An Open-Label Comparison of Duloxetine to Other Alternatives for the Management of Diabetic Peripheral Neuropathic Pain - Study Results

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Open Label; Primary Purpose: Treatment
Condition:	Diabetic Neuropathy, Painful
Interventions:	Drug: duloxetine hydrochloride Drug: pregabalin Drug: gabapentin

	Pregabalin	Duloxetine	Gabapentin + Duloxetine
STARTED	134	138	135
COMPLETED	96	87	99
NOT COMPLETED	38	51	36
Adverse Event	14	27	18
Lack of Efficacy	5	9	5
Lost to Follow-up	6	6	5
Physician Decision	2	1	2
Protocol Violation	5	2	1
Sponsor Decision	2	2	1
Withdrawal by Subject	4	4	4

Baseline Characteristics

Reporting Groups

	Description
Pregabalin	Pregabalin (PGB) 50 milligram (mg) three times a day (TID) (US & Germany) or 75 mg twice daily (BID) (Canada), orally (PO) for 2 weeks, then PGB 100 mg TID (US & Germany) or 150 mg BID (Canada), PO for 10 weeks.
Duloxetine	Duloxetine (DLX) 30 milligram (mg) once daily (QD), orally (PO) for 1 week, then DLX 60 mg QD, PO for 11 weeks.
Gabapentin + Duloxetine	Stable Gabapentin (GAB) + Duloxetine (DLX) 30 milligram (mg) once daily (QD), orally (PO) for 1 week, then stable GAB + DLX 60 mg QD, PO for 11 weeks.

