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A Study in Painful Diabetic Neuropathy (COMBO-DN)

This study has been completed.
Sponsor:
Collaborator:
Boehringer Ingelheim
Information provided by (Responsible Party):
Eli Lilly and Company
ClinicalTrials.gov Identifier:
NCT01089556
First received: March 15, 2010
Last updated: January 17, 2013
Last verified: January 2013
Results First Received: October 30, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Diabetic Neuropathy, Painful
Interventions: Drug: Duloxetine
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
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
The study consisted of 4 study periods (SP): 2 weeks screening and washout (SP I), 8 weeks initial treatment (SP II), 8 weeks intensive treatment (SP III), 2 weeks tapering (SP IV). Participants who did not achieve good pain control during SP II (<30% improvement) were considered non-responders and continued in the study and entered SP III.

Reporting Groups
  Description
Duloxetine (SP II) Duloxetine 30 milligram (mg) daily for Week 1 and 60 mg daily for Weeks 2-8 in Study Period II (SP II).
Pregabalin (SP II) Pregabalin 150 mg daily for Week 1 and 300 mg daily for Weeks 2-8 in Study Period II.
Duloxetine (SP III) Duloxetine 90 mg daily for Week 9 and 120 mg daily for Weeks 10-16 in Study Period III (SP III).
DLX + PGB (SP III) Duloxetine (DLX) 60 mg plus Pregabalin (PGB) 150 mg daily for Week 9 and Duloxetine 60 mg plus Pregabalin 300 mg daily for Weeks 10-16 in Study Period III.
PGB + DLX (SP III) Pregabalin (PGB) 300 mg plus Duloxetine (DLX) 30 mg daily for Week 9 and Pregabalin 300 mg plus Duloxetine 60 mg daily for Weeks 10-16 in Study Period III.
Pregabalin (SP III) Pregabalin 450 mg daily for Week 9 and Pregabalin 600 mg daily for Weeks 10-16 in Study Period III.

Participant Flow for 2 periods

Period 1:   Study Period II (Weeks 1-8)
    Duloxetine (SP II)     Pregabalin (SP II)     Duloxetine (SP III)     DLX + PGB (SP III)     PGB + DLX (SP III)     Pregabalin (SP III)  
STARTED     404     407     0     0     0     0  
Safety Population     401 [1]   403 [1]   0     0     0     0  
Non-responders Who Completed SPII     158     205     0     0     0     0  
COMPLETED     333     333     0     0     0     0  
NOT COMPLETED     71     74     0     0     0     0  
Adverse Event                 35                 39                 0                 0                 0                 0  
Entry Criteria Not Met                 12                 8                 0                 0                 0                 0  
Lack of Efficacy                 1                 2                 0                 0                 0                 0  
Lost to Follow-up                 0                 3                 0                 0                 0                 0  
Physician Decision                 4                 0                 0                 0                 0                 0  
Protocol Violation                 4                 4                 0                 0                 0                 0  
Withdrawal by Subject                 12                 14                 0                 0                 0                 0  
Not received any study drug                 3                 4                 0                 0                 0                 0  
[1] Received at least 1 dose of study drug.

Period 2:   Study Period III (Weeks 9-16)
    Duloxetine (SP II)     Pregabalin (SP II)     Duloxetine (SP III)     DLX + PGB (SP III)     PGB + DLX (SP III)     Pregabalin (SP III)  
STARTED     0     0     74 [1]   75 [2]   95 [1]   99 [3]
Efficacy and Safety Population     0     0     73 [4]   75 [4]   94 [4]   97 [4]
COMPLETED     0     0     60     66     83     92  
NOT COMPLETED     0     0     14     9     12     7  
Adverse Event                 0                 0                 4                 2                 4                 3  
Entry Criteria Not Met                 0                 0                 1                 1                 1                 1  
Lack of Efficacy                 0                 0                 0                 2                 1                 0  
Lost to Follow-up                 0                 0                 1                 0                 0                 0  
Protocol Violation                 0                 0                 1                 1                 1                 0  
Satisfactory Response                 0                 0                 4                 3                 4                 1  
Withdrawal by Subject                 0                 0                 3                 0                 1                 2  
[1] Of those who completed SPII, 10 non-responders did not enter SPIII, while 4 responders entered SPIII
[2] Of those who completed SPII, 6 non-responders did not enter SPIII, while 3 responders entered SPIII
[3] Of those who completed SPII, 6 non-responders did not enter SPIII, while 1 responders entered SPIII
[4] Received ≥1 dose study drug, had Week 8 and at least 1 assessment during Weeks 9-16 (SPIII)



  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.
No text entered.

