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Trial record 76 of 88 for:    "Neuromuscular Disease" | "Norepinephrine"

A Study in Painful Diabetic Neuropathy (COMBO-DN)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01089556
Recruitment Status : Completed
First Posted : March 18, 2010
Results First Posted : December 4, 2012
Last Update Posted : January 24, 2013
Sponsor:
Collaborator:
Boehringer Ingelheim
Information provided by (Responsible Party):
Eli Lilly and Company

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Diabetic Neuropathy, Painful
Interventions Drug: Duloxetine
Drug: Pregabalin
Drug: Placebo
Enrollment 811
Recruitment Details  
Pre-assignment Details 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.
Arm/Group Title Duloxetine (SP II) Pregabalin (SP II) Duloxetine (SP III) DLX + PGB (SP III) PGB + DLX (SP III) Pregabalin (SP III)
Hide Arm/Group Description Duloxetine 30 milligram (mg) daily for Week 1 and 60 mg daily for Weeks 2-8 in Study Period II (SP II). Pregabalin 150 mg daily for Week 1 and 300 mg daily for Weeks 2-8 in Study Period II. Duloxetine 90 mg daily for Week 9 and 120 mg daily for Weeks 10-16 in Study Period III (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. 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 450 mg daily for Week 9 and Pregabalin 600 mg daily for Weeks 10-16 in Study Period III.
Period Title: Study Period II (Weeks 1-8)
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
Reason Not Completed
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 Title: Study Period III (Weeks 9-16)
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
Reason Not Completed
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)
Arm/Group Title Duloxetine Pregabalin Total
Hide Arm/Group Description Duloxetine 30 milligram (mg) daily for Week 1 and 60 mg daily for Weeks 2-8 in Study Period II. Pregabalin 150 mg daily for Week 1 and 300 mg daily for Weeks 2-8 in Study Period II. Total of all reporting groups
Overall Number of Baseline Participants 401 403 804
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 401 participants 403 participants 804 participants
61.5  (10.62) 61.9  (10.95) 61.7  (10.78)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 401 participants 403 participants 804 participants
Female
182
  45.4%
174
  43.2%
356
  44.3%
Male
219
  54.6%
229
  56.8%
448
  55.7%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 401 participants 403 participants 804 participants
American Indian or Alaska Native
37
   9.2%
36
   8.9%
73
   9.1%
Asian
34
   8.5%
34
   8.4%
68
   8.5%
Native Hawaiian or Other Pacific Islander
1
   0.2%
0
   0.0%
1
   0.1%
Black or African American
2
   0.5%
2
   0.5%
4
   0.5%
White
324
  80.8%
328
  81.4%
652
  81.1%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
3
   0.7%
3
   0.7%
6
   0.7%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 401 participants 403 participants 804 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] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 401 participants 403 participants 804 participants
4.0  (1.07) 4.0  (1.09) 4.0  (1.08)
[1]
Measure Description: 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).
Patient Global Impressions of Severity Scale (PGI-S)   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 401 participants 403 participants 804 participants
3.4  (1.42) 3.4  (1.41) 3.4  (1.42)
[1]
Measure Description: 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).
Brief Pain Inventory (BPI) Severity: Average Pain Score   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 401 participants 403 participants 804 participants
6.0  (1.55) 6.0  (1.57) 6.0  (1.56)
[1]
Measure Description: 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.
Neuropathic Pain Symptom Inventory (NPSI)   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 401 participants 403 participants 804 participants
47.3  (19.16) 47.7  (20.46) 47.5  (19.81)
[1]
Measure Description: 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.
Hospital Anxiety and Depression Scale (HADS) - Anxiety Subscale Score   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 401 participants 403 participants 804 participants
6.8  (4.31) 6.6  (4.32) 6.7  (4.31)
[1]
Measure Description: 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.
Hospital Anxiety and Depression Scale (HADS) - Depression Subscale Score   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 401 participants 403 participants 804 participants
5.5  (4.19) 5.5  (3.88) 5.5  (4.04)
[1]
Measure Description: 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.
Sheehan Disability Scale (SDS)   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 401 participants 403 participants 804 participants
13.3  (7.47) 13.3  (7.59) 13.3  (7.52)
[1]
Measure Description: 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.
Average number of hours worked for pay per week   [1] 
Mean (Standard Deviation)
Unit of measure:  Hours
Number Analyzed 401 participants 403 participants 804 participants
39.5  (20.33) 41.4  (16.36) 40.4  (18.47)
[1]
Measure Description: 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.
Number of days of work/school missed   [1] 
Mean (Standard Deviation)
Unit of measure:  Days
Number Analyzed 401 participants 403 participants 804 participants
2.3  (7.98) 1.3  (4.69) 1.8  (6.56)
[1]
Measure Description: 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.
Number of days hospitalized   [1] 
Mean (Standard Deviation)
Unit of measure:  Days
Number Analyzed 401 participants 403 participants 804 participants
0.0  (0.45) 0.1  (0.67) 0.1  (0.57)
[1]
Measure Description: 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.
Blood pressure (BP)   [1] 
Mean (Standard Deviation)
Unit of measure:  Millimeter of mercury (mm Hg)
Number Analyzed 401 participants 403 participants 804 participants
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)
[1]
Measure Description: One participant in both Duloxetine group and Pregabalin group had missing data and were not included in the calculation of mean and SD.
Pulse rate   [1] 
Mean (Standard Deviation)
Unit of measure:  Beats per minute (bpm)
Number Analyzed 401 participants 403 participants 804 participants
76.0  (10.81) 75.6  (11.05) 75.8  (10.92)
[1]
Measure Description: 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.
1.Primary Outcome
Title Change From Week 8 to Week 16 Endpoint in 24 Hour Average Pain Item Score on the Brief Pain Inventory (BPI) Modified Short Form
Hide Description BPI Modified Short Form 24-Hour average pain item score is 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). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment*visit, baseline*visit and treatment in Study Period II.
Time Frame Week 8, Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug, and had Week 8 and at least one BPI measurements during Weeks 9-16 (Study Period III).
Arm/Group Title Combination Monotherapy
Hide Arm/Group Description:
All participants who received Duloxetine Combination therapy (Duloxetine 60 milligram [mg] plus Pregabalin 150 mg daily for Week 9 and Duloxetine 60 mg plus Pregabalin 300 mg daily for Weeks 10-16) or Pregabalin Combination therapy (Pregabalin 300 mg plus Duloxetine 30 mg daily for Week 9 and Pregabalin 300 mg plus Duloxetine 60 mg daily for Weeks 10-16) in Study Period III were pooled together.
All participants who received Duloxetine Monotherapy (Duloxetine 90 mg daily for Week 9 and 120 mg daily for Weeks 10-16) or Pregabalin Monotherapy (Pregabalin 450 mg daily for Week 9 and Pregabalin 600 mg daily for Weeks 10-16) in Study Period III were pooled together.
Overall Number of Participants Analyzed 169 170
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-2.353
(-2.688 to -2.017)
-2.161
(-2.509 to -1.812)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination, Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.370
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Differences (Final Values)
Estimated Value -0.192
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Mean Change From Week 8 to Week 16 Endpoint in Items of the Brief Pain Inventory (BPI) Modified Short Form Worst Pain Score
Hide Description BPI Modified Short Form worst pain score is a self-reported scale that measures the severity of pain based on the worst pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment*visit, baseline*visit and treatment in Study Period II.
Time Frame Week 8, Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug, and had Week 8 and at least one BPI measurements during Weeks 9-16 (Study Period III).
Arm/Group Title Combination Monotherapy
Hide Arm/Group Description:
All participants who received Duloxetine Combination therapy (Duloxetine 60 milligram [mg] plus Pregabalin 150 mg daily for Week 9 and Duloxetine 60 mg plus Pregabalin 300 mg daily for Weeks 10-16) or Pregabalin Combination therapy (Pregabalin 300 mg plus Duloxetine 30 mg daily for Week 9 and Pregabalin 300 mg plus Duloxetine 60 mg daily for Weeks 10-16) in Study Period III were pooled together.
