Treatment of Neuropathic Pain Associated With Diabetic Peripheral Neuropathy

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability and effectiveness of DS-5565 compared to placebo (inactive substance) and pregabalin in diabetic subjects with DPN.

Detailed Description
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Diabetic peripheral neuropathy (DPN) affects up to 50% of patients who have diabetes for at least 25 years. Up to 26% of all patients with DPN experience neuropathic pain. DPN pain contributes to sleep disorders, depression, and anxiety, which together may have an impact on a patient's well-being and quality of life. There are currently several drugs used to treat painful DPN. For example, Lyrica® (pregabalin) is approved by the United States Food and Drug Administration (FDA) to treat neuropathic pain associated with DPN and is commonly prescribed. The dosage of the FDA-approved drugs is limited by side-effects such as dizziness, sleepiness, weight gain and swelling of the hands, legs, and feet. As a result, many patients suffering from DPN pain do not get satisfactory pain relief.

Official Title
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A Randomized, Double-Blind, Placebo and Active Comparator-Controlled Study of DS-5565 for Treatment of Neuropathic Pain Associated With Diabetic Peripheral Neuropathy

Conditions
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Diabetic Peripheral Neuropathy

Intervention / Treatment
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* Drug: DS-5565 tablet
* Drug: pregabalin capsule
* Drug: Placebo tablet
* Drug: placebo capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years of age Able to give informed consent and willing to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures Type 1 or type 2 diabetes with a hemoglobin A1c (HbA1c) ≤ 10% at Screening and on a stable antidiabetic medication regimen for at least 30 days prior to Screening (insulin therapy is acceptable) Painful distal symmetrical sensorimotor polyneuropathy (as per American Society of Pain Educators guidelines ) diagnosed for at least 6 months, based on neurological history and/or examination; diagnosis includes absent or reduced deep tendon reflexes at both ankles At Screening, a pain score of ≥ 40 mm on the SF-MPQ VAS At Randomization, a pain score of ≥ 40 mm on the SF-MPQ VAS and an ADPS of ≥ 4 on the 11-point NRS, the latter calculated from a minimum of 4 pain ratings in daily diaries obtained during the 1-week Baseline Period (prior to randomization) Creatinine clearance > 60 mL/min (estimated using the Cockcroft-Gault equation) Antidiabetic and other medications anticipated to remain stable and constant during the study period Women of child bearing potential (WOCBP) must be using an adequate method of contraception as detailed in the protocol to avoid pregnancy during the study and for 4 weeks after study completion Exclusion Criteria: Diagnosis of mononeuropathy Use of concomitant medications that may confound assessments of efficacy and/or safety (see Section 5.2) Major psychiatric disorders Have had a malignancy other than basal cell carcinoma within the past 2 years At Visit 1, have a white blood cell count < 2500/mm3, neutrophil count < 1500/mm3, or platelet count < 100 x 103/mm3 Clinically significant unstable diabetes mellitus, unstable hepatic, respiratory, or hematologic illness, unstable cardiovascular disease (including myocardial infarction in the 3 months prior to Visit 1), or symptomatic peripheral vascular disease Clinically significant findings on the Screening ECG History of pernicious anemia, untreated hypothyroidism, chronic hepatitis B, hepatitis B within the past 3 months, or human immunodeficiency virus infection Amputations of body parts other than toes Prior therapeutic failure of pregabalin or gabapentin (considered unresponsive or intolerant to treatment); therapeutic failure implies lack of efficacy following full titration to effective doses (eg, 300 mg/day for pregabalin) Known hypersensitivity to pregabalin or gabapentin Requirement for