Reporting Groups
  Description
Duloxetine Duloxetine 30 milligram (mg) daily for Week 1 and 60 mg daily for Weeks 2-8 in Study Period II.
Pregabalin Pregabalin 150 mg daily for Week 1 and 300 mg daily for Weeks 2-8 in Study Period II.
Total Total of all reporting groups

Baseline Measures
    Duloxetine     Pregabalin     Total  
Number of Participants  
[units: participants]
  401     403     804  
Age  
[units: years]
Mean ± Standard Deviation
  61.5  ± 10.62     61.9  ± 10.95     61.7  ± 10.78  
Gender  
[units: participants]
     
Female     182     174     356  
Male     219     229     448  
Race (NIH/OMB)  
[units: participants]
     
American Indian or Alaska Native     37     36     73  
Asian     34     34     68  
Native Hawaiian or Other Pacific Islander     1     0     1  
Black or African American     2     2     4  
White     324     328     652  
More than one race     0     0     0  
Unknown or Not Reported     3     3     6  
Region of Enrollment  
[units: participants]
     
Greece     16     12     28  
Spain     6     8     14  
Turkey     5     7     12  
United Kingdom     31     31     62  
Italy     16     18     34  
France     22     24     46  
Mexico     75     71     146  
Canada     19     19     38  
Poland     56     57     113  
Croatia     27     29     56  
Australia     27     22     49  
Netherlands     5     4     9  
Germany     52     54     106  
Korea, Republic of     31     32     63  
Sweden     13     15     28  
Clinical Global Impressions of Severity Scale (CGI-S) [1]
[units: units on a scale]
Mean ± Standard Deviation
  4.0  ± 1.07     4.0  ± 1.09     4.0  ± 1.08  
Patient Global Impressions of Severity Scale (PGI-S) [2]
[units: units on a scale]
Mean ± Standard Deviation
  3.4  ± 1.42     3.4  ± 1.41     3.4  ± 1.42  
Brief Pain Inventory (BPI) Severity: Average Pain Score [3]
[units: units on a scale]
Mean ± Standard Deviation
  6.0  ± 1.55     6.0  ± 1.57     6.0  ± 1.56  
Neuropathic Pain Symptom Inventory (NPSI) [4]
[units: units on a scale]
Mean ± Standard Deviation
  47.3  ± 19.16     47.7  ± 20.46     47.5  ± 19.81  
Hospital Anxiety and Depression Scale (HADS) - Anxiety Subscale Score [5]
[units: units on a scale]
Mean ± Standard Deviation
  6.8  ± 4.31     6.6  ± 4.32     6.7  ± 4.31  
Hospital Anxiety and Depression Scale (HADS) - Depression Subscale Score [6]
[units: units on a scale]
Mean ± Standard Deviation
  5.5  ± 4.19     5.5  ± 3.88     5.5  ± 4.04  
Sheehan Disability Scale (SDS) [7]
[units: units on a scale]
Mean ± Standard Deviation
  13.3  ± 7.47     13.3  ± 7.59     13.3  ± 7.52  
Average number of hours worked for pay per week [8]
[units: hours]
Mean ± Standard Deviation
  39.5  ± 20.33     41.4  ± 16.36     40.4  ± 18.47  
Number of days of work/school missed [9]
[units: days]
Mean ± Standard Deviation
  2.3  ± 7.98     1.3  ± 4.69     1.8  ± 6.56  
Number of days hospitalized [10]
[units: days]
Mean ± Standard Deviation
  0.0  ± 0.45     0.1  ± 0.67     0.1  ± 0.57  
Blood pressure (BP) [11]
[units: millimeter of mercury (mm Hg)]
Mean ± Standard Deviation
     