Baseline Measures

	Pregabalin	Duloxetine	Gabapentin + Duloxetine	Total
Number of Participants [units: participants]	134	138	135	407
Age [units: years] Mean ± Standard Deviation	61.89 ± 10.70	60.94 ± 10.18	61.85 ± 10.84	61.56 ± 10.56
Gender [units: participants]
Female	58	55	52	165
Male	76	83	83	242
Race/Ethnicity, Customized [units: participants]
Native American	1	1	1	3
East Asian	0	0	2	2
Hispanic	9	15	9	33
Black or African American	13	9	11	33
White	111	110	112	333
West Asian	0	3	0	3
Unknown or Not Reported	0	0	0	0
Region of Enrollment [units: participants]
United States	104	112	109	325
Germany	22	20	21	63
Canada	5	4	3	12
Puerto Rico	3	2	2	7
Duration of Diabetes [units: months] Mean ± Standard Deviation	150.26 ± 131.60	147.14 ± 116.04	119.82 ± 93.38	139.09 ± 115.24
Duration of Diabetic Peripheral Neuropathic Pain ^[1] [units: months] Mean ± Standard Deviation	51.54 ± 40.96	58.08 ± 57.57	50.32 ± 41.93	53.34 ± 47.51
Michigan Neuropathy Screening Instrument (MNSI) Physical Assessment - Total Score ^[2] [units: units on a scale] Mean ± Standard Deviation	5.91 ± 1.56	5.73 ± 1.58	5.94 ± 1.56	5.86 ± 1.56
Types of Diabetes Mellitus [units: participants]
Type I	13	9	9	31
Type II	121	129	126	376
Weekly mean of 24 hour average pain severity ^[3] [units: units on a scale] Mean ± Standard Deviation	5.69 ± 1.43	5.81 ± 1.51	5.78 ± 1.47	5.76 ± 1.47
Beck Depression Inventory (BDI) Total Score ^[4] [units: units on a scale] Mean ± Standard Deviation	9.45 ± 8.53	9.10 ± 7.20	10.71 ± 8.42	9.74 ± 8.07
Weekly mean of the daily worst pain severity ^[5] [units: units on a scale] Mean ± Standard Deviation	6.92 ± 1.56	7.12 ± 1.46	7.05 ± 1.48	7.03 ± 1.50
Weekly mean of nighttime pain severity ^[6] [units: units on a scale] Mean ± Standard Deviation	5.64 ± 2.06	5.86 ± 1.74	5.55 ± 2.11	5.69 ± 1.97
Leeds Sleep Evaluation Questionnaire (LSEQ) ^[7] [units: units on a scale] Mean ± Standard Deviation
Awakening Subscale	93.95 ± 41.55	88.63 ± 40.75	86.70 ± 42.46	89.75 ± 41.59
Behavior Following Wakefulness Subscale	132.22 ± 69.22	128.87 ± 65.53	131.55 ± 69.61	130.88 ± 67.98
Getting to Sleep Subscale	138.62 ± 59.68	137.61 ± 62.91	145.22 ± 64.73	140.45 ± 62.40
Quality of Sleep Subscale	95.54 ± 44.08	95.89 ± 46.82	97.01 ± 45.39	96.15 ± 45.34
Sheehan Disability Scale (SDS) Global Functional Impairment Total Score ^[8] [units: units on a scale] Mean ± Standard Deviation	11.44 ± 8.72	13.49 ± 9.00	12.69 ± 7.92	12.55 ± 8.58
Clayton Sexual Functioning Questionnaire (CSFQ) ^[9] [units: units on a scale] Mean ± Standard Deviation
male participants - total	40.41 ± 9.01	38.81 ± 9.50	39.25 ± 9.75	39.46 ± 9.42
female participants - total	35.21 ± 11.68	36.69 ± 10.43	34.45 ± 10.09	35.43 ± 10.73
male participants - arousal	7.19 ± 3.08	6.35 ± 2.88	6.41 ± 3.12	6.64 ± 3.04
female participants - arousal	6.64 ± 3.20	7.00 ± 2.72	6.47 ± 3.09	6.70 ± 3.01
male participants - desire/frequency	5.32 ± 1.73	5.09 ± 1.77	5.15 ± 1.96	5.18 ± 1.82
female participants - desire/frequency	3.79 ± 1.85	4.27 ± 1.83	3.74 ± 1.59	3.93 ± 1.77
male participants - desire/interest	7.71 ± 2.56	7.91 ± 2.72	8.06 ± 2.84	7.90 ± 2.71
female participants - desire/interest	5.96 ± 3.01	5.97 ± 2.42	5.72 ± 2.43	5.89 ± 2.63
male participants - orgasm	7.77 ± 2.93	7.21 ± 2.85	7.51 ± 3.06	7.49 ± 2.94
female participants - orgasm	6.98 ± 3.75	8.23 ± 3.94	7.53 ± 3.83	7.56 ± 3.84
male participants - pleasure	2.43 ± 1.23	2.50 ± 1.22	2.30 ± 1.11	2.41 ± 1.19
female participants - pleasure	2.06 ± 1.19	2.23 ± 1.18	2.06 ± 1.13	2.12 ± 1.16
Comorbidity with Generalized Anxiety Disorder (GAD) ^[10] [units: participants]
Yes	3	0	1	4
No	131	138	134	403
Comorbidity with Major Depressive Disorder (MDD) ^[11] [units: participants]
Yes	4	3	4	11
No	130	135	131	396