All participants who received Duloxetine Monotherapy (Duloxetine 90 mg daily for Week 9 and 120 mg daily for Weeks 10-16) or Pregabalin Monotherapy (Pregabalin 450 mg daily for Week 9 and Pregabalin 600 mg daily for Weeks 10-16) in Study Period III were pooled together.
Overall Number of Participants Analyzed 169 170
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-2.374
(-2.757 to -1.990)
-2.371
(-2.771 to -1.971)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination, Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.991
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Differences (Final Values)
Estimated Value -0.003
Estimation Comments [Not Specified]
3.Secondary Outcome
Title 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
Hide Description BPI Modified Short Form 24-Hour average pain item score is 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).
Time Frame Week 8 through Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug, and had Week 8 and at least one BPI measurements during Weeks 9-16 (Study Period III). Last observation carried forward (LOCF) principle was used.
Arm/Group Title Combination Monotherapy
Hide Arm/Group Description:
All participants who received Duloxetine Combination therapy (Duloxetine 60 milligram [mg] plus Pregabalin 150 mg daily for Week 9 and Duloxetine 60 mg plus Pregabalin 300 mg daily for Weeks 10-16) or Pregabalin Combination therapy (Pregabalin 300 mg plus Duloxetine 30 mg daily for Week 9 and Pregabalin 300 mg plus Duloxetine 60 mg daily for Weeks 10-16) in Study Period III were pooled together.
All participants who received Duloxetine Monotherapy (Duloxetine 90 mg daily for Week 9 and 120 mg daily for Weeks 10-16) or Pregabalin Monotherapy (Pregabalin 450 mg daily for Week 9 and Pregabalin 600 mg daily for Weeks 10-16) in Study Period III were pooled together.
Overall Number of Participants Analyzed 165 163
Measure Type: Number
Unit of Measure: percentage of participants
61.8 55.8
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination, Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.565
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.052
Confidence Interval (2-Sided) 95%
0.884 to 1.253
Estimation Comments [Not Specified]
4.Secondary Outcome
Title 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
Hide Description BPI Modified Short Form 24-Hour average pain item score is 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).
Time Frame Week 8 through Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug, and had Week 8 and at least one BPI measurements during Weeks 9-16 (Study Period III). Last observation carried forward (LOCF) principle was used.
Arm/Group Title Combination Monotherapy
Hide Arm/Group Description:
All participants who received Duloxetine Combination therapy (Duloxetine 60 milligram [mg] plus Pregabalin 150 mg daily for Week 9 and Duloxetine 60 mg plus Pregabalin 300 mg daily for Weeks 10-16) or Pregabalin Combination therapy (Pregabalin 300 mg plus Duloxetine 30 mg daily for Week 9 and Pregabalin 300 mg plus Duloxetine 60 mg daily for Weeks 10-16) in Study Period III were pooled together.
All participants who received Duloxetine Monotherapy (Duloxetine 90 mg daily for Week 9 and 120 mg daily for Weeks 10-16) or Pregabalin Monotherapy (Pregabalin 450 mg daily for Week 9 and Pregabalin 600 mg daily for Weeks 10-16) in Study Period III were pooled together.
Overall Number of Participants Analyzed 165 163
Measure Type: Number
Unit of Measure: percentage of participants
52.1 39.3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination, Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.068
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.233
Confidence Interval (2-Sided) 95%
0.980 to 1.550
Estimation Comments [Not Specified]
5.Secondary Outcome
Title 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
Hide Description BPI Modified Short Form 24-Hour average pain item score is 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).
Time Frame Week 8 through Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug, and had Week 8 and at least one BPI measurements during Weeks 9-16 (Study Period III). Last observation carried forward (LOCF) principle was used.
Arm/Group Title Combination Monotherapy
Hide Arm/Group Description:
All participants who received Duloxetine Combination therapy (Duloxetine 60 milligram [mg] plus Pregabalin 150 mg daily for Week 9 and Duloxetine 60 mg plus Pregabalin 300 mg daily for Weeks 10-16) or Pregabalin Combination therapy (Pregabalin 300 mg plus Duloxetine 30 mg daily for Week 9 and Pregabalin 300 mg plus Duloxetine 60 mg daily for Weeks 10-16) in Study Period III were pooled together.
All participants who received Duloxetine Monotherapy (Duloxetine 90 mg daily for Week 9 and 120 mg daily for Weeks 10-16) or Pregabalin Monotherapy (Pregabalin 450 mg daily for Week 9 and Pregabalin 600 mg daily for Weeks 10-16) in Study Period III were pooled together.
Overall Number of Participants Analyzed 165 163
Measure Type: Number
Unit of Measure: percentage of participants
66.7 64.4
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination, Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.843
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.985
Confidence Interval (2-Sided) 95%
0.842 to 1.151
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Clinical Global Impression of Improvement (CGI-I) at Week 16 Endpoint
Hide Description Measures clinician's perception of participant improvement at the time of assessment compared with the start of treatment for Study Period III. Scores range from 1 (very much better) to 7 (very much worse). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment*visit, baseline*visit and treatment in Study Period II.
Time Frame Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug, and had at least one CGI-I measurement during Weeks 9-16 (Study Period III).
Arm/Group Title Combination Monotherapy
Hide Arm/Group Description:
All participants who received Duloxetine Combination therapy (Duloxetine 60 milligram [mg] plus Pregabalin 150 mg daily for Week 9 and Duloxetine 60 mg plus Pregabalin 300 mg daily for Weeks 10-16) or Pregabalin Combination therapy (Pregabalin 300 mg plus Duloxetine 30 mg daily for Week 9 and Pregabalin 300 mg plus Duloxetine 60 mg daily for Weeks 10-16) in Study Period III were pooled together.
All participants who received Duloxetine Monotherapy (Duloxetine 90 mg daily for Week 9 and 120 mg daily for Weeks 10-16) or Pregabalin Monotherapy (Pregabalin 450 mg daily for Week 9 and Pregabalin 600 mg daily for Weeks 10-16) in Study Period III were pooled together.
Overall Number of Participants Analyzed 169 170
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
2.286
(2.127 to 2.444)
2.359
(2.193 to 2.524)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination, Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.475
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -0.073
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Mean Change From Week 8 to Week 16 Endpoint on the Neuropathic Pain Symptom Inventory (NPSI) Questionnaire
Hide Description 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. A total score ranges from 0 to 100. Higher score indicates a greater intensity of pain. Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment*visit, baseline*visit and treatment in Study Period II.
Time Frame Week 8, Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug, and had Week 8 and at least one NPSI measurements during Weeks 9-16 (Study Period III).
Arm/Group Title Combination Monotherapy
Hide Arm/Group Description:
All participants who received Duloxetine Combination therapy (Duloxetine 60 milligram [mg] plus Pregabalin 150 mg daily for Week 9 and Duloxetine 60 mg plus Pregabalin 300 mg daily for Weeks 10-16) or Pregabalin Combination therapy (Pregabalin 300 mg plus Duloxetine 30 mg daily for Week 9 and Pregabalin 300 mg plus Duloxetine 60 mg daily for Weeks 10-16) in Study Period III were pooled together.
All participants who received Duloxetine Monotherapy (Duloxetine 90 mg daily for Week 9 and 120 mg daily for Weeks 10-16) or Pregabalin Monotherapy (Pregabalin 450 mg daily for Week 9 and Pregabalin 600 mg daily for Weeks 10-16) in Study Period III were pooled together.
