Trial Outcomes & Findings for Effect Of Pregabalin Treatment In Patients With Diabetic Nerve Pain Who Currently Use A Non-Steroid Anti-Inflammatory Drug (NSAID) For Another Pain (NCT NCT01455415)

NCT ID: NCT01455415

Last Updated: 2021-01-28

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 306 participants
• Primary outcome timeframe: End of Period (includes both Visits 5 and 9)
• Results posted on: 2021-01-28

Participant Flow

501 participants were screened, of whom 197 were withdrawn before randomization. 304 were randomized, of whom 3 discontinued before being treated.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.

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.

Participant milestones

Measure	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.	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.
Period 1 STARTED	154	147
Period 1 COMPLETED	135	123
Period 1 NOT COMPLETED	19	24
Washout STARTED	135	123
Washout COMPLETED	127	116
Washout NOT COMPLETED	8	7
Period 2 STARTED	127	116
Period 2 COMPLETED	114	106
Period 2 NOT COMPLETED	13	10
Follow-up STARTED	114	106
Follow-up COMPLETED	111	104
Follow-up NOT COMPLETED	3	2

Reasons for withdrawal

Measure	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.	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.
Period 1 Adverse Event (AE) Related to Study Drug	9	6
Period 1 Lost To Follow-up Related to Study Drug	3	3
Period 1 Drug Error not Associated to AE	0	1
Period 1 AE Not Related to Study Drug	2	6
Period 1 Withdrawal by Subject	4	5
Period 1 Unspecified Reason	1	1
Period 1 Protocol Violation	0	2
Washout AE Related to Study Drug	2	0
Washout Lost to Follow-up	1	0
Washout Drug Error not Associated to AE	2	1
Washout AE Not Related to Study Drug	2	3
Washout Unspecified Reason	1	2
Washout Protocol Violation	0	1
Period 2 AE Related to Study Drug	1	2
Period 2 Lost to Follow-up	2	1
Period 2 AE Not Related to Study Drug	2	1
Period 2 Lack of Efficacy	2	0
Period 2 Withdrawal by Subject	2	3
Period 2 Unspecified Reason	2	3
Period 2 Protocol Violation	2	0
Follow-up AE Related to Study Drug	0	1
Follow-up Lack of Efficacy	0	1
Follow-up Withdrawal by Subject	2	0
Follow-up Unspecified Reason	1	0

Baseline Characteristics

Effect Of Pregabalin Treatment In Patients With Diabetic Nerve Pain Who Currently Use A Non-Steroid Anti-Inflammatory Drug (NSAID) For Another Pain

Baseline characteristics by cohort

Measure	Pregabalin/Placebo n=154 Participants 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.	Placebo/Pregablin n=147 Participants 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.	Total n=301 Participants Total of all reporting groups
Age, Continuous	59.4 years STANDARD_DEVIATION 9.8 • n=5 Participants	58.4 years STANDARD_DEVIATION 9.5 • n=7 Participants	58.9 years STANDARD_DEVIATION 9.7 • n=5 Participants
Sex: Female, Male Female	65 Participants n=5 Participants	72 Participants n=7 Participants	137 Participants n=5 Participants
Sex: Female, Male Male	89 Participants n=5 Participants	75 Participants n=7 Participants	164 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Pregabalin n=272 Participants The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=276 Participants The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
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	5.018 units on a scale Standard Error 0.126

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Pregabalin n=272 Participants The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=276 Participants The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
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	31.16 percentage of participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Pregabalin n=272 Participants The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=276 Participants The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
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	15.58 percentage of participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Pregabalin n=272 Participants The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=276 Participants The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
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	4.48 units on a scale Standard Error 0.11

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Pregabalin n=272 Participants The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=276 Participants The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
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	3.59 units on a scale Standard Error 0.11

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Pregabalin n=272 Participants The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=276 Participants The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
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	4.35 units on a scale Standard Error 0.12

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Pregabalin n=272 Participants The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=276 Participants The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
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	4.96 units on a scale Standard Error 0.18

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Pregabalin n=272 Participants The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=276 Participants The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
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	4.50 units on a scale Standard Error 0.17

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Pregabalin n=272 Participants The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=276 Participants The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
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	38.30 units on a scale Standard Error 1.02

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Pregabalin n=272 Participants The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=276 Participants The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
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	7.86 units on a scale Standard Error 0.25

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Pregabalin n=272 Participants The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=276 Participants The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
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	2.94 units on a scale Standard Error 0.16

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Pregabalin n=272 Participants The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=276 Participants The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
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	23.66 units on a scale Standard Error 0.60

