Diabetic Peripheral Neuropathic Pain
Conditions
Brief summary
The main purpose of this study is to evaluate the effectiveness and safety of the study drug known as duloxetine in participants with diabetic peripheral neuropathic pain.
Interventions
DRUGDuloxetine
Administered orally
DRUGPregabalin
Administered orally
DRUGPlacebo
Administered orally
Sponsors
Shionogi
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
* Participants present with pain due to bilateral, peripheral neuropathy * Participants who have hemoglobin A1c (HbA1c) ≤9.4% (National Glycohemoglobin Standardization Program \[NGSP\]) at screening * Participants who have HbA1c that has been measured 42 to 70 days prior to screening, and the range of variation in the values measured, thereafter, is within ±1.0% of the value measured at screening * Participants who have a score of at least 4 on the mean of the 24-hour average pain score measured using 11-point NRS (Numeric Rating Scale) in the daily diary (should be calculated from records 7 days immediately prior to randomization) * Participants who have made complete daily diary entries 80% or more of the time from screening to randomization
Exclusion criteria
* Participants who have undergone renal transplant, or are currently undergoing renal dialysis * Participants who have uncontrolled narrow-angle glaucoma, history of uncontrolled seizures, or uncontrolled or poorly controlled hypertension * Participants whose glycemic control has been poor within 70 days immediately prior to screening (for example, ketoacidosis requiring hospitalization, or hypoglycemia that may cause consciousness disorder) * Pregnant or lactating female participants, or male participants who are planning for their partners to be or become pregnant during the timeframe of the study * Participants who have hypersensitivity to multiple medications * Participants who answered yes to either question 4 (active suicidal ideation with some intent to act, without specific plan) or question 5 (active suicidal ideation with specific plan and intent) on the suicidal ideation portion of the Columbia-Suicide Severity Rating Scale (C-SSRS) or answered yes to any of the suicide-related behaviors (actual attempt, interrupted attempt, aborted attempt, preparatory act or behavior) on the suicidal behavior portion of the C-SSRS; and the ideation or behavior occurred within the past month * Participants who have past history of psychiatric diseases, such as depression, anxiety disorder, eating disorder, etc., that required drug therapy in the past 1 year, or who are currently having complications of these diseases or any history of manic psychosis or bipolar disorder * Participants who have major depressive disorder as determined using the depression module of the Mini-International Neuropsychiatric Interview (MINI) * Participants who have complications of diseases that are considered to affect the assessment of diabetic peripheral neuropathic pain. For example, nerve diseases with pain other than diabetic peripheral neuropathic pain (cervical spondylosis, carpal tunnel syndrome, spinal canal stenosis, and post-herpetic pain), pain diseases other than nerve diseases (collagen diseases, gout, chronic obstructive arteriosclerosis, and arthritis), and other pain at the site of evaluation (skin diseases and traumatic injury) are excluded * Participants who have neuropathic pain suspected to be caused by alcohol * Participants who have been treated with a monoamine oxidase (MAO) inhibitor(s) within 14 days immediately prior to randomization. Participants who visited the investigator site 14 days prior to randomization, those who have been treated with MAO inhibitors(s), thereafter, are excluded * Participants who have alanine aminotransferase (ALT) and aspartate aminotransferase (AST) at a level ≥100 units/liter at screening * Participants who have total bilirubin at a level ≥1.5 milligrams/deciliter (mg/dL) at screening * Participants who have creatinine clearance (CrCL), calculated by Cockcroft-Gault, that is \<1.0 milliliters/second (mL/s) (\<60 mL/minute) at screening * Participants who have a white blood cell (WBC) value \<2500/cubic millimeters (mm3), neutrophils \<1500/mm3, or platelets \<100×103/mm3 on their hematology tests at screening * Participants who are introduced to any