% CI: [-0.42, 0.3]Mixed Models Analysis
Secondary
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.
Time frame: End of Period (includes both Visits 5 and 9)
Population: The ITT population included all randomized participants with at least one dose of study drug. The ITT population was analyzed according to what the randomization schedule intended for the participants to take in each period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Mean Sleep Interference Rating Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 4.11 units on a scale | Standard Error 0.12 |
| Placebo | Mean Sleep Interference Rating Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 4.35 units on a scale | Standard Error 0.12 |
Comparison: Analysis was done using linear mixed effects model including baseline score, sequence, period, and treatment as fixed effect factors and participant within sequence and within-participant error as random factors.p-value: 0.027295% CI: [-0.44, -0.03]Mixed Models Analysis
Secondary
Norfolk QOL-DN Activities of Daily Living Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period)
Norfolk QOL-DN is a 35-item participant-rated questionnaire used to assess the impact of diabetic neuropathy on quality of life of participants with diabetic neuropathy. The items are scored according to the 5-point Likert Scale (0 - 4, no problem to severe problem). Activities of the daily living domain score should be summed as follow: Σ (12, 22, 23, 25, 26). Scales and subscales are calculated without weighting of any kind, and reported as integer sum of listed questionnaire items (range: 0 - 20). The QOL-DN version that was administered in the study was modified with a 2-week recall period.
Time frame: End of Period (includes both Visits 5 and 9)
Population: The ITT population included all randomized participants with at least one dose of study drug. The ITT population was analyzed according to what the randomization schedule intended for the participants to take in each period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Norfolk QOL-DN Activities of Daily Living Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 2.82 units on a scale | Standard Error 0.16 |
| Placebo | Norfolk QOL-DN Activities of Daily Living Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 2.94 units on a scale | Standard Error 0.16 |
Comparison: Analysis was done using a linear mixed effects model which included baseline activities of daily living domain score, sequence, period, and treatment as fixed effect factors and participant within sequence and within-participant error as random factors. The treatment difference (pregabalin - placebo) has been tested using within-participant variability as error term.p-value: 0.511995% CI: [-0.48, 0.24]Mixed Models Analysis
Secondary
Norfolk QOL-DN Autonomic Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period)
Norfolk QOL-DN is a 35-item participant-rated questionnaire used to assess the impact of diabetic neuropathy on quality of life of participants with diabetic neuropathy. The items are scored according to the 5-point Likert Scale (0 - 4, no problem to severe problem). 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 (range: 0 - 12). The QOL-DN version that was administered in this study was modified with a 2-week recall period.
Time frame: End of Period (includes both Visits 5 and 9)
Population: The ITT population included all randomized participants with at least one dose of study drug. The ITT population was analyzed according to what the randomization schedule intended for the participants to take in each period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Norfolk QOL-DN Autonomic Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 1.12 units on a scale | Standard Error 0.1 |
| Placebo | Norfolk QOL-DN Autonomic Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 1.26 units on a scale | Standard Error 0.1 |
Comparison: Analysis was done using a linear mixed effects model which included baseline autonomic domain score, sequence, period, and treatment as fixed effect factors and participant within sequence and within-participant error as random factors. The treatment difference (pregabalin - placebo) has been tested using within-participant variability as error term.p-value: 0.26995% CI: [-0.38, 0.11]Mixed Models Analysis
Secondary
Norfolk QOL-DN Physical Functioning / Large Fiber Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period)
Norfolk QOL-DN is a 35-item participant-rated questionnaire used to assess the impact of diabetic neuropathy on quality of life of participants with diabetic neuropathy. With exception of questions 31 and 32, items are scored according to the 5-point Likert Scale (0 - 4, no problem to severe problem). In question 31, good, 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, middle item, is scored as 0, somewhat better as -1, much better as -2, somewhat worse as 1, and much worse as 2. Physical functioning / large fiber domain score should be summed as follow: Σ (8, 11, 13 - 15, 24, 27 - 35). Scales and subscales are calculated without weighting of any kind, and reported as integer sum of listed questionnaire items (range: -4 - 56). QOL-DN version that was administered in the study was modified with a 2-week recall period.