Overall Number of Participants Analyzed 169 170
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-13.734
(-16.588 to -10.880)
-11.801
(-14.774 to -8.828)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination, Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.289
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -1.933
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Mean Change From Week 8 to Week 16 Endpoint in Sheehan Disability Scale (SDS)
Hide Description The SDS is completed by the participant and is used to assess the effect of the participant's symptoms on their 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 to 30 with higher values indicating greater disruption in the participant's work/social/family life. Least Squares (LS) Mean values are controlled for treatment, site, baseline value, treatment*site and treatment in Study Period II.
Time Frame Week 8, Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug, and had Week 8 and at least one SDS measurement during Weeks 9-16 (Study Period III). Last observation carried forward (LOCF) principle was used.
Arm/Group Title Combination Monotherapy
Hide Arm/Group Description:
All participants who received Duloxetine Combination therapy (Duloxetine 60 milligram [mg] plus Pregabalin 150 mg daily for Week 9 and Duloxetine 60 mg plus Pregabalin 300 mg daily for Weeks 10-16) or Pregabalin Combination therapy (Pregabalin 300 mg plus Duloxetine 30 mg daily for Week 9 and Pregabalin 300 mg plus Duloxetine 60 mg daily for Weeks 10-16) in Study Period III were pooled together.
All participants who received Duloxetine Monotherapy (Duloxetine 90 mg daily for Week 9 and 120 mg daily for Weeks 10-16) or Pregabalin Monotherapy (Pregabalin 450 mg daily for Week 9 and Pregabalin 600 mg daily for Weeks 10-16) in Study Period III were pooled together.
Overall Number of Participants Analyzed 108 106
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-2.625
(-3.589 to -1.661)
-2.431
(-3.410 to -1.453)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination, Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.780
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -0.193
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Mean Change From Week 8 to Week 16 Endpoint in Hospital Anxiety and Depression Scale (HADS)
Hide Description 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 represent 'normal.' Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment*visit, baseline*visit and treatment in Study Period II.
Time Frame Week 8, Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug, and had Week 8 and at least one HADS measurements during Weeks 9-16 (Study Period III).
Arm/Group Title Combination Monotherapy
Hide Arm/Group Description:
All participants who received Duloxetine Combination therapy (Duloxetine 60 milligram [mg] plus Pregabalin 150 mg daily for Week 9 and Duloxetine 60 mg plus Pregabalin 300 mg daily for Weeks 10-16) or Pregabalin Combination therapy (Pregabalin 300 mg plus Duloxetine 30 mg daily for Week 9 and Pregabalin 300 mg plus Duloxetine 60 mg daily for Weeks 10-16) in Study Period III were pooled together.
All participants who received Duloxetine Monotherapy (Duloxetine 90 mg daily for Week 9 and 120 mg daily for Weeks 10-16) or Pregabalin Monotherapy (Pregabalin 450 mg daily for Week 9 and Pregabalin 600 mg daily for Weeks 10-16) in Study Period III were pooled together.
Overall Number of Participants Analyzed 169 170
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Anxiety Subscale Score (n=169, 169)
-0.860
(-1.342 to -0.377)
-0.245
(-0.742 to 0.253)
Depression Subscale Score (n=168, 170)
-0.461
(-0.916 to -0.007)
-0.083
(-0.550 to 0.384)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination, Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.049
Comments P-value is for anxiety subscale score.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -0.615
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combination, Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.198
Comments P-value is for depression subscale score.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -0.378
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Resource Utilization (Number of Days Hospitalized, Number of Days of Sick Leave) Week 8 Through Week 16
Hide Description Data presented are the number of days hospitalized and work/school missed (sick leave) due to diabetic peripheral neuropathic pain (DPNP) during the last 8 weeks.
Time Frame Week 8 through Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug and provided information of hospitalization and sick leave during Weeks 9-16 (Study Period III).
Arm/Group Title Combination Monotherapy
Hide Arm/Group Description:
All participants who received Duloxetine Combination therapy (Duloxetine 60 milligram [mg] plus Pregabalin 150 mg daily for Week 9 and Duloxetine 60 mg plus Pregabalin 300 mg daily for Weeks 10-16) or Pregabalin Combination therapy (Pregabalin 300 mg plus Duloxetine 30 mg daily for Week 9 and Pregabalin 300 mg plus Duloxetine 60 mg daily for Weeks 10-16) in Study Period III were pooled together.
All participants who received Duloxetine Monotherapy (Duloxetine 90 mg daily for Week 9 and 120 mg daily for Weeks 10-16) or Pregabalin Monotherapy (Pregabalin 450 mg daily for Week 9 and Pregabalin 600 mg daily for Weeks 10-16) in Study Period III were pooled together.
Overall Number of Participants Analyzed 140 146
Mean (Standard Deviation)
Unit of Measure: days
Days hospitalized (n=140, 146) 0  (0.00) 0  (0.00)
Days of sick leave (n=41, 36) 0.1  (0.65) 0.4  (2.67)
11.Secondary Outcome
Title Patient Global Impression of Improvement (PGI-I) Score at Week 16 Endpoint
Hide Description Measures participant's perception of improvement at the time of assessment compared with the start of treatment for Study Period III. The score ranges from 1 (very much better) to 7 (very much worse). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment*visit, baseline*visit and treatment in Study Period II.
Time Frame Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug, and at least one PGI-I measurement during Weeks 9-16 (Study Period III).
Arm/Group Title Combination Monotherapy
Hide Arm/Group Description:
All participants who received Duloxetine Combination therapy (Duloxetine 60 milligram [mg] plus Pregabalin 150 mg daily for Week 9 and Duloxetine 60 mg plus Pregabalin 300 mg daily for Weeks 10-16) or Pregabalin Combination therapy (Pregabalin 300 mg plus Duloxetine 30 mg daily for Week 9 and Pregabalin 300 mg plus Duloxetine 60 mg daily for Weeks 10-16) in Study Period III were pooled together.
All participants who received Duloxetine Monotherapy (Duloxetine 90 mg daily for Week 9 and 120 mg daily for Weeks 10-16) or Pregabalin Monotherapy (Pregabalin 450 mg daily for Week 9 and Pregabalin 600 mg daily for Weeks 10-16) in Study Period III were pooled together.
Overall Number of Participants Analyzed 169 170
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
2.256
(2.085 to 2.426)
2.350
(2.174 to 2.526)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination, Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.385
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -0.095
Estimation Comments [Not Specified]
12.Secondary Outcome
Title Mean Change in Blood Pressure (BP) From Week 8 to Week 16 Endpoint
Hide Description Least Squares (LS) mean values are controlled for treatment, site, baseline value, treatment*site and treatment in Study Period II.
Time Frame Week 8, Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug, and had Week 8 and at least one BP measurement during Weeks 9-16 (Study Period III). Last observation carried forward (LOCF) principle was used.
Arm/Group Title Combination Monotherapy
Hide Arm/Group Description:
All participants who received Duloxetine Combination therapy (Duloxetine 60 milligram [mg] plus Pregabalin 150 mg daily for Week 9 and Duloxetine 60 mg plus Pregabalin 300 mg daily for Weeks 10-16) or Pregabalin Combination therapy (Pregabalin 300 mg plus Duloxetine 30 mg daily for Week 9 and Pregabalin 300 mg plus Duloxetine 60 mg daily for Weeks 10-16) in Study Period III were pooled together.
All participants who received Duloxetine Monotherapy (Duloxetine 90 mg daily for Week 9 and 120 mg daily for Weeks 10-16) or Pregabalin Monotherapy (Pregabalin 450 mg daily for Week 9 and Pregabalin 600 mg daily for Weeks 10-16) in Study Period III were pooled together.