[1]	Duration of Diabetic Peripheral Neuropathic Pain Since Onset.
[2]	Assesses degree of neuropathy. Responses to 13 out of 15 items are added to obtain total score. Responses of “yes” to items 1,2,3,5,6,8,9,11,12,14,15 are each counted as one point. A “no” response on items 7 and 13 counts as 1 point. Items 4 and 10 are not included in scoring. Total scores range from 0 (no neuropathy) to 13 (severe neuropathy).
[3]	This is an ordinal scale with scores from 0 (no pain) to 10 (worst possible pain). Data presented represent the weekly mean of the scores of the average pain severity over the last 24 hours. Scores are based on daily assessments recorded by patients in their diaries.
[4]	A 21-item, patient-completed questionnaire to assess characteristics of depression. Each of the 21 items corresponding to a symptom of depression is summed to give a single score. There is a four-point scale for each item ranging from 0 to 3. Total score of 0-13 is considered minimal range, 14-19 is mild, 20-28 is moderate, and 29-63 is severe.
[5]	This is an ordinal scale with scores from 0 (no pain) to 10 (worst possible pain). Data presented represent the weekly mean of the scores of the daily worst pain severity over the last 24 hours. Scores are based on daily assessments recorded by patients in their diaries.
[6]	This is an ordinal scale with scores from 0 (no pain) to 10 (worst possible pain). Data presented represent the weekly mean of the scores of the daily nighttime pain severity over the last 24 hours. Scores are based on daily assessments recorded by patients in their diaries.
[7]	The LSEQ assesses the effects of psychoactive compounds on sleep and early morning behavior. Participants mark a series of 100 mm line analogue scales, indicating the direction and magnitude of any changes in behavioral state they experience following administration of the drug. Scores are represented in millimeters, higher scores indicate better sleep and better early morning behvior. Subscale score ranges: going to sleep=0-300, quality of sleep=0-200, awakening=0-200, behavior following wakefullness=0-300.
[8]	The SDS is completed by the patient and is used to assess the effect of the patient's symptoms on their work/social/family life. Total scores range from 0 to 30 with higher values indicating greater disruption in the patient's work/social/family life.
[9]	The CSFQ is a 14-item subject-rated scale designed to assess changes in sexual activity and functioning. The CSFQ is a structured interview/questionnaire, which is designed to measure medication related changes in sexual functioning. The CSFQ measures five dimensions of sexual behavior: pleasure; desire/frequency; desire/interest; arousal; and orgasm. The CSFQ total score is also obtained across all 5 dimensions and ranges from 14 to 70. Subscale score ranges: desire/frequency=2-10; desire/interest=3-15; pleasure=1-5; arousal=3-15; orgasm=3-15. Higher scores indicate greater changes.
[10]	Frequency of current comorbid Generalized Anxiety Disorder-Text-Revised (DSM-IV-TR) based on specific modules of the Mini-International Neuropsychiatric Interview (MINI), a short, structured diagnostic interview developed for DSM-IV psychiatric disorders.
[11]	Frequency of current comorbid Major Depressive Disorder-Text revision (DSM-IV-TR) based on specific modules of the Mini-International Neuropsychiatric Interview (MINI), a short, structured diagnostic interview developed for DSM-IV psychiatric disorders.

Outcome Measures

Show All Outcome Measures

1. Primary:

Mean Change From Baseline to 12 Weeks in Weekly Mean of Daily 24 Hour Average Pain Score, Pregabalin Compared With Duloxetine [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 1

2. Secondary:

Mean Change From Baseline to 12 Weeks in Weekly Mean of Daily 24 Hour Average Pain Score, Duloxetine Compared With Duloxetine+Gabapentin [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 2

3. Secondary:

Mean Change From Baseline to 12 Weeks in Weekly Mean of Nighttime Pain Severity [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 3

4. Secondary:

Mean Change From Baseline to 12 Weeks in Weekly Mean of the Daily Worst Pain Severity Score [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 4

5. Secondary:

Mean Change From Baseline to 12 Weeks in Clinical Global Impression of Severity Scale (CGI Severity) [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 5

6. Secondary:

Patient's Global Impression of Improvement Scale (PGI - Improvement) at 12 Weeks [ Time Frame: 12 weeks ]

Show Outcome Measure 6

7. Secondary:

Mean Change From Baseline to 12 Weeks in Brief Pain Inventory (BPI) - Severity: 24-hour Average Pain [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 7

8. Secondary:

Mean Change From Baseline to 12 Weeks in Brief Pain Inventory (BPI) - Severity: Worst Pain [ Time Frame: baseline, 12 Weeks ]

Show Outcome Measure 8

9. Secondary:

Mean Change From Baseline to 12 Weeks in Brief Pain Inventory (BPI) - Severity: Least Pain [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 9

10. Secondary:

Mean Change From Baseline to 12 Weeks in Brief Pain Inventory (BPI) - Severity: Pain Right Now [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 10

