Treatment of Neuropathic Pain Associated With Diabetic Peripheral Neuropathy

Phase 2

Completed

• Conditions: Diabetic Peripheral Neuropathy
• Interventions: Drug: DS-5565 tablet; Drug: pregabalin capsule; Drug: placebo capsule; Drug: Placebo tablet

• Registration Number: NCT01496365
• Lead Sponsor: Daiichi Sankyo

Brief Summary

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

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.

Study Timeline

• Study Start: 2011-11-28
• Study First Submitted: 2011-12-19
• Study First Submitted QC: 2011-12-20
• Study First Posted: 2011-12-21
• Primary Completion: 2012-09-07
• Study Completion: 2012-09-07
• Disposition First Submitted: 2014-02-07
• Disposition First Submitted QC: 2014-02-07
• Disposition First Posted: 2014-03-11
• Results First Submitted: 2020-11-03
• Status Verified: 2020-12
• Results First Submitted QC: 2020-12-08
• Last Update Submitted: 2020-12-08
• Results First Posted: 2021-01-05
• Last Update Posted: 2021-01-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 452

Inclusion Criteria

1. Age > 18 years of age
2. Able to give informed consent and willing to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures
3. 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)
4. 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
5. At Screening, a pain score of ≥ 40 mm on the SF-MPQ VAS
6. 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)
7. Creatinine clearance > 60 mL/min (estimated using the Cockcroft-Gault equation)
8. Antidiabetic and other medications anticipated to remain stable and constant during the study period
9. 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

1. Diagnosis of mononeuropathy
2. Use of concomitant medications that may confound assessments of efficacy and/or safety (see Section 5.2)
3. Major psychiatric disorders
4. Have had a malignancy other than basal cell carcinoma within the past 2 years
5. At Visit 1, have a white blood cell count < 2500/mm3, neutrophil count < 1500/mm3, or platelet count < 100 x 103/mm3
6. 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
7. Clinically significant findings on the Screening ECG
8. History of pernicious anemia, untreated hypothyroidism, chronic hepatitis B, hepatitis B within the past 3 months, or human immunodeficiency virus infection
9. Amputations of body parts other than toes
10. 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)
11. Known hypersensitivity to pregabalin or gabapentin
12. Requirement for concomitant anticonvulsant and antidepressant therapy, with the exception of stable doses of SSRIs
13. Neurologic disorders unrelated to DPN that may confound the assessment of pain associated with DPN
14. Skin conditions that could alter sensation
15. Other sources of pain that may confound assessment or self-evaluation of the pain due to DPN
16. Abuse of prescription medications, street drugs or alcohol (including alcohol dependence) within the last 1 year
17. 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
18. Pregnancy (as based on lab test results) or breast feeding
19. Laboratory values exceeding limits listed in Table 4.1 of the protocol

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
DS-5565 5mg nighttime	DS-5565 tablet	DS-5565 5 mg/day (one 5 mg tablet at bedtime)
DS-5565 5mg nighttime	placebo capsule	DS-5565 5 mg/day (one 5 mg tablet at bedtime)
DS-5565 10 mg at bedtime	DS-5565 tablet	DS-5565 10 mg/day (one 10 mg tablet at bedtime)
DS-5565 10 mg at bedtime	placebo capsule	DS-5565 10 mg/day (one 10 mg tablet at bedtime)
DS-5565 15 mg at bedtime	DS-5565 tablet	DS-5565 15 mg/day (one 5 mg tablet plus one 10 mg tablet at bedtime)
DS-5565 15 mg at bedtime	placebo capsule	DS-5565 15 mg/day (one 5 mg tablet plus one 10 mg tablet at bedtime)
DS-5565 20 mg total per day	DS-5565 tablet	DS-5565 20 mg/day (one 10 mg tablet in the morning and one 10 mg tablet at bedtime)
DS-5565 20 mg total per day	placebo capsule	DS-5565 20 mg/day (one 10 mg tablet in the morning and one 10 mg tablet at bedtime)
DS-5565 30 mg total per day	DS-5565 tablet	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)
DS-5565 30 mg total per day	placebo capsule	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)
Pregabalin 300 mg total per day	pregabalin capsule	Pregabalin 300 mg/day (two 150 mg capsules, in the morning and at bedtime)
Pregabalin 300 mg total per day	Placebo tablet	Pregabalin 300 mg/day (two 150 mg capsules, in the morning and at bedtime)

Primary Outcome Measures

Name	Time	Method
Mean Change From Baseline to Week 5 in Average Daily Pain Score (ADPS) Following Treatment With DS-5565 Compared to Pregabalin and Placebo	Baseline up to Week 5 postdose, up to 10 months total follow up	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).

Secondary Outcome Measures

Name	Time	Method
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	Baseline up to Week 5 postdose, up to 10 months total follow up	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.
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	Baseline up to Week 5 postdose, up to 10 months total follow up	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.
Mean Change From Baseline to End-of-Treatment in Average Daily Sleep Interference Score Following Treatment With DS-5565 Compared to Pregabalin and Placebo	Baseline up to Week 5 postdose, up to 10 months total follow up	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.
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	Baseline up to Week 5 postdose, up to 10 months total follow up	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).
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	Baseline up to Week 5 postdose, up to 10 months total follow up	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.
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	Baseline up to Week 5 postdose, up to 10 months total follow up	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.
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	Baseline up to Week 5 postdose, up to 10 months total follow up	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.
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	Baseline up to Week 5 postdose, up to 10 months total follow up	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.
Mean Change From Baseline to Endpoint of Modified BPI Subscale, Pain Right Now, Following Treatment With DS-5565 Compared to Pregabalin and Placebo	Baseline up to Week 5 postdose, up to 10 months total follow up	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.
Mean Change From Baseline to Endpoint of Modified BPI Subscale, Relief From Pain, Following Treatment With DS-5565 Compared to Pregabalin and Placebo	Baseline up to Week 5 postdose, up to 10 months total follow up	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.
Patient Global Impression of Change at End-of-Treatment or Early Termination Following Treatment With DS-5565 Compared to Pregabalin and Placebo	Baseline up to Week 5 postdose, up to 10 months total follow up	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).
Drug-related Treatment-Emergent Adverse Events (n ≥2 Participants in Any Treatment Group) Following Treatment With DS-5565 Compared to Pregabalin and Placebo	From the time of signing the informed consent form (ICF) up to 10 months postdose	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.