Overall Number of Participants Analyzed 169 168
Least Squares Mean (95% Confidence Interval)
Unit of Measure: millimeter of mercury (mm Hg)
Systolic BP
-1.206
(-3.202 to 0.790)
0.124
(-1.891 to 2.138)
Diastolic BP
-0.555
(-1.865 to 0.755)
-0.551
(-1.873 to 0.771)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination, Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.354
Comments P-value is for systolic BP.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -1.329
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Combination, Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.997
Comments P-value is for diastolic BP.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -0.003
Estimation Comments [Not Specified]
13.Secondary Outcome
Title Mean Change in Heart Rate From Week 8 to Week 16 Endpoint
Hide Description Least Squares (LS) mean values are controlled for treatment, site, baseline value, treatment*site and treatment in Study Period II.
Time Frame Week 8, Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug, and had Week 8 and at least one heart rate measurement during Weeks 9- 16 (Study Period III). Last observation carried forward (LOCF) principle was used.
Arm/Group Title Combination Monotherapy
Hide Arm/Group Description:
All participants who received Duloxetine Combination therapy (Duloxetine 60 milligram [mg] plus Pregabalin 150 mg daily for Week 9 and Duloxetine 60 mg plus Pregabalin 300 mg daily for Weeks 10-16) or Pregabalin Combination therapy (Pregabalin 300 mg plus Duloxetine 30 mg daily for Week 9 and Pregabalin 300 mg plus Duloxetine 60 mg daily for Weeks 10-16) in Study Period III were pooled together.
All participants who received Duloxetine Monotherapy (Duloxetine 90 mg daily for Week 9 and 120 mg daily for Weeks 10-16) or Pregabalin Monotherapy (Pregabalin 450 mg daily for Week 9 and Pregabalin 600 mg daily for Weeks 10-16) in Study Period III were pooled together.
Overall Number of Participants Analyzed 169 168
Least Squares Mean (95% Confidence Interval)
Unit of Measure: beats per minute (bpm)
1.025
(-0.326 to 2.376)
1.968
(0.602 to 3.333)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination, Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.332
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -0.942
Estimation Comments [Not Specified]
14.Secondary Outcome
Title Number of Participants With Treatment Emergent Adverse Events (TEAEs) Between Week 8 and Week 16 Endpoint
Hide Description TEAEs in Study Period III are events that began or worsened after Week 8 compared with the period before Week 8.
Time Frame Week 8 through Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug during Weeks 9-16 (Study Period III).
Arm/Group Title Combination Monotherapy
Hide Arm/Group Description:
All participants who received Duloxetine Combination therapy (Duloxetine 60 milligram [mg] plus Pregabalin 150 mg daily for Week 9 and Duloxetine 60 mg plus Pregabalin 300 mg daily for Weeks 10-16) or Pregabalin Combination therapy (Pregabalin 300 mg plus Duloxetine 30 mg daily for Week 9 and Pregabalin 300 mg plus Duloxetine 60 mg daily for Weeks 10-16) in Study Period III were pooled together.
All participants who received Duloxetine Monotherapy (Duloxetine 90 mg daily for Week 9 and 120 mg daily for Weeks 10-16) or Pregabalin Monotherapy (Pregabalin 450 mg daily for Week 9 and Pregabalin 600 mg daily for Weeks 10-16) in Study Period III were pooled together.
Overall Number of Participants Analyzed 169 170
Measure Type: Number
Unit of Measure: participants
62 57
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination, Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.571
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
15.Secondary Outcome
Title Number of Participants Who Discontinued From Study Between Week 8 and Week 16 Endpoint
Hide Description [Not Specified]
Time Frame Week 8 through Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug during Weeks 9-16 (Study Period III).
Arm/Group Title Combination Monotherapy
Hide Arm/Group Description:
All participants who received Duloxetine Combination therapy (Duloxetine 60 milligram [mg] plus Pregabalin 150 mg daily for Week 9 and Duloxetine 60 mg plus Pregabalin 300 mg daily for Weeks 10-16) or Pregabalin Combination therapy (Pregabalin 300 mg plus Duloxetine 30 mg daily for Week 9 and Pregabalin 300 mg plus Duloxetine 60 mg daily for Weeks 10-16) in Study Period III were pooled together.
All participants who received Duloxetine Monotherapy (Duloxetine 90 mg daily for Week 9 and 120 mg daily for Weeks 10-16) or Pregabalin Monotherapy (Pregabalin 450 mg daily for Week 9 and Pregabalin 600 mg daily for Weeks 10-16) in Study Period III were pooled together.
Overall Number of Participants Analyzed 169 170
Measure Type: Number
Unit of Measure: participants
21 21
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Combination, Monotherapy
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.000
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
16.Other Pre-specified Outcome
Title Mean Change From Baseline to Week 8 Endpoint in 24 Hour Average Pain Item Score on the Brief Pain Inventory (BPI) Modified Short Form
Hide Description BPI Modified Short Form 24-Hour average pain item score is 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). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment*visit and baseline*visit.
Time Frame Baseline, Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug, and had baseline and at least one post-baseline BPI measurements during Weeks 1-8 (Study Period II).
Arm/Group Title Duloxetine Pregabalin
Hide Arm/Group Description:
Duloxetine 30 milligram (mg) daily for Week 1 and 60 mg daily for Weeks 2-8 in Study Period II.
Pregabalin 150 mg daily for Week 1 and 300 mg daily for Weeks 2-8 in Study Period II.
Overall Number of Participants Analyzed 401 401
Least Squares Mean (90% Confidence Interval)
Unit of Measure: units on a scale
-2.295
(-2.508 to -2.083)
-1.682
(-1.893 to -1.471)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Duloxetine, Pregabalin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Differences (Final Values)
Estimated Value -0.614
Estimation Comments [Not Specified]
17.Other Pre-specified Outcome
Title 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
Hide Description BPI Modified Short Form 24-Hour average pain item score is 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).
Time Frame Baseline through Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug, and had baseline and at least one post-baseline BPI measurements during Weeks 1-8 (Study Period II). Last observation carried forward (LOCF) principle was used.
Arm/Group Title Duloxetine Pregabalin
Hide Arm/Group Description:
Duloxetine 30 milligram (mg) daily for Week 1 and 60 mg daily for Weeks 2-8 in Study Period II.
Pregabalin 150 mg daily for Week 1 and 300 mg daily for Weeks 2-8 in Study Period II.
Overall Number of Participants Analyzed 375 374
Measure Type: Number
Unit of Measure: percentage of participants
52.0 36.9
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Duloxetine, Pregabalin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.431
Confidence Interval (2-Sided) 95%
1.233 to 1.662
Estimation Comments [Not Specified]
18.Other Pre-specified Outcome
Title 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
Hide Description BPI Modified Short Form 24-Hour average pain item score is 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).
Time Frame Baseline through Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug, and had baseline and at least one post-baseline BPI measurements during Weeks 1-8 (Study Period II). Last observation carried forward (LOCF) principle was used.
Arm/Group Title Duloxetine Pregabalin
Hide Arm/Group Description:
Duloxetine 30 milligram (mg) daily for Week 1 and 60 mg daily for Weeks 2-8 in Study Period II.
Pregabalin 150 mg daily for Week 1 and 300 mg daily for Weeks 2-8 in Study Period II.
Overall Number of Participants Analyzed 375 374
Measure Type: Number
Unit of Measure: percentage of participants
40.3 27.8
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Duloxetine, Pregabalin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.467
Confidence Interval (2-Sided) 95%
1.214 to 1.771
Estimation Comments [Not Specified]
19.Other Pre-specified Outcome
Title 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
Hide Description BPI Modified Short Form 24-Hour average pain item score is 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).
Time Frame Baseline through Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug, and had baseline and at least one post-baseline BPI measurements during Weeks 1-8 (Study Period II). Last observation carried forward (LOCF) principle was used.
Arm/Group Title Duloxetine Pregabalin
Hide Arm/Group Description:
Duloxetine 30 milligram (mg) daily for Week 1 and 60 mg daily for Weeks 2-8 in Study Period II.
Pregabalin 150 mg daily for Week 1 and 300 mg daily for Weeks 2-8 in Study Period II.