11. Secondary:

Mean Change From Baseline to 12 Weeks in Brief Pain Inventory (BPI) - Interference: With General Activity [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 11

12. Secondary:

Mean Change From Baseline to 12 Weeks in Brief Pain Inventory (BPI) - Interference With Mood [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 12

13. Secondary:

Mean Change From Baseline to 12 Weeks in Brief Pain Inventory (BPI) - Interference With Walking Ability [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 13

14. Secondary:

Mean Change From Baseline to 12 Weeks in Brief Pain Inventory (BPI) - Interference With Normal Work [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 14

15. Secondary:

Mean Change From Baseline to 12 Weeks in Brief Pain Inventory (BPI) - Interference With Relations With Other People [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 15

16. Secondary:

Mean Change From Baseline to 12 Weeks in Brief Pain Inventory (BPI) - Interference With Sleep [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 16

17. Secondary:

Mean Change From Baseline to 12 Weeks in Brief Pain Inventory (BPI) - Interference With Enjoyment of Life [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 17

18. Secondary:

Mean Change From Baseline to 12 Weeks in Brief Pain Inventory (BPI) - Mean Interference Score [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 18

19. Secondary:

Number of Participants With ≥ 30% Reduction in the Weekly Mean 24 Hour Average Pain Score at 12 Weeks [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 19

20. Secondary:

Number of Patients With a Reduction of ≥ 50% in Weekly Mean of 24 Hour Average Pain Score [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 20

21. Secondary:

Number of Participants With a ≥ 2-points Reduction on the Weekly Average of the Daily 24-hour Average Pain Scale at 12 Weeks [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 21

22. Secondary:

Mean Change From Baseline to 12 Weeks in Leeds Sleep Evaluation Questionnaire (LSEQ) Subscales of Ease of Going to Sleep (GTS), Awakening (AFS), and Behavior Following Wakefulness (BFW), Quality of Sleep (QOS) [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 22

23. Secondary:

Mean Change From Baseline to 12 Weeks in Sheehan Disability Scale (SDS) - Total Score and Scores for Items 1 to 3 [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 23

24. Secondary:

Summary of Adverse Events and Serious Adverse Events Leading to Discontinuation [ Time Frame: baseline through 12 weeks ]

Show Outcome Measure 24

25. Secondary:

Mean Change From Baseline to 12 Weeks in Sexual Functioning Questionnaire (CSFQ) Total Score and Subscale Scores [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 25

26. Secondary:

Categorical Change From Baseline to 12 Weeks in Sexual Functioning Questionnaire (CSFQ) Total Score and Subscale Scores [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 26

27. Secondary:

Mean Change From Baseline to 12 Weeks in Portland Neurotoxicity Scale - Total Score and Subscale Scores [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 27

28. Secondary:

Categorial Change From Baseline to 12 Weeks in Portland Neurotoxicity Scale - Total Score and Subscale Scores [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 28

29. Secondary:

Path Analysis of Improvement in Pain Through Improvement in Depressive Symptoms [ Time Frame: baseline through 12 weeks ]

Show Outcome Measure 29

30. Secondary:

Mean Change From Baseline to 12 Weeks in Beck Depression Inventory II (BDI-II) Total Score [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 30

31. Secondary:

Categorical Change From Baseline to 12 Weeks in Number of Patients Using Health Care as Measured by the Resource Utilization Scale [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 31

32. Secondary:

Summary of Number of Participants Who Discontinued [ Time Frame: baseline through 12 weeks ]

Show Outcome Measure 32

33. Secondary:

Time to First ≥ 30% Reduction in Weekly Mean 24 Hour Average Pain Score [ Time Frame: baseline through 12 weeks ]

Show Outcome Measure 33

34. Secondary:

Time to First ≥ 50 % Reduction in Weekly Mean 24 Hour Average Pain Score [ Time Frame: baseline through 12 weeks ]

