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

This study has been completed.
Sponsor:
Collaborator:
Boehringer Ingelheim
Information provided by:
Eli Lilly and Company
ClinicalTrials.gov Identifier:
NCT00385671
First received: October 6, 2006
Last updated: July 22, 2011
Last verified: July 2011
Results First Received: August 23, 2010  
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

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

Participant Flow:   Overall Study
    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
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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.
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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.
Total Total of all reporting groups

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 ]

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 ]

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

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

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

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

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

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

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

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

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

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

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

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

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 ]

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

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

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

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 ]

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

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 ]

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 ]

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 ]

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

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

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

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

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

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

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

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 ]

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

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

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

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

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

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

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 ]

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 ]

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

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

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

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

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

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

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

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

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

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

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

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


  Serious Adverse Events


  Other Adverse Events


  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:
unchecked 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.
unchecked Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.


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


Publications of Results:

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