Overall Number of Participants Analyzed 375 374
Measure Type: Number
Unit of Measure: percentage of participants
57.1 45.7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Duloxetine, Pregabalin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.279
Confidence Interval (2-Sided) 95%
1.125 to 1.456
Estimation Comments [Not Specified]
20.Other Pre-specified Outcome
Title Clinical Global Impression of Improvement (CGI-I) at Week 8 Endpoint
Hide Description Measures clinician's perception of participant improvement at the time of assessment compared with the start of treatment. Scores range from 1 (very much better) to 7 (very much worse). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, visit, and treatment*visit.
Time Frame Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug, and had at least one post-baseline CGI-I measurement during Weeks 1-8 (Study Period II).
Arm/Group Title Duloxetine Pregabalin
Hide Arm/Group Description:
Duloxetine 30 milligram (mg) daily for Week 1 and 60 mg daily for Weeks 2-8 in Study Period II.
Pregabalin 150 mg daily for Week 1 and 300 mg daily for Weeks 2-8 in Study Period II.
Overall Number of Participants Analyzed 400 401
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
2.508
(2.396 to 2.619)
2.848
(2.737 to 2.959)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Duloxetine, Pregabalin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -0.341
Estimation Comments [Not Specified]
21.Other Pre-specified Outcome
Title Mean Change From Baseline to Week 8 Endpoint on the Neuropathic Pain Symptom Inventory (NPSI) Questionnaire
Hide Description 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. A total score ranges from 0 to 100. Higher score indicates a greater intensity of pain. Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment*visit and baseline*visit.
Time Frame Baseline, Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug, and had baseline and at least one post-baseline NPSI measurements during Weeks 1-8 (Study Period II).
Arm/Group Title Duloxetine Pregabalin
Hide Arm/Group Description:
Duloxetine 30 milligram (mg) daily for Week 1 and 60 mg daily for Weeks 2-8 in Study Period II.
Pregabalin 150 mg daily for Week 1 and 300 mg daily for Weeks 2-8 in Study Period II.
Overall Number of Participants Analyzed 399 397
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-19.442
(-21.366 to -17.518)
-14.684
(-16.606 to -12.762)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Duloxetine, Pregabalin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -4.758
Estimation Comments [Not Specified]
22.Other Pre-specified Outcome
Title Mean Change From Baseline to Week 8 Endpoint in Sheehan Disability Scale (SDS)
Hide Description The SDS is completed by the participant and is used to assess the effect of the participant's symptoms on their 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 to 30 with higher values indicating greater disruption in the participant's work/social/family life. Least Squares (LS) mean values are controlled for treatment, site, baseline value and treatment*site.
Time Frame Baseline, Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug, and had baseline and at least one post-baseline SDS measurement during Weeks 1-8 (Study Period II). Last observation carried forward (LOCF) principle was used.
Arm/Group Title Duloxetine Pregabalin
Hide Arm/Group Description:
Duloxetine 30 milligram (mg) daily for Week 1 and 60 mg daily for Weeks 2-8 in Study Period II.
Pregabalin 150 mg daily for Week 1 and 300 mg daily for Weeks 2-8 in Study Period II.
Overall Number of Participants Analyzed 235 234
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-4.387
(-5.185 to -3.590)
-3.367
(-4.133 to -2.601)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Duloxetine, Pregabalin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.071
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -1.020
Estimation Comments [Not Specified]
23.Other Pre-specified Outcome
Title Mean Change From Baseline to Week 8 Endpoint in Hospital Anxiety and Depression Scale (HADS)
Hide Description 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 represent 'normal.' Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment*visit and baseline*visit.
Time Frame Baseline, Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug, and had baseline and at least one post-baseline HADS measurements during Weeks 1-8 (Study Period II).
Arm/Group Title Duloxetine Pregabalin
Hide Arm/Group Description:
Duloxetine 30 milligram (mg) daily for Week 1 and 60 mg daily for Weeks 2-8 in Study Period II.
Pregabalin 150 mg daily for Week 1 and 300 mg daily for Weeks 2-8 in Study Period II.
Overall Number of Participants Analyzed 399 402
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Anxiety Subscale Score (n= 398, 400)
-1.991
(-2.301 to -1.681)
-1.433
(-1.739 to -1.127)
Depression Subscale Score
-1.064
(-1.351 to -0.778)
-0.642
(-0.925 to -0.359)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Duloxetine, Pregabalin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.008
Comments P-value is for anxiety subscale score.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -0.558
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Duloxetine, Pregabalin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.031
Comments p-value is for depression subscale score.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -0.423
Estimation Comments [Not Specified]
24.Other Pre-specified Outcome
Title Resource Utilization (Number of Days Hospitalized, Number of Days of Sick Leave) Baseline Through Week 8
Hide Description Data presented are the number of days hospitalized and work/school missed (sick leave) due to diabetic peripheral neuropathic pain (DPNP) during the last 8 weeks.
Time Frame Baseline through Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug and provided information of hospitalization and sick leave during Weeks 1-8 (Study Period II).
Arm/Group Title Duloxetine Pregabalin
Hide Arm/Group Description:
Duloxetine 30 milligram (mg) daily for Week 1 and 60 mg daily for Weeks 2-8 in Study Period II.
Pregabalin 150 mg daily for Week 1 and 300 mg daily for Weeks 2-8 in Study Period II.
Overall Number of Participants Analyzed 314 319
Mean (Standard Deviation)
Unit of Measure: days
Days hospitalized 0  (0.00) 0  (0.00)
Days of sick leave (n=108, 101) 1.9  (8.34) 0.3  (2.04)
25.Other Pre-specified Outcome
Title Average Number of Hours Worked for Pay Per Week Baseline Through Week 8
Hide Description Data presented are the average number of hours worked for pay per week during the last 8 weeks.
Time Frame Baseline through Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug and had worked for pay during Weeks 1-8 (Study Period II).
Arm/Group Title Duloxetine Pregabalin
Hide Arm/Group Description:
Duloxetine 30 milligram (mg) daily for Week 1 and 60 mg daily for Weeks 2-8 in Study Period II.
Pregabalin 150 mg daily for Week 1 and 300 mg daily for Weeks 2-8 in Study Period II.
Overall Number of Participants Analyzed 102 100
Mean (Standard Deviation)
Unit of Measure: hours
37.6  (18.72) 42.4  (15.52)
26.Other Pre-specified Outcome
Title Average Number of Hours Worked for Pay Per Week Week 8 Through Week 16
Hide Description Data presented are the average number of hours worked for pay per week during the last 8 weeks.
Time Frame Week 8 through Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug and had worked for pay during Weeks 9-16 (Study Period III).
Arm/Group Title Combination Monotherapy
Hide Arm/Group Description:
All participants who received Duloxetine Combination therapy (Duloxetine 60 milligram [mg] plus Pregabalin 150 mg daily for Week 9 and Duloxetine 60 mg plus Pregabalin 300 mg daily for Weeks 10-16) or Pregabalin Combination therapy (Pregabalin 300 mg plus Duloxetine 30 mg daily for Week 9 and Pregabalin 300 mg plus Duloxetine 60 mg daily for Weeks 10-16) in Study Period III were pooled together.
All participants who received Duloxetine Monotherapy (Duloxetine 90 mg daily for Week 9 and 120 mg daily for Weeks 10-16) or Pregabalin Monotherapy (Pregabalin 450 mg daily for Week 9 and Pregabalin 600 mg daily for Weeks 10-16) in Study Period III were pooled together.
Overall Number of Participants Analyzed 42 36
Mean (Standard Deviation)
Unit of Measure: hours
39.8  (15.98) 34.7  (21.46)
27.Other Pre-specified Outcome
Title Patient Global Impression of Improvement (PGI-I) Score at Week 8 Endpoint
Hide Description Measures participant's perception of improvement at the time of assessment compared with the start of treatment. The score ranges from 1 (very much better) to 7 (very much worse). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, visit, and treatment*visit.
