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

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
Condition:	Painful Diabetic Peripheral Neuropathy
Interventions:	Drug: pregabalin; Drug: placebo

  Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
501 participants were screened, of whom 197 were withdrawn before randomization. 304 were randomized, of whom 3 discontinued before being treated.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

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups

	Description
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.

Participant Flow for 4 periods

Period 1:   Period 1

	Pregabalin/Placebo	Placebo/Pregablin
STARTED	154 [1]	147 [1]
COMPLETED	135	123
NOT COMPLETED	19	24
Adverse Event (AE) Related to Study Drug	9	6
Lost To Follow-up Related to Study Drug	3	3
Drug Error not Associated to AE	0	1
AE Not Related to Study Drug	2	6
Withdrawal by Subject	4	5
Unspecified Reason	1	1
Protocol Violation	0	2

[1]	Started=Treated

Period 2:   Washout

	Pregabalin/Placebo	Placebo/Pregablin
STARTED	135	123
COMPLETED	127	116
NOT COMPLETED	8	7
AE Related to Study Drug	2	0
Lost to Follow-up	1	0
Drug Error not Associated to AE	2	1
AE Not Related to Study Drug	2	3
Unspecified Reason	1	2
Protocol Violation	0	1

Period 3:   Period 2

	Pregabalin/Placebo	Placebo/Pregablin
STARTED	127	116
COMPLETED	114	106
NOT COMPLETED	13	10
AE Related to Study Drug	1	2
Lost to Follow-up	2	1
AE Not Related to Study Drug	2	1
Lack of Efficacy	2	0
Withdrawal by Subject	2	3
Unspecified Reason	2	3
Protocol Violation	2	0

Period 4:   Follow-up

	Pregabalin/Placebo	Placebo/Pregablin
STARTED	114	106
COMPLETED	111	104
NOT COMPLETED	3	2
AE Related to Study Drug	0	1
Lack of Efficacy	0	1
Withdrawal by Subject	2	0
Unspecified Reason	1	0

  Baseline Characteristics

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Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-Treat Population (ITT) 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.

Reporting Groups

	Description
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.
Total	Total of all reporting groups

Baseline Measures

	Pregabalin/Placebo	Placebo/Pregablin	Total
Overall Participants Analyzed; [Units: Participants]	154	147	301
Age; [Units: Years]; Mean (Standard Deviation)	59.4 (9.8)	58.4 (9.5)	58.9 (9.7)
Gender; [Units: Participants]
Female	65	72	137
Male	89	75	164

  Outcome Measures

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1. 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) [ Time Frame: End of Period (includes both Visits 5 and 9) ]

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Measure Type	Primary
Measure Title	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)
Measure Description	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 Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
Pregabalin	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	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.

Measured Values

	Pregabalin	Placebo
Participants Analyzed	272	276
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); [Units: Units on a scale]; Least Squares Mean (Standard Error)	4.980 (0.127)	5.018 (0.126)

Statistical Analysis 1 for 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)

Groups [1]	All groups
Statistical Test Type [2]	Superiority or Other
Statistical Method [3]	Repeated measure mixed effects model
P Value [4]	0.7174
Mean Difference (Final Values) [5]	-0.038
95% Confidence Interval	-0.248 to 0.171
Standard Error of the mean	(0.106)

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	The Kenward-Roger method was used to estimate denominator degrees of freedom.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Primary analysis was two-sided and performed at the 0.05 significance level.
[5]	Other relevant estimation information:
	No text entered.