Time frame: End of Period (includes both Visits 5 and 9)
Population: The ITT population included all randomized participants with at least one dose of study drug. The ITT population was analyzed according to what the randomization schedule intended for the participants to take in each period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Norfolk QOL-DN Physical Functioning / Large Fiber Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 23.17 units on a scale | Standard Error 0.61 |
| Placebo | Norfolk QOL-DN Physical Functioning / Large Fiber Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 23.66 units on a scale | Standard Error 0.6 |
Comparison: Analysis was done using a linear mixed effects model which included baseline physical functioning / large fiber domain score, sequence, period, and treatment as fixed effect factors and participant within sequence and within-participant error as random factors. The treatment difference (pregabalin - placebo) has been tested using within-participant variability as error term.p-value: 0.433595% CI: [-1.72, 0.74]Mixed Models Analysis
Secondary
Norfolk QOL-DN Small Fiber Domain Score at the End 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 quality of life of participants with diabetic neuropathy. The items are scored according to the 5-point Likert Scale (0 - 4, no problem to severe problem). The small fiber domain score should be summed as follow: Σ (10, 16, 17, 18). Scales and subscales are calculated without weighting of any kind, and reported as integer sum of the listed questionnaire items (range: 0 - 16). The QOL-DN version that was administered in this study was modified with a 2-week recall period.
Time frame: End of Period (includes both Visits 5 and 9)
Population: The ITT population included all randomized participants with at least one dose of study drug. The ITT population was analyzed according to what the randomization schedule intended for the participants to take in each period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Norfolk QOL-DN Small Fiber Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 2.57 units on a scale | Standard Error 0.16 |
| Placebo | Norfolk QOL-DN Small Fiber Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 2.58 units on a scale | Standard Error 0.16 |
Comparison: Analysis was done using a linear mixed effects model which included baseline small fiber domain score, sequence, period, and treatment as fixed effect factors and participant within sequence and within-participant error as random factors. The treatment difference (pregabalin - placebo) has been tested using within-participant variability as error term.p-value: 0.965395% CI: [-0.31, 0.3]Mixed Models Analysis
Secondary
Norfolk QOL-DN Symptoms Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period)
Norfolk QOL-DN is a 35-item participant-rated questionnaire used to assess the impact of diabetic neuropathy on 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. Item 9 is scored according to the 5-point Likert Scale (0 - 4, no problem to severe problem). 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 (range: 0 - 32). The QOL-DN version that was administered in this study was modified with a 2-week recall period.
Time frame: End of Period (includes both Visits 5 and 9)
Population: The ITT population included all randomized participants with at least one dose of study drug. The ITT population was analyzed according to what the randomization schedule intended for the participants to take in each period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Norfolk QOL-DN Symptoms Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 7.51 units on a scale | Standard Error 0.25 |
| Placebo | Norfolk QOL-DN Symptoms Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 7.86 units on a scale | Standard Error 0.25 |
Comparison: Analysis was done using a linear mixed effects model which included baseline symptoms domain score, sequence, period, and treatment as fixed effect factors and participant within sequence and within-participant error as random factors. The treatment difference (pregabalin - placebo) has been tested using within-participant variability as error term.p-value: 0.176995% CI: [-0.85, 0.16]Mixed Models Analysis
Secondary
Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) Total Quality of Life (TQOL) Score at the End 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 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 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 (sub)scales are calculated without weighting of any kind, and reported as the integer sum of listed questionnaire items (range: -4 - 136). The QOL-DN version that was administered in this study was modified with a 2-week recall period.
Time frame: End of Period (includes both Visits 5 and 9)
Population: The ITT population included all randomized participants with at least one dose of study drug. The ITT population was analyzed according to what the randomization schedule intended for the participants to take in each period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) Total Quality of Life (TQOL) Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 37.22 units on a scale | Standard Error 1.03 |
| Placebo | Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) Total Quality of Life (TQOL) Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) | 38.30 units on a scale | Standard Error 1.02 |
Comparison: Analysis was done using a linear mixed effects model which included baseline total score, sequence, period, and treatment as fixed effect factors and participant within sequence and within-participant error as random factors. The treatment difference (pregabalin - placebo) has been tested using within-participant variability as error term.p-value: 0.298795% CI: [-3.13, 0.96]Mixed Models Analysis
Secondary
Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores
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). Due to the crossover design, PGIC was analyzed at the end of period 1 (V5).