Time Frame Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug, and at least one post-baseline PGI-I measurement during Weeks 1-8 (Study Period II).
Arm/Group Title Duloxetine Pregabalin
Hide Arm/Group Description:
Duloxetine 30 milligram (mg) daily for Week 1 and 60 mg daily for Weeks 2-8 in Study Period II.
Pregabalin 150 mg daily for Week 1 and 300 mg daily for Weeks 2-8 in Study Period II.
Overall Number of Participants Analyzed 401 403
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
2.601
(2.477 to 2.725)
2.944
(2.821 to 3.067)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Duloxetine, Pregabalin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -0.343
Estimation Comments [Not Specified]
28.Other Pre-specified Outcome
Title Mean Change in Blood Pressure (BP) From Baseline to Week 8 Endpoint
Hide Description Least Squares (LS) mean values are controlled for treatment, site, baseline value, and treatment*site.
Time Frame Baseline, Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug, and had baseline and at least one post-baseline BP measurement during Week 1-8 (Study Period II). Last observation carried forward (LOCF) principle was used.
Arm/Group Title Duloxetine Pregabalin
Hide Arm/Group Description:
Duloxetine 30 milligram (mg) daily for Week 1 and 60 mg daily for Weeks 2-8 in Study Period II.
Pregabalin 150 mg daily for Week 1 and 300 mg daily for Weeks 2-8 in Study Period II.
Overall Number of Participants Analyzed 386 389
Least Squares Mean (95% Confidence Interval)
Unit of Measure: millimeter of mercury (mm Hg)
Systolic BP
-3.702
(-5.216 to -2.188)
-1.682
(-3.191 to -0.174)
Diastolic BP
-0.816
(-1.766 to 0.134)
-0.951
(-1.898 to -0.003)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Duloxetine, Pregabalin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.064
Comments P-value is for systolic BP.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value -2.020
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Duloxetine, Pregabalin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.843
Comments P-value is for diastolic BP.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value 0.135
Estimation Comments [Not Specified]
29.Other Pre-specified Outcome
Title Mean Change in Heart Rate From Baseline to Week 8 Endpoint
Hide Description Least Squares (LS) mean values are controlled for treatment, site, baseline value, and treatment*site.
Time Frame Baseline, Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug, and had baseline and at least one post-baseline heart rate measurement during Weeks 1-8 (Study Period II). Last observation carried forward (LOCF) principle was used.
Arm/Group Title Duloxetine Pregabalin
Hide Arm/Group Description:
Duloxetine 30 milligram (mg) daily for Week 1 and 60 mg daily for Weeks 2-8 in Study Period II.
Pregabalin 150 mg daily for Week 1 and 300 mg daily for Weeks 2-8 in Study Period II.
Overall Number of Participants Analyzed 384 389
Least Squares Mean (95% Confidence Interval)
Unit of Measure: beats per minute (bpm)
0.839
(-0.062 to 1.741)
-2.478
(-3.369 to -1.588)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Duloxetine, Pregabalin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
Estimated Value 3.317
Estimation Comments [Not Specified]
30.Other Pre-specified Outcome
Title Number of Participants With Treatment Emergent Adverse Events (TEAE) Between Baseline and Week 8 Endpoint
Hide Description TEAEs in Study Period II are events that began or worsened after Week 0 compared with the period before Week 0.
Time Frame Baseline through Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug during Weeks 1-8 (Study Period II).
Arm/Group Title Duloxetine Pregabalin
Hide Arm/Group Description:
Duloxetine 30 milligram (mg) daily for Week 1 and 60 mg daily for Weeks 2-8 in Study Period II.
Pregabalin 150 mg daily for Week 1 and 300 mg daily for Weeks 2-8 in Study Period II.
Overall Number of Participants Analyzed 401 403
Measure Type: Number
Unit of Measure: participants
223 232
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Duloxetine, Pregabalin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.618
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
31.Other Pre-specified Outcome
Title Number of Participants Who Discontinued From Study Between Baseline and Week 8 Endpoint
Hide Description [Not Specified]
Time Frame Baseline through Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants who received at least one dose of study drug during Weeks 1-8 (Study Period II).
Arm/Group Title Duloxetine Pregabalin
Hide Arm/Group Description:
Duloxetine 30 milligram (mg) daily for Week 1 and 60 mg daily for Weeks 2-8 in Study Period II.
Pregabalin 150 mg daily for Week 1 and 300 mg daily for Weeks 2-8 in Study Period II.
Overall Number of Participants Analyzed 401 403
Measure Type: Number
Unit of Measure: participants
68 70
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Duloxetine, Pregabalin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.744
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Duloxetine (SP II) Pregabalin (SP II) Duloxetine (SP III) DLX + PGB (SP III) PGB + DLX (SP III) Pregabalin (SP III)
Hide Arm/Group Description Duloxetine 30 milligram (mg) daily for Week 1 and 60 mg daily for Weeks 2-8 in Study Period II (SP II). Pregabalin 150 mg daily for Week 1 and 300 mg daily for Weeks 2-8 in Study Period II. Duloxetine 90 mg daily for Week 9 and 120 mg daily for Weeks 10-16 in Study Period III (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. 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 450 mg daily for Week 9 and Pregabalin 600 mg daily for Weeks 10-16 in Study Period III.
All-Cause Mortality
Duloxetine (SP II) Pregabalin (SP II) Duloxetine (SP III) DLX + PGB (SP III) PGB + DLX (SP III) Pregabalin (SP III)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Duloxetine (SP II) Pregabalin (SP II) Duloxetine (SP III) DLX + PGB (SP III) PGB + DLX (SP III) Pregabalin (SP III)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   12/401 (2.99%)      13/403 (3.23%)      3/73 (4.11%)      3/75 (4.00%)      5/94 (5.32%)      2/97 (2.06%)    
Cardiac disorders             
Cardiac failure  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 1/97 (1.03%)  1
Gastrointestinal disorders             
Abdominal pain  1  0/401 (0.00%)  0 1/403 (0.25%)  1 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Abdominal pain upper  1  0/401 (0.00%)  0 1/403 (0.25%)  1 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Constipation  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 1/97 (1.03%)  1
Duodenal ulcer  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 1/94 (1.06%)  1 0/97 (0.00%)  0
Duodenitis  1  1/401 (0.25%)  1 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Flatulence  1  0/401 (0.00%)  0 1/403 (0.25%)  1 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Gastritis  1  1/401 (0.25%)  1 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Nausea  1  0/401 (0.00%)  0 1/403 (0.25%)  1 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Vomiting  1  0/401 (0.00%)  0 1/403 (0.25%)  1 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
General disorders             