Systolic BP     135.0  ± 16.27     134.3  ± 15.62     134.7  ± 15.94  
Diastolic BP     77.6  ± 10.04     76.7  ± 9.43     77.1  ± 9.74  
Pulse rate [12]
[units: beats per minute (bpm)]
Mean ± Standard Deviation
  76.0  ± 10.81     75.6  ± 11.05     75.8  ± 10.92  
[1] The clinician recorded how ill the participant was at the time of assessment, in relation to the clinician’s total experience with this participant population. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). One participant in Duloxetine group and 2 participants in Pregabalin group had missing data and were not included in the calculation of mean and standard deviation (SD).
[2] Measures participant's perception of severity of illness at the time of assessment. Scores range from 1 (normal, not at all ill) to 7 (extremely ill).
[3] A self-reported scale that measures the severity of pain based on the average pain experienced over the past 24-hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). Two participants in Pregabalin group had missing data and were not included in the calculation of mean and SD.
[4] The NPSI is a 12-item self-administered questionnaire to assess 5 different dimensions of neuropathic pain: superficial spontaneous burning pain, deep spontaneous pressing pain, paroxysmal pain, evoked pains, and paresthesias/dysesthesias. Questionnaire generates a score in each of the relevant dimensions and a total score of 0-100. Higher score indicates a greater intensity of pain. Two participants in Duloxetine group and 6 participants in Pregabalin group had missing data and were not included in the calculation of mean and SD.
[5] A 14-item questionnaire with 2 subscales: anxiety and depression. Each item is rated on a 4-point scale (0-3), giving maximum scores of 21 for anxiety and for depression. Scores of 11 or more on either subscale are considered to be a significant case of psychological morbidity, while scores of 8-10 represent 'borderline' and 0-7, 'normal.' Three participants in both Duloxetine group and Pregabalin group had missing data and were not included in the calculation of mean and SD.
[6] A 14-item questionnaire with 2 subscales: anxiety and depression. Each item is rated on a 4-point scale (0-3), giving maximum scores of 21 for anxiety and for depression. Scores of 11 or more on either subscale are considered to be a significant case of psychological morbidity, while scores of 8-10 represent 'borderline' and 0-7, 'normal.' Two participants in Duloxetine group and 1 participant in Pregabalin group had missing data and were not included in the calculation of mean and SD.
[7] The SDS is completed by the participants and is used to assess the effect of their symptoms on work (Item 1), social (Item 2) and family life (Item 3). Each item is measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. Total scores is the sum of the 3 items and range from 0-30 with higher values indicating greater disruption in the participant's work/social/family life. There were 118 participants in Duloxetine group and 128 participants in Pregabalin group who had missing data and were not included in the calculation of mean and SD.
[8] Data presented are average number of hours worked for pay per week during last 8 weeks prior to entering Study Period II. There were 275 participants in Duloxetine group and 281 participants in Pregabalin group who had missing data and were not included in the calculation of mean and SD.
[9] Data presented are the number of days of work/school missed due to diabetic peripheral neuropathic pain (DPNP) during the last 8 weeks prior to entering Study Period II. There were 278 participants in Duloxetine group and 281 participants in Pregabalin group who had missing data and were not included in the calculation of mean and SD.
[10] Data presented are the number of days hospitalized due to DPNP during the last 8 weeks prior to entering Study Period II. There were 21 participants in Duloxetine group and 23 participants in Pregabalin group who had missing data and were not included in the calculation of mean and SD.
[11] One participant in both Duloxetine group and Pregabalin group had missing data and were not included in the calculation of mean and SD.
[12] Three participants in Duloxetine group and 1 participant in Pregabalin group had missing data and were not included in the calculation of mean and SD.



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Change From Week 8 to Week 16 Endpoint in 24 Hour Average Pain Item Score on the Brief Pain Inventory (BPI) Modified Short Form   [ Time Frame: Week 8, Week 16 ]

2.  Secondary:   Mean Change From Week 8 to Week 16 Endpoint in Items of the Brief Pain Inventory (BPI) Modified Short Form Worst Pain Score   [ Time Frame: Week 8, Week 16 ]

3.  Secondary:   Percentage of Participants With a Reduction of Greater Than or Equal to 30% on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 16 Endpoint   [ Time Frame: Week 8 through Week 16 ]

4.  Secondary:   Percentage of Participants With a Reduction of Greater Than or Equal to 50% on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 16 Endpoint   [ Time Frame: Week 8 through Week 16 ]

5.  Secondary:   Percentage of Participants With a Decrease of Greater Than or Equal to 2 Points on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 16 Endpoint   [ Time Frame: Week 8 through Week 16 ]

6.  Secondary:   Clinical Global Impression of Improvement (CGI-I) at Week 16 Endpoint   [ Time Frame: Week 16 ]

7.  Secondary:   Mean Change From Week 8 to Week 16 Endpoint on the Neuropathic Pain Symptom Inventory (NPSI) Questionnaire   [ Time Frame: Week 8, Week 16 ]

8.  Secondary:   Mean Change From Week 8 to Week 16 Endpoint in Sheehan Disability Scale (SDS)   [ Time Frame: Week 8, Week 16 ]

9.  Secondary:   Mean Change From Week 8 to Week 16 Endpoint in Hospital Anxiety and Depression Scale (HADS)   [ Time Frame: Week 8, Week 16 ]

10.  Secondary:   Resource Utilization (Number of Days Hospitalized, Number of Days of Sick Leave) Week 8 Through Week 16   [ Time Frame: Week 8 through Week 16 ]