treatments for diabetes, or a change in dosing regimen of any treatments for diabetes (exclude insulin treatment), or resumption of insulin treatment after screening * Participants who have been treated with prohibited concomitant drug(s), or who have undergone prohibited concomitant treatment(s) after screening * Participants who have taken restricted concomitant drugs 27 days immediately before screening, with continued use of the restricted concomitant drug prior to screening * Participants who have taken acetaminophen for 4 days or more 7 days immediately prior to randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 12 Weeks in the Weekly Mean of the 24-Hour Average Pain Score on the 11-Point Numeric Rating Scale (NRS) | Baseline, Week 12 | 11-point NRS measures the severity of pain over the previous 24 hours. Participants were asked to provide 24-hour average pain scores in the daily Participant diary and among these, the weekly mean of the 24-hour average pain score was calculated. Scores range from 0 (no pain) to 10 (pain as bad as you can imagine). Mixed Model Repeated Measures (MMRM) model with baseline value, Duration of diabetic peripheral neuropathic pain (DPNP), treatment, week, treatment-by-week interaction as fixed effects was used to produce Least Square Mean (LS Mean). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | Baseline, Week 12 | Brief Pain Inventory Severity and Interference Scores: BPI-S and BPI-I are self-reported scales measuring severity of pain and interference on function. Severity scores: 0 (no pain) to 10 (pain as bad as you can imagine) on each question assessing worst pain, least pain, and average pain in past 24 hours, and pain right now. Interference scores: 0 (does not interfere) to 10 (completely interferes) on each question assessing interference of pain in past 24 hours for general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life. Average interference = average of non-missing scores of individual interference items. MMRM model with baseline, duration of DPNP, treatment, visit, treatment-by-visit interaction as fixed effects was used to produce LS mean. |
| Change From Baseline to 12 Weeks on the Neuropathic Pain Symptom Inventory (NPSI) | Baseline, Week 12 | NPSI questionnaire is a 12-item self-administered questionnaire that will be completed by the participant. It assesses 5 different dimensions of neuropathic pain on a scale of 0 (no symptom) to 10 (worst imaginable symptom): burning spontaneous pain, pressing spontaneous pain, paroxysmal pain, evoked pain, and paresthesias/dysesthesias. The NPSI includes 12 items: 10 descriptors of the different symptoms and 2 items for assessing the duration of spontaneous ongoing and paroxysmal pain. A total score can be calculated as the sum of the scores of the 10 descriptors with scale range: 0 (no pain) -100 (worst pain imaginable). Analysis of Covariance (ANCOVA) model with last observation carried forward (LOCF) with baseline, treatment, and duration of DPNP as fixed effects was used to produce LS mean. |
| Clinical Global Impression of Improvement (CGI-I) at 12 Weeks | Week 12 | CGI-I measures clinician's perception of participant improvement at the time of assessment (compared with the start of treatment) with scores ranging from 1 (very much better) to 7 (very much worse). MMRM model with duration of DPNP, treatment, visit and treatment-by-visit interaction as fixed effects was used to produce LS Mean. |
| Change From Baseline to 12 Weeks on the EuroQol 5 Dimension (EQ-5D) | Baseline, Week 12 | The EQ-5D is a self-reported, 5-item scale used to assess the patient's health utility (mobility, self-care, usual activities, pain and discomfort, and depression/anxiety). Scoring is on a 3-point scale.These combinations of attributes were converted into a weighted health-state Index Score according to the Japan population-based algorithm (range of the Index score is -0.111 - 1).A higher score indicates better health state. ANCOVA model with LOCF with baseline value, treatment and duration of DPNP as fixed effects was used to produce LS mean. |