2. 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) [ Time Frame: End of Period (includes both Visits 5 and 9) ]

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3. 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) [ Time Frame: End of Period (includes both Visits 5 and 9) ]

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4. 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) [ Time Frame: End of Period (includes both Visits 5 and 9) ]

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5. Secondary:

BPI-sf Score for Pain-Interference Domain at the End of Each Treatment Period (Week 6 of Each Treatment Period) [ Time Frame: End of Period (includes both Visits 5 and 9) ]

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6. Secondary:

Mean Sleep Interference Rating Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) [ Time Frame: End of Period (includes both Visits 5 and 9) ]

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7. Secondary:

Hospital Anxiety and Depression Scale - Anxiety (HADS-A) Total Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) [ Time Frame: End of Period (includes both Visits 5 and 9) ]

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8. Secondary:

HADS-D Total Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) [ Time Frame: End of Period (includes both Visits 5 and 9) ]

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9. 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) [ Time Frame: End of Period (includes both Visits 5 and 9) ]

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10. Secondary:

Norfolk QOL-DN Symptoms Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) [ Time Frame: End of Period (includes both Visits 5 and 9) ]

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11. Secondary:

Norfolk QOL-DN Activities of Daily Living Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) [ Time Frame: End of Period (includes both Visits 5 and 9) ]

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12. Secondary:

Norfolk QOL-DN Physical Functioning / Large Fiber Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) [ Time Frame: End of Period (includes both Visits 5 and 9) ]

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13. Secondary:

Norfolk QOL-DN Small Fiber Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) [ Time Frame: End of Period (includes both Visits 5 and 9) ]

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14. Secondary:

Norfolk QOL-DN Autonomic Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) [ Time Frame: End of Period (includes both Visits 5 and 9) ]

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15. Secondary:

Euro QoL-5 Dimensions (EQ-5D) Mobility Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) [ Time Frame: End of Period (includes both Visits 5 and 9) ]

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16. Secondary:

EQ-5D Self-Care Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) [ Time Frame: End of Period (includes both Visits 5 and 9) ]

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17. Secondary:

EQ-5D Usual Activities Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) [ Time Frame: End of Period (includes both Visits 5 and 9) ]

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18. Secondary:

EQ-5D Pain / Discomfort Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) [ Time Frame: End of Period (includes both Visits 5 and 9) ]

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19. Secondary:

EQ-5D Anxiety / Depression Domain Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) [ Time Frame: End of Period (includes both Visits 5 and 9) ]

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20. Secondary:

EQ-5D Dolan 1997 Index Summary Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) [ Time Frame: End of Period (includes both Visits 5 and 9) ]

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21. Secondary:

EQ-5D Dolan 2002 Index Summary Score at the End of Each Treatment Period (Week 6 of Each Treatment Period) [ Time Frame: End of Period (includes both Visits 5 and 9) ]

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22. Secondary:

Patient Global Impression of Change (PGIC) Score at the End of Period 1 (Week 6) - Original Scores [ Time Frame: End of Period 1 (V5) ]

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23. Secondary:

PGIC Score at the End of Period 1 (Week 6) - Categorized Scores [ Time Frame: End of Period 1 (V5) ]

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  Serious Adverse Events

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  Other Adverse Events

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  Limitations and Caveats

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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information

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Certain Agreements:  

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is: The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo. The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo. Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.; Restriction Description: Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.

Results Point of Contact:  

Name/Title: Pfizer ClinicalTrials.gov Call Center
Organization: Pfizer, Inc.
phone: 1-800-718-1021
e-mail: ClinicalTrials.gov_Inquiries@pfizer.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Raskin P, Huffman C, Yurkewicz L, Pauer L, Scavone JM, Yang R, Parsons B. Pregabalin in Patients With Painful Diabetic Peripheral Neuropathy Using an NSAID for Other Pain Conditions: A Double-Blind Crossover Study. Clin J Pain. 2016 Mar;32(3):203-10. doi: 10.1097/AJP.0000000000000254.

Responsible Party:	Pfizer
ClinicalTrials.gov Identifier:	NCT01455415 History of Changes
Other Study ID Numbers:	A0081268; 2011-002743-10 ( EudraCT Number )
First Submitted:	October 17, 2011
First Posted:	October 20, 2011
Results First Submitted:	October 30, 2014
Results First Posted:	April 23, 2015
Last Update Posted:	April 23, 2015