concomitant anticonvulsant and antidepressant therapy, with the exception of stable doses of SSRIs Neurologic disorders unrelated to DPN that may confound the assessment of pain associated with DPN Skin conditions that could alter sensation Other sources of pain that may confound assessment or self-evaluation of the pain due to DPN Abuse of prescription medications, street drugs or alcohol (including alcohol dependence) within the last 1 year Current enrollment in another investigational study, participation in another investigational study with the past 30 days, or other current or recent use of any investigational drug Pregnancy (as based on lab test results) or breast feeding Laboratory values exceeding limits listed in Table 4.1 of the protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DS-5565 5mg nighttime<br>DS-5565 5 mg/day (one 5 mg tablet at bedtime) | Drug: DS-5565 tablet<br>* 5mg and 10mg tablets<br>Drug: placebo capsule<br> <br> * Other names: placebo capsule matching over-encapsulated pregabalin;|
| Experimental: DS-5565 10 mg at bedtime<br>DS-5565 10 mg/day (one 10 mg tablet at bedtime) | Drug: DS-5565 tablet<br>* 5mg and 10mg tablets<br>Drug: placebo capsule<br> <br> * Other names: placebo capsule matching over-encapsulated pregabalin;|
| Experimental: DS-5565 15 mg at bedtime<br>DS-5565 15 mg/day (one 5 mg tablet plus one 10 mg tablet at bedtime) | Drug: DS-5565 tablet<br>* 5mg and 10mg tablets<br>Drug: placebo capsule<br> <br> * Other names: placebo capsule matching over-encapsulated pregabalin;|
| Experimental: DS-5565 20 mg total per day<br>DS-5565 20 mg/day (one 10 mg tablet in the morning and one 10 mg tablet at bedtime) | Drug: DS-5565 tablet<br>* 5mg and 10mg tablets<br>Drug: placebo capsule<br> <br> * Other names: placebo capsule matching over-encapsulated pregabalin;|
| Experimental: DS-5565 30 mg total per day<br>DS-5565 30 mg/day (one 5 mg tablet plus one 10 mg tablet in the morning and one 5 mg tablet plus one 10 mg tablet at bedtime) | Drug: DS-5565 tablet<br>* 5mg and 10mg tablets<br>Drug: placebo capsule<br> <br> * Other names: placebo capsule matching over-encapsulated pregabalin;|
| Active Comparator: Pregabalin 300 mg total per day<br>Pregabalin 300 mg/day (two 150 mg capsules, in the morning and at bedtime) | Drug: pregabalin capsule<br>* 75mg and 150mg over-encapsulated<br>* Other names: Lyrica;Drug: Placebo tablet<br> <br> * Other names: placebo tablet matching DS-5565 tablet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline to Week 5 in Average Daily Pain Score (ADPS) Following Treatment With DS-5565 Compared to Pregabalin and Placebo | Average daily pain score (ADPS) is a participant-reported instrument that measures pain intensity using an 11-point numeric rating scale (NRS) where 0 is defined as no pain and 10 is defined as worst possible pain. Higher scores indicate worse pain intensity level. The change from baseline to Week 5 is reported where a negative value is considered an improvement in pain intensity. A minimally meaningful effect was defined as a decrease of at least 1.0 point [scale of 0 to 10] versus placebo). | Baseline up to Week 5 postdose, up to 10 months total follow up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Least Square Means of Average Daily Pain Score by Week Mixed Effects Model for Repeated Measures (MMRM) Following Treatment With DS-5565 Compared to Pregabalin and Placebo | Average daily pain score (ADPS) is a participant-reported instrument that measures pain intensity using an 11-point numeric rating scale (NRS) where 0 is defined as no pain and 10 is defined as worst possible pain. Higher scores indicate worse pain intensity level. The least square means of ADPS (assessed by MMRM) are reported where a negative value is considered an improvement in pain intensity. A minimally meaningful effect was defined as a decrease of at least 1.0 point [scale of 0 to 10] versus placebo). | Baseline up to Week 5 postdose, up to 10 months total follow up | 
