Safety and Efficacy Study of ADL5859 in Participants With Neuropathic Pain Associated With Diabetic Peripheral Neuropathy

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the effectiveness of ADL5859 in relieving the pain associated with diabetic peripheral neuropathy (DPN) compared with placebo and duloxetine (a marketed drug approved for the treatment of painful DPN). The pain symptoms of DPN are thought to be due to damage to nerves caused by the diabetes.

Detailed Description
-----------------
Participants were permitted to take acetaminophen 650 to 975 mg every 4 to 6 hours (up to a total of 4 grams in 24 hours) as needed for pain relief.

Official Title
-----------------
A Phase 2a, Randomized, Double-Blind, Placebo- and Active-Controlled, Parallel-Group, Multicenter Study to Assess the Safety and Efficacy of ADL5859 100 mg BID in Subjects With Neuropathic Pain Associated With Diabetic Peripheral Neuropathy

Conditions
-----------------
Peripheral Neuropathy, Neuropathic Pain

Intervention / Treatment
-----------------
* Drug: ADL5859
* Drug: Duloxetine
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male and female participants between 18 and 75 years of age, inclusive Body weight of at least 45 kilograms (kg) Diabetes mellitus (type I or II) that is documented to be under stable glycemic control over a period of at least 3 months, as indicated by a glycosylated hemoglobin (HbgAIC) of less than or equal to 12% and a stable dose of insulin or oral diabetic medication for 90 days prior to starting study medication No change in diabetic medications is planned for the duration of the study Evidence of symmetrical, bilateral pain in the lower extremities due to diabetic peripheral neuropathy (DPN) Presence of daily pain due to DPN for at least 3 months Score greater than or equal to 3 on the physical examination portion of the Michigan Neuropathy Screening Instrument (MNSI) Average weekly pain score of greater than or equal to 4 on the numeric pain rating scale (NPRS) for symmetrical neuropathic pain in the feet and legs For male participants, be surgically sterile or agree to use an appropriate method of contraception For female participants of childbearing potential, be surgically sterile or using an intrauterine device, or injectable, transdermal, or combination oral contraceptive deemed highly effective by the Food and Drug Administration (FDA) Be willing and able to comply with the protocol requirements Be able to understand and willing to provide written informed consent in English Exclusion Criteria: Presence of pain conditions that cannot be distinguished from DPN Presence of significant renal disease, as indicated by a serum creatinine greater than or equal to 2.0 milligrams per deciliter (mg/dL), or presence of significant hepatic disease Have a history of a seizure disorder Presence of serious or unstable cardiovascular disease, respiratory disease, hematologic illness, or a psychiatric condition History of evidence of symptomatic orthostatic hypotension History of a major depressive disorder, generalized anxiety disorder, eating disorder, or substance abuse (including alcohol) within the past year History or evidence of mania, bipolar disorder, or psychosis History of allergy to acetaminophen or duloxetine Score of greater than or equal to 18 on the Beck Depression Inventory II (BDI-II) or score of greater than zero on Item 9 of the BDI-II Use of any of the following concomitant medications: fluvoxamine; quinolone antimicrobials (ciprofloxacin and enoxacin); selective serotonin reuptake inhibitors (SSRIs); serotonin norepinephrine reuptake inhibitors (SNRIs); tricyclic antidepressants; opioids; nonsteroidal anti-inflammatory drugs (NSAIDS); anticonvulsants; aspirin (with the exception of low-dose aspirin as cardiovascular prophylaxis); or cytochrome P4503A (CYP3A) and P-glycoprotein transporter inhibitors Pregnant, lactating, or plans to become pregnant during the study Presence of foot or toe amputation Participation in another study with an investigational compound within the previous 30 days prior to study medication administration, or concurrent participation in another clinical study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 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: ADL5859<br>2 x 50 milligrams (mg) ADL5859 capsules administered orally once in the morning and once in the evening for 28 days | Drug: ADL5859<br> <br> |
| Active Comparator: Duloxetine<br>2 x 30 mg duloxetine capsules administered orally once in the morning and 2 placebo capsules filled with lactose administered orally once in the evening for 28 days | Drug: Duloxetine<br> <br> * Other names: Cymbalta;Drug: Placebo<br> <br> |
| Placebo Comparator: Placebo<br>2 placebo capsules filled with lactose administered orally once in the morning and once in the evening for 28 days | Drug: Placebo<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Numeric Pain Rating Scale (NPRS) Score | The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. The mean of the daily average scores were calculated from the NPRS pain assessments obtained up to 3 times per day over a 7-day period. Least Squares (LS) means were calculated using analysis of covariance (ANCOVA) with treatment group as a main factor and baseline NPRS score as a covariate. Change from Baseline = NPRS at baseline - NPRS at Week 4; a positive number in the LS mean indicates a reduction in pain intensity from baseline. | Baseline, Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Responders | A responder was defined as a participant who showed a reduction in average pain (as measured by NPRS) of at least 30% from baseline to Week 4. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. The percentage of participants who qualified as responders is presented per treatment arm. | Baseline, Week 4 | 
| Patient Global Impression of Change (PGIC) | PGIC is a participant-rated instrument that measures the change in the participant's overall status for the previous 2 weeks based on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). The number of participants in each category is presented. | Week 4 | 
| Change in Sleep Interference Scale (SIS) From Baseline | Sleep Interference was assessed on an 11-point Numeric Rating Scale where a score of 0 indicated pain did not interfere with sleep and a score of 10 indicated pain completely interfered with sleep. Here, n signifies Number of participants for Baseline and Month 3 telephone interview whereas n signifies number of observations for Month 1, 2, and 3 because a participant could have had multiple visits during Month 1, 2, and 3 as this was a non-interventional study with no scheduled study visits, except Baseline visit and the Month 3 telephone interview. LS means were calculated using ANCOVA with treatment group as a main factor and baseline SIS score as a covariate. Change from baseline = SIS score at baseline - SIS score at Week 4. | Baseline, Week 4 | 
| Change From Baseline in the Evening Assessment of the 24-hour Overall Mean Pain Intensity Score | At each of the evening pain assessments, participants assessed their overall pain intensity over the preceding 24 hours using NPRS. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. The mean of the daily average scores were calculated from the NPRS pain assessments obtained at Baseline and Week 4. Change from baseline = NPRS at baseline - NPRS at Week 4. | Baseline, Week 4 | 
| Change From Baseline in NPRS at Rest in the Clinic | The mean of the daily average scores were calculated from the NPRS pain assessments obtained 1 time per week over a 4-week period. NPRS assessments were taken while the participant was at rest. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. LS means were calculated using ANCOVA with treatment group as a main factor and baseline NPRS score as a covariate. Change from baseline = NPRS at baseline - NPRS at Weeks 1, 2, 3, and 4. | Baseline, Week 1, Week 2, Week 3, Week 4 | 
| Change From Baseline in NPRS After Walking 50 Feet in the Clinic | The mean of the daily average scores were calculated from the NPRS pain assessments obtained 1 time per week over a 4-week period. NPRS assessments were taken after the participant walked 50 feet in the clinic. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain. LS means were calculated using ANCOVA with treatment group as a main factor and baseline NPRS score as a covariate. Change from baseline = NPRS at baseline - NPRS at Weeks 1, 2, 3, and 4. | Baseline, Week 1, Week 2, Week 3, Week 4 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diabetic Peripheral Neuropathy, Neuropathic Pain