| Patient Global Impression of Improvement (PGI-I) at 12 Weeks | Week 12 | PGI-I assessments was completed by the participant. The participant records how he/she perceives the degree of improvement (or worsening) at the time of assessment since taking treatment. The score ranges from 1 (very much better) to 7 (very much worse). MMRM model with duration of DPNP, treatment, visit, treatment-by-visit interaction as fixed effects was used to produce LS Mean. |
| Change From Baseline to 12 Weeks in the Weekly Mean of Night Pain Scores on the 11-Point NRS | Baseline, Week 12 | Night pain severity scores were recorded on an 11-point NRS in the daily patient diary, ranging from 0 (no pain) to 10 (pain as bad as you can imagine).The weekly mean of the night pain score was calculated based on the daily pain score. MMRM model with baseline value, treatment, week, duration of DPNP and treatment-by-week interaction as fixed effects was used to produce LS mean. |
| Change From Baseline to 12 Weeks in the Weekly Mean of the 24-Hour Worst Pain Scores on the 11-Point NRS | Baseline, Week 12 | 24-hour worst pain severity scores were recorded on an 11-point NRS in the daily patient diary, ranging from 0 (no pain) to 10 (pain as bad as you can imagine).The weekly mean of the worst pain score was calculated based on the daily score. MMRM model with baseline value, duration of DPNP, treatment, week, treatment-by-week interaction as fixed effects was used to produce LS mean. |
| Number of Participants With a 30% and 50% Reduction in the Weekly Mean of the 24-Hour Average Pain Score on the 11-Point NRS at 12 Weeks | Week 12 | 11-point NRS measures the severity of pain over the previous 24 hours. Patients were asked to provide 24-hour average pain scores in the daily patient diary. scores range from 0 (no pain) to 10 (pain as bad as you can imagine) and among these, the weekly mean of the 24-hour average pain score was calculated based on daily score. |
| Change From Baseline to 12 Weeks on the Beck Depression Inventory-II (BDI-II) Total Score | Baseline, Week 12 | Beck Depression Inventory-II: BDI-II is a 21-item, participant-completed questionnaire to assess characteristics of depression. Each of the 21 items corresponding to symptoms of depression were scored on a 4-point scale ranging from 0 to 3 and was summed to give a single score. A total score of 0-13 was considered minimal range, 14-19 was mild, 20-28 was moderate, and 29-63 was severe. MMRM model with baseline value, duration of DPNP, treatment, visit and treatment-by-visit interaction as fixed effects was used to produce LS mean. |
Participant flow
Recruitment details
12 week Treatment period, followed by 1 week Tapering period, followed by 1 week follow-up period.
Participants by arm
| Arm | Count |
|---|---|
| Pregabalin Participants received flexible doses of 150 to 600 mg Pregabalin orally twice a day (BID) along with Duloxetine placebo during treatment period.
Participants who received higher doses of Pregabalin in treatment period received gradually the lower doses of Pregabalin along with Duloxetine placebo during tapering period. | 151 |
| Duloxetine Participants received flexible doses of 20 to 60 mg Duloxetine orally once a day (QD) along with Pregabalin placebo during treatment period.
Participants who received higher doses of Duloxetine in treatment period received gradually the lower doses of Duloxetine along with Pregabalin placebo during tapering period. | 152 |
| Total | 303 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period | Adverse Event | 12 | 10 |
| Treatment Period | Entry Criteria not met | 0 | 1 |
| Treatment Period | Lost to Follow-up | 1 | 0 |
| Treatment Period | Physician Decision | 3 | 1 |
| Treatment Period | Protocol Violation | 2 | 1 |
| Treatment Period | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | Pregabalin | Duloxetine | Total |
|---|---|---|---|
| Age, Continuous | 60.0 years STANDARD_DEVIATION 9.84 | 59.3 years STANDARD_DEVIATION 8.16 | 59.6 years STANDARD_DEVIATION 9.03 |
| Beck Depression Inventory-II (BDI-II) | 6.2 units on a scale STANDARD_DEVIATION 5.41 | 6.8 units on a scale STANDARD_DEVIATION 5.9 | 6.5 units on a scale STANDARD_DEVIATION 5.66 |
| Brief Pain Inventory - Short Form (BPI-SF) Average Interference Score | 2.66 units on a scale STANDARD_DEVIATION 1.744 | 2.63 units on a scale STANDARD_DEVIATION 1.875 | 2.64 units on a scale STANDARD_DEVIATION 1.807 |
| Brief Pain Inventory - Short Form (BPI-SF) Average Pain | 5.3 units on a scale STANDARD_DEVIATION 1.21 | 5.3 units on a scale STANDARD_DEVIATION 1.17 | 5.3 units on a scale STANDARD_DEVIATION 1.19 |