Chest pain  1  1/401 (0.25%)  1 2/403 (0.50%)  2 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Hernia  1  1/401 (0.25%)  1 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Infections and infestations             
Bronchopneumonia  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 1/94 (1.06%)  1 0/97 (0.00%)  0
Cellulitis  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 1/97 (1.03%)  1
Erysipelas  1  0/401 (0.00%)  0 1/403 (0.25%)  1 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Gastroenteritis  1  0/401 (0.00%)  0 0/403 (0.00%)  0 1/73 (1.37%)  1 0/75 (0.00%)  0 1/94 (1.06%)  1 0/97 (0.00%)  0
Gastrointestinal infection  1  1/401 (0.25%)  1 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Pilonidal cyst  1  1/401 (0.25%)  1 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Pneumonia  1  0/401 (0.00%)  0 1/403 (0.25%)  1 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Respiratory tract infection viral  1  1/401 (0.25%)  1 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Viral infection  1  0/401 (0.00%)  0 1/403 (0.25%)  1 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Injury, poisoning and procedural complications             
Brain contusion  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 1/94 (1.06%)  1 0/97 (0.00%)  0
Fall  1  0/401 (0.00%)  0 0/403 (0.00%)  0 1/73 (1.37%)  1 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Hip fracture  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 1/75 (1.33%)  1 0/94 (0.00%)  0 0/97 (0.00%)  0
Investigations             
Haemoglobin decreased  1  1/401 (0.25%)  1 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Hepatitis c antibody positive  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 1/94 (1.06%)  1 0/97 (0.00%)  0
Metabolism and nutrition disorders             
Diabetes mellitus  1  1/401 (0.25%)  1 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Gout  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 1/94 (1.06%)  1 0/97 (0.00%)  0
Hyperglycaemia  1  0/401 (0.00%)  0 3/403 (0.74%)  3 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Musculoskeletal and connective tissue disorders             
Bursitis  1  0/401 (0.00%)  0 1/403 (0.25%)  1 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Rotator cuff syndrome  1  0/401 (0.00%)  0 1/403 (0.25%)  1 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)             
Large intestine carcinoma  1  1/401 (0.25%)  1 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Thyroid cancer  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 1/94 (1.06%)  1 0/97 (0.00%)  0
Nervous system disorders             
Ischaemic stroke  1  0/401 (0.00%)  0 1/403 (0.25%)  1 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Myelitis transverse  1  0/401 (0.00%)  0 1/403 (0.25%)  1 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Presyncope  1  1/401 (0.25%)  1 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Psychiatric disorders             
Confusional state  1  1/401 (0.25%)  1 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Disorientation  1  1/401 (0.25%)  1 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Hallucination  1  1/401 (0.25%)  1 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Suicidal ideation  1  0/401 (0.00%)  0 2/403 (0.50%)  2 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Skin and subcutaneous tissue disorders             
Skin ulcer  1  0/401 (0.00%)  0 1/403 (0.25%)  1 0/73 (0.00%)  0 1/75 (1.33%)  1 0/94 (0.00%)  0 0/97 (0.00%)  0
Vascular disorders             
Deep vein thrombosis  1  0/401 (0.00%)  0 0/403 (0.00%)  0 1/73 (1.37%)  1 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Hypertension  1  1/401 (0.25%)  1 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Hypertensive crisis  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 1/75 (1.33%)  1 0/94 (0.00%)  0 0/97 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MEDDRA (13.1)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
Duloxetine (SP II) Pregabalin (SP II) Duloxetine (SP III) DLX + PGB (SP III) PGB + DLX (SP III) Pregabalin (SP III)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   216/401 (53.87%)      225/403 (55.83%)      18/73 (24.66%)      21/75 (28.00%)      39/94 (41.49%)      37/97 (38.14%)    
Blood and lymphatic system disorders             
Anaemia  1  0/401 (0.00%)  0 2/403 (0.50%)  2 0/73 (0.00%)  0 1/75 (1.33%)  1 0/94 (0.00%)  0 0/97 (0.00%)  0
Thrombocytopenia  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 1/94 (1.06%)  1 0/97 (0.00%)  0
Cardiac disorders             
Angina pectoris  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 1/97 (1.03%)  1
Cardiac failure chronic  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 1/97 (1.03%)  1
Palpitations  1  4/401 (1.00%)  4 1/403 (0.25%)  1 0/73 (0.00%)  0 0/75 (0.00%)  0 1/94 (1.06%)  1 0/97 (0.00%)  0
Tachycardia  1  4/401 (1.00%)  4 1/403 (0.25%)  1 0/73 (0.00%)  0 1/75 (1.33%)  1 0/94 (0.00%)  0 0/97 (0.00%)  0
Ear and labyrinth disorders             
Hearing impaired  1  0/401 (0.00%)  0 0/403 (0.00%)  0 1/73 (1.37%)  1 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Tinnitus  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 1/94 (1.06%)  1 0/97 (0.00%)  0
Vertigo  1  8/401 (2.00%)  8 26/403 (6.45%)  27 1/73 (1.37%)  1 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Endocrine disorders             
Hyperthyroidism  1  1/401 (0.25%)  1 0/403 (0.00%)  0 0/73 (0.00%)  0 1/75 (1.33%)  1 0/94 (0.00%)  0 0/97 (0.00%)  0
Eye disorders             
Eyelid oedema  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 1/97 (1.03%)  1
Vision blurred  1  5/401 (1.25%)  6 3/403 (0.74%)  3 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Visual impairment  1  2/401 (0.50%)  2 1/403 (0.25%)  1 1/73 (1.37%)  1 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Gastrointestinal disorders             
Abdominal discomfort  1  2/401 (0.50%)  2 0/403 (0.00%)  0 1/73 (1.37%)  1 0/75 (0.00%)  0 2/94 (2.13%)  2 0/97 (0.00%)  0
Abdominal pain upper  1  5/401 (1.25%)  5 3/403 (0.74%)  3 0/73 (0.00%)  0 0/75 (0.00%)  0 1/94 (1.06%)  1 0/97 (0.00%)  0
Aphthous stomatitis  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 1/97 (1.03%)  1
Chapped lips  1  0/401 (0.00%)  0 0/403 (0.00%)  0 1/73 (1.37%)  1 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Constipation  1  16/401 (3.99%)  17 13/403 (3.23%)  14 1/73 (1.37%)  1 0/75 (0.00%)  0 1/94 (1.06%)  1 1/97 (1.03%)  1
Diarrhoea  1  14/401 (3.49%)  14 11/403 (2.73%)  12 0/73 (0.00%)  0 0/75 (0.00%)  0 1/94 (1.06%)  1 3/97 (3.09%)  3
Dry mouth  1  16/401 (3.99%)  17 9/403 (2.23%)  11 2/73 (2.74%)  2 1/75 (1.33%)  1 2/94 (2.13%)  2 0/97 (0.00%)  0
Dyspepsia  1  4/401 (1.00%)  4 4/403 (0.99%)  4 0/73 (0.00%)  0 0/75 (0.00%)  0 1/94 (1.06%)  1 0/97 (0.00%)  0
Flatulence  1  4/401 (1.00%)  4 5/403 (1.24%)  5 0/73 (0.00%)  0 0/75 (0.00%)  0 1/94 (1.06%)  1 0/97 (0.00%)  0
Gastritis  1  5/401 (1.25%)  5 1/403 (0.25%)  1 0/73 (0.00%)  0 0/75 (0.00%)  0 1/94 (1.06%)  1 0/97 (0.00%)  0
Gastrooesophageal reflux disease  1  2/401 (0.50%)  2 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 1/94 (1.06%)  1 0/97 (0.00%)  0