11.  Secondary:   Patient Global Impression of Improvement (PGI-I) Score at Week 16 Endpoint   [ Time Frame: Week 16 ]

12.  Secondary:   Mean Change in Blood Pressure (BP) From Week 8 to Week 16 Endpoint   [ Time Frame: Week 8, Week 16 ]

13.  Secondary:   Mean Change in Heart Rate From Week 8 to Week 16 Endpoint   [ Time Frame: Week 8, Week 16 ]

14.  Secondary:   Number of Participants With Treatment Emergent Adverse Events (TEAEs) Between Week 8 and Week 16 Endpoint   [ Time Frame: Week 8 through Week 16 ]

15.  Secondary:   Number of Participants Who Discontinued From Study Between Week 8 and Week 16 Endpoint   [ Time Frame: Week 8 through Week 16 ]

16.  Other Pre-specified:   Mean Change From Baseline to Week 8 Endpoint in 24 Hour Average Pain Item Score on the Brief Pain Inventory (BPI) Modified Short Form   [ Time Frame: Baseline, Week 8 ]

17.  Other Pre-specified:   Percentage of Participants With a Reduction of Greater Than or Equal to 30% on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 8 Endpoint   [ Time Frame: Baseline through Week 8 ]

18.  Other Pre-specified:   Percentage of Participants With a Reduction of Greater Than or Equal to 50% on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 8 Endpoint   [ Time Frame: Baseline through Week 8 ]

19.  Other Pre-specified:   Percentage of Participants With a Decrease of Greater Than or Equal to 2 Points on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 8 Endpoint   [ Time Frame: Baseline through Week 8 ]

20.  Other Pre-specified:   Clinical Global Impression of Improvement (CGI-I) at Week 8 Endpoint   [ Time Frame: Week 8 ]

21.  Other Pre-specified:   Mean Change From Baseline to Week 8 Endpoint on the Neuropathic Pain Symptom Inventory (NPSI) Questionnaire   [ Time Frame: Baseline, Week 8 ]

22.  Other Pre-specified:   Mean Change From Baseline to Week 8 Endpoint in Sheehan Disability Scale (SDS)   [ Time Frame: Baseline, Week 8 ]

23.  Other Pre-specified:   Mean Change From Baseline to Week 8 Endpoint in Hospital Anxiety and Depression Scale (HADS)   [ Time Frame: Baseline, Week 8 ]

24.  Other Pre-specified:   Resource Utilization (Number of Days Hospitalized, Number of Days of Sick Leave) Baseline Through Week 8   [ Time Frame: Baseline through Week 8 ]

25.  Other Pre-specified:   Average Number of Hours Worked for Pay Per Week Baseline Through Week 8   [ Time Frame: Baseline through Week 8 ]

26.  Other Pre-specified:   Average Number of Hours Worked for Pay Per Week Week 8 Through Week 16   [ Time Frame: Week 8 through Week 16 ]

27.  Other Pre-specified:   Patient Global Impression of Improvement (PGI-I) Score at Week 8 Endpoint   [ Time Frame: Week 8 ]

28.  Other Pre-specified:   Mean Change in Blood Pressure (BP) From Baseline to Week 8 Endpoint   [ Time Frame: Baseline, Week 8 ]

29.  Other Pre-specified:   Mean Change in Heart Rate From Baseline to Week 8 Endpoint   [ Time Frame: Baseline, Week 8 ]

30.  Other Pre-specified:   Number of Participants With Treatment Emergent Adverse Events (TEAE) Between Baseline and Week 8 Endpoint   [ Time Frame: Baseline through Week 8 ]

31.  Other Pre-specified:   Number of Participants Who Discontinued From Study Between Baseline and Week 8 Endpoint   [ Time Frame: Baseline through Week 8 ]


  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
No text entered.


  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


No publications provided


Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT01089556     History of Changes
Other Study ID Numbers: 13084, F1J-EW-HMGQ
Study First Received: March 15, 2010
Results First Received: October 30, 2012
Last Updated: January 17, 2013
Health Authority: Australia: Human Research Ethics Committee
Canada: Health Canada
Croatia: Agency for Medicinal Product and Medical Devices
Croatia: Ethics Committee
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
France: Institutional Ethical Committee
Germany: Federal Institute for Drugs and Medical Devices
Germany: Ethics Commission
Greece: Ethics Committee
Greece: National Organization of Medicines
Italy: The Italian Medicines Agency
South Korea: Korea Food and Drug Administration (KFDA)
Mexico: Federal Commission for Sanitary Risks Protection
Netherlands: Medical Ethics Review Committee (METC)
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Spain: Ministry of Health
Sweden: Medical Products Agency
Switzerland: Swissmedic
Turkey: Ministry of Health
United Kingdom: Medicines and Healthcare Products Regulatory Agency