| Brief Pain Inventory - Short Form (BPI-SF) Enjoyment of Life | 2.6 units on a scale STANDARD_DEVIATION 2.27 | 2.5 units on a scale STANDARD_DEVIATION 2.24 | 2.5 units on a scale STANDARD_DEVIATION 2.25 |
| Brief Pain Inventory - Short Form (BPI-SF) General Activity | 3.1 units on a scale STANDARD_DEVIATION 2.14 | 3.4 units on a scale STANDARD_DEVIATION 2.21 | 3.3 units on a scale STANDARD_DEVIATION 2.18 |
| Brief Pain Inventory - Short Form (BPI-SF) Least Pain | 3.8 units on a scale STANDARD_DEVIATION 1.74 | 3.9 units on a scale STANDARD_DEVIATION 1.7 | 3.9 units on a scale STANDARD_DEVIATION 1.72 |
| Brief Pain Inventory - Short Form (BPI-SF) Mood | 3.3 units on a scale STANDARD_DEVIATION 2.32 | 2.9 units on a scale STANDARD_DEVIATION 2.23 | 3.1 units on a scale STANDARD_DEVIATION 2.28 |
| Brief Pain Inventory - Short Form (BPI-SF) Normal Work | 2.6 units on a scale STANDARD_DEVIATION 2.11 | 2.6 units on a scale STANDARD_DEVIATION 2.41 | 2.6 units on a scale STANDARD_DEVIATION 2.26 |
| Brief Pain Inventory - Short Form (BPI-SF) Pain Right Now | 4.9 units on a scale STANDARD_DEVIATION 1.6 | 4.9 units on a scale STANDARD_DEVIATION 1.58 | 4.9 units on a scale STANDARD_DEVIATION 1.59 |
| Brief Pain Inventory - Short Form (BPI-SF) Relations With Other People | 1.4 units on a scale STANDARD_DEVIATION 1.81 | 1.4 units on a scale STANDARD_DEVIATION 1.81 | 1.4 units on a scale STANDARD_DEVIATION 1.8 |
| Brief Pain Inventory - Short Form (BPI-SF) Sleep | 2.7 units on a scale STANDARD_DEVIATION 2.39 | 2.8 units on a scale STANDARD_DEVIATION 2.37 | 2.8 units on a scale STANDARD_DEVIATION 2.38 |
| Brief Pain Inventory - Short Form (BPI-SF) Walking Ability | 2.9 units on a scale STANDARD_DEVIATION 2.28 | 2.8 units on a scale STANDARD_DEVIATION 2.51 | 2.8 units on a scale STANDARD_DEVIATION 2.39 |
| Brief Pain Inventory - Short Form (BPI-SF) Worst Pain | 6.3 units on a scale STANDARD_DEVIATION 1.45 | 6.3 units on a scale STANDARD_DEVIATION 1.24 | 6.3 units on a scale STANDARD_DEVIATION 1.35 |
| EuroQol 5 Dimension (EQ-5D) | 0.7253 units on a scale STANDARD_DEVIATION 0.0903 | 0.7337 units on a scale STANDARD_DEVIATION 0.123 | 0.7296 units on a scale STANDARD_DEVIATION 0.1079 |
| Neuropathic Pain Symptom Inventory (NPSI) | 31.8 units on a scale STANDARD_DEVIATION 15.6 | 32.1 units on a scale STANDARD_DEVIATION 16.49 | 31.9 units on a scale STANDARD_DEVIATION 16.03 |
| Numeric Rating Scale (NRS) Average Pain Score | 5.35 units on a scale STANDARD_DEVIATION 1.129 | 5.38 units on a scale STANDARD_DEVIATION 1.079 | 5.37 units on a scale STANDARD_DEVIATION 1.102 |
| Numeric Rating Scale (NRS) Night Pain Score | 4.61 units on a scale STANDARD_DEVIATION 1.855 | 4.92 units on a scale STANDARD_DEVIATION 1.65 | 4.76 units on a scale STANDARD_DEVIATION 1.759 |
| Numeric Rating Scale (NRS) Worst Pain Score | 6.25 units on a scale STANDARD_DEVIATION 1.311 | 6.22 units on a scale STANDARD_DEVIATION 1.237 | 6.23 units on a scale STANDARD_DEVIATION 1.273 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 151 Participants | 152 Participants | 303 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Japan | 151 Participants | 152 Participants | 303 Participants |
| Sex: Female, Male Female | 42 Participants | 41 Participants | 83 Participants |
| Sex: Female, Male Male | 109 Participants | 111 Participants | 220 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 151 | 0 / 152 |
| other Total, other adverse events | 91 / 151 | 86 / 152 |
| serious Total, serious adverse events | 6 / 151 | 1 / 152 |
Outcome results
Primary
Change From Baseline to 12 Weeks in the Weekly Mean of the 24-Hour Average Pain Score on the 11-Point Numeric Rating Scale (NRS)
11-point NRS measures the severity of pain over the previous 24 hours. Participants were asked to provide 24-hour average pain scores in the daily Participant diary and among these, the weekly mean of the 24-hour average pain score was calculated. Scores range from 0 (no pain) to 10 (pain as bad as you can imagine). Mixed Model Repeated Measures (MMRM) model with baseline value, Duration of diabetic peripheral neuropathic pain (DPNP), treatment, week, treatment-by-week interaction as fixed effects was used to produce Least Square Mean (LS Mean).