Nausea  1  57/401 (14.21%)  61 25/403 (6.20%)  26 2/73 (2.74%)  2 1/75 (1.33%)  1 4/94 (4.26%)  4 1/97 (1.03%)  1
Paraesthesia oral  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 1/94 (1.06%)  1 0/97 (0.00%)  0
Toothache  1  0/401 (0.00%)  0 1/403 (0.25%)  1 1/73 (1.37%)  1 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Vomiting  1  12/401 (2.99%)  13 6/403 (1.49%)  7 0/73 (0.00%)  0 0/75 (0.00%)  0 4/94 (4.26%)  4 1/97 (1.03%)  1
General disorders             
Asthenia  1  6/401 (1.50%)  8 7/403 (1.74%)  7 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 1/97 (1.03%)  1
Chest discomfort  1  1/401 (0.25%)  1 0/403 (0.00%)  0 1/73 (1.37%)  1 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Chest pain  1  2/401 (0.50%)  2 3/403 (0.74%)  3 1/73 (1.37%)  1 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Discomfort  1  2/401 (0.50%)  2 1/403 (0.25%)  1 1/73 (1.37%)  1 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Facial pain  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 1/75 (1.33%)  1 0/94 (0.00%)  0 0/97 (0.00%)  0
Fatigue  1  18/401 (4.49%)  18 13/403 (3.23%)  13 2/73 (2.74%)  2 1/75 (1.33%)  1 2/94 (2.13%)  2 1/97 (1.03%)  1
Gait disturbance  1  1/401 (0.25%)  1 4/403 (0.99%)  4 0/73 (0.00%)  0 1/75 (1.33%)  1 0/94 (0.00%)  0 0/97 (0.00%)  0
Oedema  1  1/401 (0.25%)  1 7/403 (1.74%)  7 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 1/97 (1.03%)  1
Oedema peripheral  1  4/401 (1.00%)  5 21/403 (5.21%)  23 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 2/97 (2.06%)  2
Pain  1  2/401 (0.50%)  2 2/403 (0.50%)  2 0/73 (0.00%)  0 1/75 (1.33%)  1 0/94 (0.00%)  0 0/97 (0.00%)  0
Therapeutic response unexpected  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 1/97 (1.03%)  1
Infections and infestations             
Bronchitis  1  0/401 (0.00%)  0 3/403 (0.74%)  3 0/73 (0.00%)  0 1/75 (1.33%)  1 1/94 (1.06%)  1 1/97 (1.03%)  1
Cystitis  1  0/401 (0.00%)  0 1/403 (0.25%)  1 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 1/97 (1.03%)  1
Erysipelas  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 1/94 (1.06%)  1 0/97 (0.00%)  0
Gastroenteritis  1  1/401 (0.25%)  1 1/403 (0.25%)  1 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 1/97 (1.03%)  1
Gastroenteritis viral  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 1/75 (1.33%)  1 0/94 (0.00%)  0 0/97 (0.00%)  0
Infection  1  0/401 (0.00%)  0 1/403 (0.25%)  1 0/73 (0.00%)  0 1/75 (1.33%)  1 0/94 (0.00%)  0 0/97 (0.00%)  0
Influenza  1  1/401 (0.25%)  1 1/403 (0.25%)  1 0/73 (0.00%)  0 1/75 (1.33%)  1 0/94 (0.00%)  0 1/97 (1.03%)  1
Nasopharyngitis  1  3/401 (0.75%)  3 5/403 (1.24%)  5 0/73 (0.00%)  0 0/75 (0.00%)  0 2/94 (2.13%)  3 1/97 (1.03%)  1
Onychomycosis  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 1/75 (1.33%)  1 0/94 (0.00%)  0 0/97 (0.00%)  0
Pharyngitis  1  0/401 (0.00%)  0 2/403 (0.50%)  2 1/73 (1.37%)  1 1/75 (1.33%)  1 1/94 (1.06%)  1 0/97 (0.00%)  0
Pneumonia  1  1/401 (0.25%)  1 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 1/94 (1.06%)  1 0/97 (0.00%)  0
Tooth abscess  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 1/97 (1.03%)  1
Upper respiratory tract infection  1  1/401 (0.25%)  1 2/403 (0.50%)  2 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 1/97 (1.03%)  1
Urinary tract infection  1  0/401 (0.00%)  0 2/403 (0.50%)  2 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 1/97 (1.03%)  1
Vaginal infection  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 1/97 (1.03%)  2
Injury, poisoning and procedural complications             
Concussion  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 1/94 (1.06%)  1 0/97 (0.00%)  0
Contusion  1  0/401 (0.00%)  0 3/403 (0.74%)  3 0/73 (0.00%)  0 1/75 (1.33%)  1 0/94 (0.00%)  0 1/97 (1.03%)  1
Excoriation  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 1/97 (1.03%)  2
Fall  1  1/401 (0.25%)  1 2/403 (0.50%)  2 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 1/97 (1.03%)  1
Foot fracture  1  1/401 (0.25%)  1 0/403 (0.00%)  0 1/73 (1.37%)  1 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Laceration  1  1/401 (0.25%)  1 0/403 (0.00%)  0 1/73 (1.37%)  1 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Ligament sprain  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 1/97 (1.03%)  1
Muscle rupture  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 1/97 (1.03%)  1
Subcutaneous haematoma  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 1/75 (1.33%)  1 0/94 (0.00%)  0 0/97 (0.00%)  0
Investigations             
Blood creatine phosphokinase increased  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 2/97 (2.06%)  2
Gamma-glutamyltransferase increased  1  1/401 (0.25%)  1 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 1/94 (1.06%)  1 0/97 (0.00%)  0
Hepatic enzyme increased  1  0/401 (0.00%)  0 0/403 (0.00%)  0 1/73 (1.37%)  1 1/75 (1.33%)  1 0/94 (0.00%)  0 0/97 (0.00%)  0
Visual acuity tests abnormal  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 1/97 (1.03%)  1
Vitamin b12 decreased  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 1/94 (1.06%)  1 0/97 (0.00%)  0
Weight increased  1  2/401 (0.50%)  2 9/403 (2.23%)  9 0/73 (0.00%)  0 1/75 (1.33%)  1 0/94 (0.00%)  0 3/97 (3.09%)  3
Metabolism and nutrition disorders             
Decreased appetite  1  17/401 (4.24%)  18 2/403 (0.50%)  2 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 0/97 (0.00%)  0
Hyperglycaemia  1  2/401 (0.50%)  2 2/403 (0.50%)  2 0/73 (0.00%)  0 1/75 (1.33%)  1 0/94 (0.00%)  0 1/97 (1.03%)  1
Hypoglycaemia  1  4/401 (1.00%)  7 1/403 (0.25%)  1 0/73 (0.00%)  0 0/75 (0.00%)  0 1/94 (1.06%)  1 3/97 (3.09%)  3
Increased appetite  1  0/401 (0.00%)  0 6/403 (1.49%)  6 1/73 (1.37%)  1 1/75 (1.33%)  1 0/94 (0.00%)  0 0/97 (0.00%)  0
Musculoskeletal and connective tissue disorders             
Arthralgia  1  3/401 (0.75%)  4 4/403 (0.99%)  4 0/73 (0.00%)  0 1/75 (1.33%)  1 1/94 (1.06%)  1 1/97 (1.03%)  1
Back pain  1  3/401 (0.75%)  3 5/403 (1.24%)  6 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 2/97 (2.06%)  2
Joint swelling  1  1/401 (0.25%)  1 3/403 (0.74%)  3 0/73 (0.00%)  0 0/75 (0.00%)  0 2/94 (2.13%)  2 0/97 (0.00%)  0
Muscle contracture  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 1/94 (1.06%)  1 0/97 (0.00%)  0
Muscle spasms  1  4/401 (1.00%)  5 2/403 (0.50%)  2 1/73 (1.37%)  1 0/75 (0.00%)  0 1/94 (1.06%)  1 1/97 (1.03%)  1
Musculoskeletal chest pain  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 1/97 (1.03%)  1
Osteoarthritis  1  0/401 (0.00%)  0 2/403 (0.50%)  2 0/73 (0.00%)  0 0/75 (0.00%)  0 1/94 (1.06%)  1 0/97 (0.00%)  0
Pain in extremity  1  3/401 (0.75%)  3 3/403 (0.74%)  4 3/73 (4.11%)  3 3/75 (4.00%)  3 2/94 (2.13%)  3 0/97 (0.00%)  0
Plantar fasciitis  1  0/401 (0.00%)  0 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 1/97 (1.03%)  2
Nervous system disorders             
Amnesia  1  1/401 (0.25%)  1 0/403 (0.00%)  0 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 1/97 (1.03%)  1
Balance disorder  1  4/401 (1.00%)  5 7/403 (1.74%)  7 0/73 (0.00%)  0 0/75 (0.00%)  0 0/94 (0.00%)  0 2/97 (2.06%)  2
Disturbance in attention  1  2/401 (0.50%)  2 7/403 (1.74%)  8 0/73 (0.00%)  0 0/75 (0.00%)  0 2/94 (2.13%)  2 1/97 (1.03%)  1
Dizziness  1