Show Outcome Measure 34

35. Secondary:

Time to First Sustained Response in Weekly Mean 24 Hour Average Pain Score [ Time Frame: baseline through 12 weeks ]

Show Outcome Measure 35

36. Secondary:

Time to First ≥ 2 Points Reduction in Weekly Mean 24 Hour Average Pain Score [ Time Frame: baseline through 12 weeks ]

Show Outcome Measure 36

37. Secondary:

Weekly Mean Change in 24 Hour Average Pain Severity +/- Generalized Anxiety Disorder (GAD) [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 37

38. Secondary:

Weekly Mean Change From Baseline to 12 Weeks in 24 Hour Average Pain Severity - Only Participants Who Adhered to Key Protocol Requirements (Per-Protocol Population) [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 38

39. Secondary:

Weekly Mean Change in 24 Hour Average Pain Severity by Week by Gabapentin Exposure Subgroup (de Novo Versus Prior Use) [ Time Frame: baseline, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks ]

Show Outcome Measure 39

40. Secondary:

Discontinuations for Abnormal Laboratory Analytes, Vital Signs, Overall and for Each Measure [ Time Frame: baseline through 12 weeks ]

Show Outcome Measure 40

41. Secondary:

Mean Change From Baseline to 12 Weeks in Blood Pressure [ Time Frame: baseline through 12 weeks ]

Show Outcome Measure 41

42. Secondary:

Mean Change From Baseline to 12 Weeks in Heart Rate [ Time Frame: baseline through 12 weeks ]

Show Outcome Measure 42

43. Secondary:

Mean Change From Baseline to 12 Weeks in Body Weight [ Time Frame: baseline through 12 weeks ]

Show Outcome Measure 43

44. Secondary:

Number of Participants With Treatment-emergent Elevated Blood Pressure [ Time Frame: baseline through 12 weeks ]

Show Outcome Measure 44

45. Secondary:

Number of Participants With Treatment-Emergent Elevated Heart Rate [ Time Frame: baseline through 12 weeks ]

Show Outcome Measure 45

46. Secondary:

Number of Participants With Treatment-Emergent Changes in Body Weight [ Time Frame: baseline through 12 weeks ]

Show Outcome Measure 46

47. Secondary:

Mean Change From Baseline to 12 Weeks in Hepatic Enzyme Serum Levels [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 47

48. Secondary:

Mean Change From Baseline to 12 Weeks in Total Bilirubin [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 48

49. Secondary:

Mean Change From Baseline to 12 Weeks in Fasting Plasma Glucose [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 49

50. Secondary:

Mean Change From Baseline to 12 Weeks in Hemoglobin A1C [ Time Frame: baseline, 12 weeks ]

Show Outcome Measure 50

51. Secondary:

Number of Patients With Treatment-Emergent Elevated Laboratory Analytes [ Time Frame: baseline through 12 weeks ]

Show Outcome Measure 51

Serious Adverse Events

Show Serious Adverse Events

Other Adverse Events

Show Other Adverse Events

More Information

Hide More Information

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.

Limitations and Caveats

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
No text entered.

Results Point of Contact:

Name/Title: Chief Medical Officer
Organization: Eli Lilly and Company
phone: 800-545-5979

Publications of Results:

Tanenberg RJ, Irving GA, Risser RC, Ahl J, Robinson MJ, Skljarevski V, Malcolm SK. Duloxetine, pregabalin, and duloxetine plus gabapentin for diabetic peripheral neuropathic pain management in patients with inadequate pain response to gabapentin: an open-label, randomized, noninferiority comparison. Mayo Clin Proc. 2011 Jul;86(7):615-26.

Responsible Party:	Chief Medical Officer, Eli Lilly
ClinicalTrials.gov Identifier:	NCT00385671 History of Changes
Other Study ID Numbers:	10822, F1J-US-HMEZ
Study First Received:	October 6, 2006
Results First Received:	August 23, 2010
Last Updated:	July 22, 2011
Health Authority:	United States: Food and Drug Administration