Time frame: Baseline, Week 12
Population: All randomized participants who received at least one dose of study drug and had baseline and at least one post baseline observation for NRS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Change From Baseline to 12 Weeks in the Weekly Mean of the 24-Hour Average Pain Score on the 11-Point Numeric Rating Scale (NRS) | -2.358 units on a scale | Standard Error 0.133 |
| Duloxetine | Change From Baseline to 12 Weeks in the Weekly Mean of the 24-Hour Average Pain Score on the 11-Point Numeric Rating Scale (NRS) | -2.286 units on a scale | Standard Error 0.133 |
p-value: 0.795% CI: [-0.295, 0.439]Mixed Models Analysis
Secondary
Change From Baseline to 12 Weeks in the Weekly Mean of Night Pain Scores on the 11-Point NRS
Night pain severity scores were recorded on an 11-point NRS in the daily patient diary, ranging from 0 (no pain) to 10 (pain as bad as you can imagine).The weekly mean of the night pain score was calculated based on the daily pain score. MMRM model with baseline value, treatment, week, duration of DPNP and treatment-by-week interaction as fixed effects was used to produce LS mean.
Time frame: Baseline, Week 12
Population: All randomized participants who received at least one dose of study drug and had baseline and at least one post baseline observation for night pain NRS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Change From Baseline to 12 Weeks in the Weekly Mean of Night Pain Scores on the 11-Point NRS | -2.166 units on a scale | Standard Error 0.131 |
| Duloxetine | Change From Baseline to 12 Weeks in the Weekly Mean of Night Pain Scores on the 11-Point NRS | -2.160 units on a scale | Standard Error 0.131 |
p-value: 0.97695% CI: [-0.355, 0.366]Mixed Models Analysis
Secondary
Change From Baseline to 12 Weeks in the Weekly Mean of the 24-Hour Worst Pain Scores on the 11-Point NRS
24-hour worst pain severity scores were recorded on an 11-point NRS in the daily patient diary, ranging from 0 (no pain) to 10 (pain as bad as you can imagine).The weekly mean of the worst pain score was calculated based on the daily score. MMRM model with baseline value, duration of DPNP, treatment, week, treatment-by-week interaction as fixed effects was used to produce LS mean.
Time frame: Baseline, Week 12
Population: All randomized participants who received at least one dose of study drug and had baseline and at least one post baseline observation for worst pain score NRS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Change From Baseline to 12 Weeks in the Weekly Mean of the 24-Hour Worst Pain Scores on the 11-Point NRS | -2.553 units on a scale | Standard Error 0.145 |
| Duloxetine | Change From Baseline to 12 Weeks in the Weekly Mean of the 24-Hour Worst Pain Scores on the 11-Point NRS | -2.416 units on a scale | Standard Error 0.145 |
p-value: 0.50395% CI: [-0.264, 0.537]Mixed Models Analysis
Secondary
Change From Baseline to 12 Weeks on the Beck Depression Inventory-II (BDI-II) Total Score
Beck Depression Inventory-II: BDI-II is a 21-item, participant-completed questionnaire to assess characteristics of depression. Each of the 21 items corresponding to symptoms of depression were scored on a 4-point scale ranging from 0 to 3 and was summed to give a single score. A total score of 0-13 was considered minimal range, 14-19 was mild, 20-28 was moderate, and 29-63 was severe. MMRM model with baseline value, duration of DPNP, treatment, visit and treatment-by-visit interaction as fixed effects was used to produce LS mean.
Time frame: Baseline, Week 12
Population: All randomized participants who received at least one dose of study drug and had baseline and at least one post baseline observation for BDI-II.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Change From Baseline to 12 Weeks on the Beck Depression Inventory-II (BDI-II) Total Score | -2.5 units on a scale | Standard Error 0.3 |
| Duloxetine | Change From Baseline to 12 Weeks on the Beck Depression Inventory-II (BDI-II) Total Score | -2.3 units on a scale | Standard Error 0.3 |
p-value: 0.70195% CI: [-0.8, 1.1]Mixed Models Analysis
Secondary
Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF)
Brief Pain Inventory Severity and Interference Scores: BPI-S and BPI-I are self-reported scales measuring severity of pain and interference on function. Severity scores: 0 (no pain) to 10 (pain as bad as you can imagine) on each question assessing worst pain, least pain, and average pain in past 24 hours, and pain right now. Interference scores: 0 (does not interfere) to 10 (completely interferes) on each question assessing interference of pain in past 24 hours for general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life. Average interference = average of non-missing scores of individual interference items. MMRM model with baseline, duration of DPNP, treatment, visit, treatment-by-visit interaction as fixed effects was used to produce LS mean.