| Average Daily Pain Score Responder Rates Based on ≥30% and ≥50% Decrease From Baseline at Endpoint) Following Treatment With DS-5565 or Placebo Compared to Pregabalin | Average daily pain score (ADPS) is a participant-reported instrument that measures pain intensity using an 11-point numeric rating scale (NRS) where 0 is defined as no pain and 10 is defined as worst possible pain. Higher scores indicate worse pain intensity level. | Baseline up to Week 5 postdose, up to 10 months total follow up | 
| Mean Change From Baseline to End-of-Treatment in Average Daily Sleep Interference Score Following Treatment With DS-5565 Compared to Pregabalin and Placebo | Average Daily Sleep Interference Score (ADSIS) is the weekly average of patient-reported sleep interference (rated every morning on a numerical scale of 0 = pain did not interfere with sleep to 10 = pain completely interfered with sleep over the past 24 h), where higher scores indicate worse outcome.The change from baseline to Week 5 in ADSIS is being reported as the average of the last 7 available daily scores. The greater the negative value, the greater the improvement in sleep. | Baseline up to Week 5 postdose, up to 10 months total follow up | 
| Short-Form McGill Pain Questionnaire (SF-MPQ) Sensory and Affective Scores Change From Baseline to Endpoint Following Treatment With DS-5565 Compared to Pregabalin and Placebo | The SF-MPQ sensory score is the sum of 11 pain descriptors each scored from 0 to 3: throbbing, shooting, stabbing, sharp cramping, gnawing, hot-burning, aching, heavy, tender, and splitting. Thus, the SF-MPQ sensory score ranges from 0 to 33, where lower scores indicate a better outcome. The SF-MPQ affective score is the sum of four pain descriptors each scored from 0 to 3: tiring-exhausting, sickening, fearful, and punishing cruel. Thus, SF-MPQ affective score ranges from 0 to 12, where lower scores indicate a better outcome. The change from baseline to Week 5 in SF-MPQ sensory and affective scores are being reported. The greater the negative value, the greater the improvement in sensory and affective scores. | Baseline up to Week 5 postdose, up to 10 months total follow up | 
| Short-Form McGill Pain Questionnaire (SF-MPQ) Total Score and Visual Analog Scale Change From Baseline to Endpoint Following Treatment With DS-5565 Compared to Pregabalin and Placebo | The SF-MPQ sensory score is the sum of 11 pain descriptors each scored from 0 to 3: throbbing, shooting, stabbing, sharp cramping, gnawing, hot-burning, aching, heavy, tender, and splitting. Thus, the SF-MPQ sensory score ranges from 0 to 33, where lower scores indicate a better outcome. The SF-MPQ affective score is the sum of four pain descriptors each scored from 0 to 3: tiring-exhausting, sickening, fearful, and punishing cruel. Thus, SF-MPQ affective score ranges from 0 to 12, where lower scores indicate a better outcome. The SF-MPQ total score comprises the sum of the sensory and affective scores. The SF-MPQ VAS ranges from 0 (no pain) to 100 (worst possible pain), where lower scores indicate a better outcome. The change from baseline to Week 5 in SF-MPQ total score and VAS are being reported. The greater the negative value, the greater the improvement in total score (sensory and affective scores) and VAS pain. | Baseline up to Week 5 postdose, up to 10 months total follow up | 
| Short-Form McGill Pain Questionnaire (SF-MPQ) Present Pain Intensity Change From Baseline to Endpoint Following Treatment With DS-5565 Compared to Pregabalin and Placebo | The SF-MPQ present pain intensity ranges from 0 (no pain) to 5 (excruciating), where lower scores indicate a better outcome. The change from baseline to Week 5 in SF-MPQ present pain intensity is being reported. The greater the negative value, the greater the improvement in present pain intensity. | Baseline up to Week 5 postdose, up to 10 months total follow up | 
