A Study of Duloxetine (LY248686) in Participants With Diabetic Peripheral Neuropathic Pain (DPNP)

Study Overview
=================
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.

Official Title
-----------------
A Japan Post-Marketing, Randomized, Double-Blind, Parallel-Group, Flexible Dose Comparative Study to Assess the Non-Inferiority of Duloxetine Compared With Pregabalin in Patients With Diabetic Peripheral Neuropathic Pain

Conditions
-----------------
Diabetic Peripheral Neuropathic Pain

Intervention / Treatment
-----------------
* Drug: Duloxetine
* Drug: Pregabalin
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 79 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Duloxetine<br>20 milligrams (mg) duloxetine orally once a day (QD) for one week and then 40 mg duloxetine orally QD for 3 weeks. Duloxetine dosage may be increased up to 60 mg QD at week 4 or week 8. Placebo will be given with duloxetine for blinding. Dosage will be tapered down during the final week of the study. | Drug: Duloxetine<br>* Administered orally<br>* Other names: LY248686;Drug: Placebo<br>* Administered orally<br>|
| Active Comparator: Pregabalin<br>150 mg pregabalin orally twice a day (BID) for 1 week and then 300 mg pregabalin orally BID for 3 weeks. Pregabalin dosage may be increased up to 450 mg BID at week 4 or 8, and increased up to 600 mg BID at week 8. Placebo will be given with pregabalin for blinding. Dosage will be tapered down during the final week of the study. | Drug: Pregabalin<br>* Administered orally<br>Drug: Placebo<br>* Administered orally<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Week 12 | 
| 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. | Baseline, Week 12 | 
| 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. | Baseline, Week 12 | 
| 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. | Week 12 | 
| 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. | Baseline, Week 12 | 
| 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. | Baseline, Week 12 | 
| 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. | Baseline, Week 12 | 
| 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. | Baseline, Week 12 | 
| 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. | Week 12 |