Time frame: Baseline, Week 12
Population: All randomized participants who received at least one dose of study drug and had baseline and at least one post baseline observation for BPI-SF.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Pregabalin | Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | Worst Pain | -2.8 units on a scale | Standard Error 0.2 |
| Pregabalin | Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | Least Pain | -1.7 units on a scale | Standard Error 0.1 |
| Pregabalin | Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | Average Interference | -1.60 units on a scale | Standard Error 0.1 |
| Pregabalin | Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | Average Pain | -2.5 units on a scale | Standard Error 0.1 |
| Pregabalin | Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | Pain Right Now | -2.4 units on a scale | Standard Error 0.1 |
| Pregabalin | Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | General Activity | -1.9 units on a scale | Standard Error 0.1 |
| Pregabalin | Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | Mood | -1.9 units on a scale | Standard Error 0.1 |
| Pregabalin | Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | Walking Ability | -1.8 units on a scale | Standard Error 0.1 |
| Pregabalin | Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | Normal Work | -1.6 units on a scale | Standard Error 0.1 |
| Pregabalin | Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | Relations with Other People | -0.7 units on a scale | Standard Error 0.1 |
| Pregabalin | Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | Sleep | -1.7 units on a scale | Standard Error 0.1 |
| Pregabalin | Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | Enjoyment of Life | -1.6 units on a scale | Standard Error 0.1 |
| Duloxetine | Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | General Activity | -2.1 units on a scale | Standard Error 0.1 |
| Duloxetine | Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | Worst Pain | -2.7 units on a scale | Standard Error 0.2 |
| Duloxetine | Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | Normal Work | -1.8 units on a scale | Standard Error 0.1 |
| Duloxetine | Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | Enjoyment of Life | -1.8 units on a scale | Standard Error 0.1 |
| Duloxetine | Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | Mood | -2.1 units on a scale | Standard Error 0.1 |
| Duloxetine | Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | Average Interference | -1.77 units on a scale | Standard Error 0.1 |
| Duloxetine | Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | Least Pain | -1.9 units on a scale | Standard Error 0.1 |
| Duloxetine | Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | Sleep | -1.7 units on a scale | Standard Error 0.1 |
| Duloxetine | Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | Average Pain | -2.4 units on a scale | Standard Error 0.1 |
| Duloxetine | Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | Walking Ability | -1.9 units on a scale | Standard Error 0.1 |
| Duloxetine | Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | Pain Right Now | -2.4 units on a scale | Standard Error 0.1 |
| Duloxetine | Change From Baseline to 12 Weeks on the Brief Pain Inventory-Severity and Interference Rating Short Form (BPI-SF) | Relations with Other People | -0.9 units on a scale | Standard Error 0.1 |
Comparison: Worst Painp-value: 0.53595% CI: [-0.3, 0.6]Mixed Models Analysis
Comparison: Least Painp-value: 0.43695% CI: [-0.5, 0.2]Mixed Models Analysis
Comparison: Average Painp-value: 0.53495% CI: [-0.2, 0.5]Mixed Models Analysis
Comparison: Pain Right Nowp-value: 0.94895% CI: [-0.4, 0.4]Mixed Models Analysis
Comparison: General Activityp-value: 0.22595% CI: [-0.6, 0.1]Mixed Models Analysis
Comparison: Moodp-value: 0.27695% CI: [-0.6, 0.2]Mixed Models Analysis
Comparison: Walking Abilityp-value: 0.50795% CI: [-0.4, 0.2]Mixed Models Analysis
Comparison: Normal Workp-value: 0.21695% CI: [-0.5, 0.1]Mixed Models Analysis
Comparison: Relations with other peoplep-value: 0.23395% CI: [-0.4, 0.1]Mixed Models Analysis
Comparison: Sleepp-value: 0.85795% CI: [-0.3, 0.3]Mixed Models Analysis
Comparison: Enjoyment of lifep-value: 0.13395% CI: [-0.5, 0.1]Mixed Models Analysis
Comparison: Average Interference Scorep-value: 0.24695% CI: [-0.44, 0.11]Mixed Models Analysis
Secondary
Change From Baseline to 12 Weeks on the EuroQol 5 Dimension (EQ-5D)
The EQ-5D is a self-reported, 5-item scale used to assess the patient's health utility (mobility, self-care, usual activities, pain and discomfort, and depression/anxiety). Scoring is on a 3-point scale.These combinations of attributes were converted into a weighted health-state Index Score according to the Japan population-based algorithm (range of the Index score is -0.111 - 1).A higher score indicates better health state. ANCOVA model with LOCF with baseline value, treatment and duration of DPNP as fixed effects was used to produce LS mean.