| Mean Change From Baseline to Endpoint of Modified Brief Pain Inventory (BPI) Subscale, Interference With Daily Functions, Following Treatment With DS-5565 Compared to Pregabalin and Placebo | The Modified Brief Pain Inventory (BPI) includes Interference with Daily Functions Subscale, Worst Pain Intensity, Least Pain Intensity, Average Pain Intensity, Pain Right Now, and Relief From Pain. The range of interference subscale is 0-10, where lower scores indicate a better outcome. The change from baseline to Week 5 in Modified Brief Pain Inventory is being reported. The greater the negative value, the greater the improvement in interference with daily functions. | Baseline up to Week 5 postdose, up to 10 months total follow up | 
| Mean Change From Baseline to Endpoint of Modified BPI Subscales, Worst, Least and Average Pain Intensity, Following Treatment With DS-5565 Compared to Pregabalin and Placebo | The Modified Brief Pain Inventory (BPI) includes Interference with Daily Functions Subscale, Worst Pain Intensity, Least Pain Intensity, Average Pain Intensity, Pain Right Now, and Relief From Pain. The range of worst pain intensity in the last 24 hours is 0-10, where lower scores indicate a better outcome. The range of least pain intensity in the last 24 hours is 0-10, where lower scores indicate a better outcome. The range of average pain intensity in the last 24 hours is 0-10, where lower scores indicate a better outcome. The change from baseline to Week 5 in Modified Brief Pain Inventory is being reported. The greater the negative value, the greater the improvement in worst, least, and average pain intensity. | Baseline up to Week 5 postdose, up to 10 months total follow up | 
| Mean Change From Baseline to Endpoint of Modified BPI Subscale, Pain Right Now, Following Treatment With DS-5565 Compared to Pregabalin and Placebo | The Modified Brief Pain Inventory (BPI) includes Interference with Daily Functions Subscale, Worst Pain Intensity, Least Pain Intensity, Average Pain Intensity, Pain Right Now, and Relief From Pain. The range of pain right now is 0-10, where lower scores indicate a better outcome. The change from baseline to Week 5 in Modified Brief Pain Inventory is being reported. For pain right now, the greater the negative value, the greater the improvement. | Baseline up to Week 5 postdose, up to 10 months total follow up | 
| Mean Change From Baseline to Endpoint of Modified BPI Subscale, Relief From Pain, Following Treatment With DS-5565 Compared to Pregabalin and Placebo | The Modified Brief Pain Inventory (BPI) includes Interference with Daily Functions Subscale, Worst Pain Intensity, Least Pain Intensity, Average Pain Intensity, Pain Right Now, and Relief From Pain. The range of % relief from pain is 0-100, where higher scores indicate a better outcome. The change from baseline to Week 5 in Modified Brief Pain Inventory is being reported. For relief from pain, the higher the score, the greater the improvement in pain relief. | Baseline up to Week 5 postdose, up to 10 months total follow up | 
| Patient Global Impression of Change at End-of-Treatment or Early Termination Following Treatment With DS-5565 Compared to Pregabalin and Placebo | Patient Global Impression of Change (PGIC) has a range of 7 possible responses for overall status since start of the study, where 0 was defined as 'Very much improved' and 7 was defined as 'Very much worse'. Lower scores indicate a better outcome. PGIC was analyzed based on the following definitions: Participant's overall status was minimally improved or better (ie, score ≤3) or Participant's overall status was much improved or better (ie, score ≤ 2). | Baseline up to Week 5 postdose, up to 10 months total follow up | 
| Drug-related Treatment-Emergent Adverse Events (n ≥2 Participants in Any Treatment Group) Following Treatment With DS-5565 Compared to Pregabalin and Placebo | Treatment-emergent adverse events (TEAEs) were defined as adverse events (AEs) which began or worsened in severity after the first administration of study drug. Drug-related TEAEs included AEs that were considered related to the study drug as judged by the Investigator. TEAEs were classified according to MedDRA 14.1. | From the time of signing the informed consent form (ICF) up to 10 months postdose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Keywords: pain, diabetes, neuropathy