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Pregabalin n=272 Participants The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=276 Participants The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
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	2.58 units on a scale Standard Error 0.16

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Pregabalin n=272 Participants The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=276 Participants The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
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 0.10	1.26 units on a scale Standard Error 0.10

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Pregabalin n=272 Participants The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=276 Participants The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
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	1.65 units on a scale Standard Error 0.03

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Pregabalin n=272 Participants The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=276 Participants The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
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	1.18 units on a scale Standard Error 0.02

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Pregabalin n=272 Participants The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=276 Participants The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
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	1.51 units on a scale Standard Error 0.03

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Pregabalin n=272 Participants The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=276 Participants The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
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	1.98 units on a scale Standard Error 0.02

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Pregabalin n=272 Participants The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=276 Participants The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
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	1.35 units on a scale Standard Error 0.03

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Pregabalin n=272 Participants The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=276 Participants The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
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	0.65 units on a scale Standard Error 0.01

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Pregabalin n=272 Participants The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=276 Participants The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
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	0.64 units on a scale Standard Error 0.01

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Measure	Pregabalin n=148 Participants The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=143 Participants The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
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	4.9 percentage of participants
Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores Much improved	27.7 percentage of participants	19.6 percentage of participants
Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores Minimally improved	39.2 percentage of participants	39.2 percentage of participants
Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores No change	14.9 percentage of participants	23.1 percentage of participants
Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores Minimally worse	6.1 percentage of participants	7.0 percentage of participants
Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores Much worse	2.0 percentage of participants	1.4 percentage of participants
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	2.1 percentage of participants
Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores Missing	0.7 percentage of participants	2.8 percentage of participants

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Measure	Pregabalin n=148 Participants The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=143 Participants The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
PGIC Score at the End of Period 1 (Week 6) - Categorized Scores Very much/much improved	35.8 percentage of participants	24.5 percentage of participants
PGIC Score at the End of Period 1 (Week 6) - Categorized Scores Any improvement	75.0 percentage of participants	63.6 percentage of participants
PGIC Score at the End of Period 1 (Week 6) - Categorized Scores No change	14.9 percentage of participants	23.1 percentage of participants
PGIC Score at the End of Period 1 (Week 6) - Categorized Scores Any worsening	9.5 percentage of participants	10.5 percentage of participants

Adverse Events

Pregabalin

Serious events: 5 serious events

Other events: 84 other events

Deaths: 0 deaths

Placebo

Serious events: 7 serious events

Other events: 45 other events

Deaths: 0 deaths

Serious adverse events

Measure	Pregabalin n=272 participants at risk The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=276 participants at risk The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/272 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.36% 1/276 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Gastritis	0.00% 0/272 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.36% 1/276 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Pancreatitis acute	0.00% 0/272 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.36% 1/276 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Multi-organ failure	0.37% 1/272 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/276 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Angina pectoris	0.37% 1/272 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/276 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Atrial fibrillation	0.37% 1/272 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/276 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Myocardial infarction	0.37% 1/272 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/276 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Bronchitis	0.37% 1/272 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/276 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Escherichia bacteraemia	0.37% 1/272 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/276 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Localised infection	0.00% 0/272 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.36% 1/276 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Lung abscess	0.00% 0/272 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.36% 1/276 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hyperglycaemia	0.37% 1/272 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/276 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Cerebrovascular accident	0.00% 0/272 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.36% 1/276 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Ischaemic cerebral infarction	0.00% 0/272 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.36% 1/276 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Vascular disorders Hypertension	0.00% 0/272 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.36% 1/276 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.

Other adverse events

Measure	Pregabalin n=272 participants at risk The below tables included data from participants while receiving pregabalin in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6- week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.	Placebo n=276 participants at risk The below table included data from participants while receiving placebo in either period of the 2-period crossover study design. This crossover study consisted of two double blind 6-week treatment periods where participants were randomized to pregabalin or placebo for the first period, and were then switched to the other treatment for the second period. 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.
Gastrointestinal disorders Diarrhoea	3.3% 9/272 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	4.0% 11/276 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Nausea	3.3% 9/272 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.9% 8/276 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Fatigue	5.1% 14/272 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.4% 4/276 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Oedema peripheral	3.7% 10/272 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.9% 8/276 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Arthralgia	2.9% 8/272 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.4% 4/276 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Pain in extremity	2.6% 7/272 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.8% 5/276 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Dizziness	10.3% 28/272 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.4% 4/276 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Headache	3.3% 9/272 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.9% 8/276 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Somnolence	5.1% 14/272 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.5% 7/276 • From the time the participants were randomized through and including 28 calender days after the last administration of the study drug. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.

Additional Information

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