Time frame: Baseline, Week 12
Population: All randomized participants who received at least one dose of study drug and had baseline and at least one post-baseline observation for EQ-5D.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Change From Baseline to 12 Weeks on the EuroQol 5 Dimension (EQ-5D) | 0.1004 units on a scale | Standard Error 0.0112 |
| Duloxetine | Change From Baseline to 12 Weeks on the EuroQol 5 Dimension (EQ-5D) | 0.1144 units on a scale | Standard Error 0.0112 |
p-value: 0.36195% CI: [-0.0161, 0.0441]ANCOVA
Secondary
Change From Baseline to 12 Weeks on the Neuropathic Pain Symptom Inventory (NPSI)
NPSI questionnaire is a 12-item self-administered questionnaire that will be completed by the participant. It assesses 5 different dimensions of neuropathic pain on a scale of 0 (no symptom) to 10 (worst imaginable symptom): burning spontaneous pain, pressing spontaneous pain, paroxysmal pain, evoked pain, and paresthesias/dysesthesias. The NPSI includes 12 items: 10 descriptors of the different symptoms and 2 items for assessing the duration of spontaneous ongoing and paroxysmal pain. A total score can be calculated as the sum of the scores of the 10 descriptors with scale range: 0 (no pain) -100 (worst pain imaginable). Analysis of Covariance (ANCOVA) model with last observation carried forward (LOCF) with baseline, treatment, and duration of DPNP as fixed effects was used to produce LS mean.
Time frame: Baseline, Week 12
Population: All randomized participants who received at least one dose of study drug \& had baseline \& at least one post-baseline observation for NPSI.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Pregabalin | Change From Baseline to 12 Weeks on the Neuropathic Pain Symptom Inventory (NPSI) | Total Score | -15.4 units on a scale | Standard Error 1.1 |
| Pregabalin | Change From Baseline to 12 Weeks on the Neuropathic Pain Symptom Inventory (NPSI) | Burning Pain | -1.1 units on a scale | Standard Error 0.2 |
| Pregabalin | Change From Baseline to 12 Weeks on the Neuropathic Pain Symptom Inventory (NPSI) | Pressing Pain | -1.4 units on a scale | Standard Error 0.1 |
| Pregabalin | Change From Baseline to 12 Weeks on the Neuropathic Pain Symptom Inventory (NPSI) | Paroxysmal Pain | -1.7 units on a scale | Standard Error 0.1 |
| Pregabalin | Change From Baseline to 12 Weeks on the Neuropathic Pain Symptom Inventory (NPSI) | Evoked Pain | -1.0 units on a scale | Standard Error 0.1 |
| Pregabalin | Change From Baseline to 12 Weeks on the Neuropathic Pain Symptom Inventory (NPSI) | Paresthesia/Dysesthesia | -2.5 units on a scale | Standard Error 0.1 |
| Duloxetine | Change From Baseline to 12 Weeks on the Neuropathic Pain Symptom Inventory (NPSI) | Evoked Pain | -1.2 units on a scale | Standard Error 0.1 |
| Duloxetine | Change From Baseline to 12 Weeks on the Neuropathic Pain Symptom Inventory (NPSI) | Total Score | -16.1 units on a scale | Standard Error 1.1 |
| Duloxetine | Change From Baseline to 12 Weeks on the Neuropathic Pain Symptom Inventory (NPSI) | Paroxysmal Pain | -1.7 units on a scale | Standard Error 0.1 |
| Duloxetine | Change From Baseline to 12 Weeks on the Neuropathic Pain Symptom Inventory (NPSI) | Burning Pain | -1.3 units on a scale | Standard Error 0.2 |
| Duloxetine | Change From Baseline to 12 Weeks on the Neuropathic Pain Symptom Inventory (NPSI) | Paresthesia/Dysesthesia | -2.6 units on a scale | Standard Error 0.1 |
| Duloxetine | Change From Baseline to 12 Weeks on the Neuropathic Pain Symptom Inventory (NPSI) | Pressing Pain | -1.4 units on a scale | Standard Error 0.1 |
Comparison: Total Scorep-value: 0.62795% CI: [-3.6, 2.2]ANCOVA
Comparison: Burning Painp-value: 0.35595% CI: [-0.6, 0.2]ANCOVA