Time frame: End of Period 1 (V5)
Population: The ITT population included all randomized participants with at least one dose of study drug. The ITT population was analyzed according to what the randomization schedule intended for the participants to take in each period. All participants who were randomized and had a period 1 PGIC value were used for this analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pregabalin | Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores | Very much improved | 8.1 percentage of participants |
| Pregabalin | Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores | Minimally worse | 6.1 percentage of participants |
| Pregabalin | Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores | Minimally improved | 39.2 percentage of participants |
| Pregabalin | Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores | Much worse | 2.0 percentage of participants |
| Pregabalin | Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores | Much improved | 27.7 percentage of participants |
| Pregabalin | Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores | Very much worse | 1.4 percentage of participants |
| Pregabalin | Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores | No change | 14.9 percentage of participants |
| Pregabalin | Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores | Missing | 0.7 percentage of participants |
| Placebo | Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores | Missing | 2.8 percentage of participants |
| Placebo | Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores | Very much improved | 4.9 percentage of participants |
| Placebo | Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores | Much improved | 19.6 percentage of participants |
| Placebo | Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores | Minimally improved | 39.2 percentage of participants |
| Placebo | Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores | No change | 23.1 percentage of participants |
| Placebo | Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores | Minimally worse | 7.0 percentage of participants |
| Placebo | Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores | Much worse | 1.4 percentage of participants |
| Placebo | Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores | Very much worse | 2.1 percentage of participants |
Comparison: Analysis was done using a Cochran-Mantel-Haenszel (CMH) test with modified ridit transformation, under alternative hypothesis of raw mean scores differ.p-value: 0.0604Cochran-Mantel-Haenszel
Secondary
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)
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 in the evening before bedtime on a telephone via IVRS (time window for completion between 6.00 pm to midnight). The endpoint mean pain score was defined as the mean of the last 7 daily diary pain ratings while taking study drug 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.
Time frame: End of Period (includes both Visits 5 and 9)
Population: The ITT population included all randomized participants with at least one dose of study drug. The ITT population was analyzed according to what the randomization schedule intended for the participants to take in each period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pregabalin | 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) | 34.56 percentage of participants |
| Placebo | 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) | 31.16 percentage of participants |
Comparison: Analysis was done using a logistic regression model which included baseline pain, sequence, period and treatment as covariate.p-value: 0.328795% CI: [0.83, 1.73]Regression, Logistic
Secondary
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)
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 in the evening before bedtime on a telephone via IVRS (time window for completion between 6.00 pm to midnight). The endpoint mean pain score was defined as the mean of the last 7 daily diary pain ratings while taking study drug 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.
Time frame: End of Period (includes both Visits 5 and 9)
Population: The ITT population included all randomized participants with at least one dose of study drug. The ITT population was analyzed according to what the randomization schedule intended for the participants to take in each period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pregabalin | 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) | 20.22 percentage of participants |
| Placebo | 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) | 15.58 percentage of participants |
Comparison: Analysis was done using a logistic regression model which included baseline pain, sequence, period and treatment as covariate.p-value: 0.062595% CI: [0.98, 2.51]Regression, Logistic
Secondary
PGIC Score at the End of Period 1 (Week 6) - Categorized Scores
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 (7 different scores) and categorized scores (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 (V5).
Time frame: End of Period 1 (V5)
Population: The ITT population included all randomized participants with at least one dose of study drug. The ITT population was analyzed according to what the randomization schedule intended for the participants to take in each period. All participants who were randomized and had a period 1 PGIC value were used for this analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pregabalin | PGIC Score at the End of Period 1 (Week 6) - Categorized Scores | Very much/much improved | 35.8 percentage of participants |
| Pregabalin | PGIC Score at the End of Period 1 (Week 6) - Categorized Scores | Any improvement | 75.0 percentage of participants |
| Pregabalin | PGIC Score at the End of Period 1 (Week 6) - Categorized Scores | No change | 14.9 percentage of participants |
| Pregabalin | PGIC Score at the End of Period 1 (Week 6) - Categorized Scores | Any worsening | 9.5 percentage of participants |
| Placebo | PGIC Score at the End of Period 1 (Week 6) - Categorized Scores | Any worsening | 10.5 percentage of participants |
| Placebo | PGIC Score at the End of Period 1 (Week 6) - Categorized Scores | Very much/much improved | 24.5 percentage of participants |
| Placebo | PGIC Score at the End of Period 1 (Week 6) - Categorized Scores | No change | 23.1 percentage of participants |
| Placebo | PGIC Score at the End of Period 1 (Week 6) - Categorized Scores | Any improvement | 63.6 percentage of participants |
Comparison: Analysis was done using a CMH test with modified ridit transformation, under alternative hypothesis of raw mean scores differ.p-value: 0.1511Cochran-Mantel-Haenszel