Comparison: Pressing Painp-value: 0.73195% CI: [-0.3, 0.4]ANCOVA
Comparison: Paroxysmal Painp-value: 0.72195% CI: [-0.3, 0.4]ANCOVA
Comparison: Evoked Painp-value: 0.34595% CI: [-0.5, 0.2]ANCOVA
Comparison: Paresthesia/Dysesthesiap-value: 0.55795% CI: [-0.5, 0.3]ANCOVA
Secondary
Clinical Global Impression of Improvement (CGI-I) at 12 Weeks
CGI-I measures clinician's perception of participant improvement at the time of assessment (compared with the start of treatment) with scores ranging from 1 (very much better) to 7 (very much worse). MMRM model with duration of DPNP, treatment, visit and treatment-by-visit interaction as fixed effects was used to produce LS Mean.
Time frame: Week 12
Population: All randomized participants who received at least one dose of study drug and had at least one post baseline observation for CGI-I
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Clinical Global Impression of Improvement (CGI-I) at 12 Weeks | 2.6 units on a scale | Standard Error 0.1 |
| Duloxetine | Clinical Global Impression of Improvement (CGI-I) at 12 Weeks | 2.5 units on a scale | Standard Error 0.1 |
p-value: 0.10695% CI: [-0.4, 0]Mixed Models Analysis
Secondary
Number of Participants With a 30% and 50% Reduction in the Weekly Mean of the 24-Hour Average Pain Score on the 11-Point NRS at 12 Weeks
11-point NRS measures the severity of pain over the previous 24 hours. Patients were asked to provide 24-hour average pain scores in the daily patient diary. scores range from 0 (no pain) to 10 (pain as bad as you can imagine) and among these, the weekly mean of the 24-hour average pain score was calculated based on daily score.
Time frame: Week 12
Population: All randomized participants who received at least one dose of study drug \& had baseline \& at least one post-baseline observation for average pain score NRS .
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pregabalin | Number of Participants With a 30% and 50% Reduction in the Weekly Mean of the 24-Hour Average Pain Score on the 11-Point NRS at 12 Weeks | 30% Reduction | 94 Participants |
| Pregabalin | Number of Participants With a 30% and 50% Reduction in the Weekly Mean of the 24-Hour Average Pain Score on the 11-Point NRS at 12 Weeks | 50% Reduction | 62 Participants |
| Duloxetine | Number of Participants With a 30% and 50% Reduction in the Weekly Mean of the 24-Hour Average Pain Score on the 11-Point NRS at 12 Weeks | 30% Reduction | 100 Participants |
| Duloxetine | Number of Participants With a 30% and 50% Reduction in the Weekly Mean of the 24-Hour Average Pain Score on the 11-Point NRS at 12 Weeks | 50% Reduction | 62 Participants |
p-value: 0.632Fisher Exact
Comparison: 50% Reductionp-value: 0.907Fisher Exact
Secondary
Patient Global Impression of Improvement (PGI-I) at 12 Weeks
PGI-I assessments was completed by the participant. The participant records how he/she perceives the degree of improvement (or worsening) at the time of assessment since taking treatment. The score ranges from 1 (very much better) to 7 (very much worse). MMRM model with duration of DPNP, treatment, visit, treatment-by-visit interaction as fixed effects was used to produce LS Mean.
Time frame: Week 12
Population: All randomized participants who received at least one dose of study drug and had at least one post baseline observation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin | Patient Global Impression of Improvement (PGI-I) at 12 Weeks | 2.6 units on a scale | Standard Error 0.1 |
| Duloxetine | Patient Global Impression of Improvement (PGI-I) at 12 Weeks | 2.4 units on a scale | Standard Error 0.1 |
p-value: 0.14995% CI: [-0.4, 0.1]Mixed Models Analysis