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Treatment of Neuropathic Pain Associated With Diabetic Peripheral Neuropathy

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01496365
Recruitment Status : Completed
First Posted : December 21, 2011
Results First Posted : January 5, 2021
Last Update Posted : January 5, 2021
Sponsor:
Information provided by (Responsible Party):
Daiichi Sankyo, Inc.

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.

Condition or disease Intervention/treatment Phase
Diabetic Peripheral Neuropathy Drug: DS-5565 tablet Drug: pregabalin capsule Drug: Placebo tablet Drug: placebo capsule Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 452 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Placebo and Active Comparator-Controlled Study of DS-5565 for Treatment of Neuropathic Pain Associated With Diabetic Peripheral Neuropathy
Actual Study Start Date : November 28, 2011
Actual Primary Completion Date : September 7, 2012
Actual Study Completion Date : September 7, 2012

Resource links provided by the National Library of Medicine

Drug Information available for: Pregabalin

Arm Intervention/treatment
Experimental: DS-5565 5mg nighttime
DS-5565 5 mg/day (one 5 mg tablet at bedtime)
Drug: DS-5565 tablet
5mg and 10mg tablets

Drug: placebo capsule
Other Name: placebo capsule matching over-encapsulated pregabalin

Experimental: DS-5565 10 mg at bedtime
DS-5565 10 mg/day (one 10 mg tablet at bedtime)
Drug: DS-5565 tablet
5mg and 10mg tablets

Drug: placebo capsule
Other Name: placebo capsule matching over-encapsulated pregabalin

Experimental: DS-5565 15 mg at bedtime
DS-5565 15 mg/day (one 5 mg tablet plus one 10 mg tablet at bedtime)
Drug: DS-5565 tablet
5mg and 10mg tablets

Drug: placebo capsule
Other Name: placebo capsule matching over-encapsulated pregabalin

Experimental: DS-5565 20 mg total per day
DS-5565 20 mg/day (one 10 mg tablet in the morning and one 10 mg tablet at bedtime)
Drug: DS-5565 tablet
5mg and 10mg tablets

Drug: placebo capsule
Other Name: placebo capsule matching over-encapsulated pregabalin

Experimental: DS-5565 30 mg total per day
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
5mg and 10mg tablets

Drug: placebo capsule
Other Name: placebo capsule matching over-encapsulated pregabalin

Active Comparator: Pregabalin 300 mg total per day
Pregabalin 300 mg/day (two 150 mg capsules, in the morning and at bedtime)
Drug: pregabalin capsule
75mg and 150mg over-encapsulated
Other Name: Lyrica

Drug: Placebo tablet
Other Name: placebo tablet matching DS-5565 tablet




Primary Outcome Measures :
  1. Mean Change From Baseline to Week 5 in Average Daily Pain Score (ADPS) Following Treatment With DS-5565 Compared to Pregabalin and Placebo [ Time Frame: 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 :
  1. 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 [ Time Frame: 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).

  2. 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 [ Time Frame: 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.

  3. Mean Change From Baseline to End-of-Treatment in Average Daily Sleep Interference Score Following Treatment With DS-5565 Compared to Pregabalin and Placebo [ Time Frame: 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.

  4. 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 [ Time Frame: 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.


  5. 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 [ Time Frame: 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.

  6. 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 [ Time Frame: 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.

  7. 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 [ Time Frame: 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.

  8. 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 [ Time Frame: 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.

  9. Mean Change From Baseline to Endpoint of Modified BPI Subscale, Pain Right Now, Following Treatment With DS-5565 Compared to Pregabalin and Placebo [ Time Frame: 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.

  10. Mean Change From Baseline to Endpoint of Modified BPI Subscale, Relief From Pain, Following Treatment With DS-5565 Compared to Pregabalin and Placebo [ Time Frame: 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.

  11. Patient Global Impression of Change at End-of-Treatment or Early Termination Following Treatment With DS-5565 Compared to Pregabalin and Placebo [ Time Frame: 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).

  12. Drug-related Treatment-Emergent Adverse Events (n ≥2 Participants in Any Treatment Group) Following Treatment With DS-5565 Compared to Pregabalin and Placebo [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01496365


Locations
Show Show 78 study locations
Sponsors and Collaborators
Daiichi Sankyo, Inc.
Investigators
Layout table for investigator information
Study Director: Domenico Merante, MD Daiichi Sankyo, Inc.
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Responsible Party: Daiichi Sankyo, Inc.
ClinicalTrials.gov Identifier: NCT01496365    
Other Study ID Numbers: DS5565-A-U201
First Posted: December 21, 2011    Key Record Dates
Results First Posted: January 5, 2021
Last Update Posted: January 5, 2021
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
URL: https://vivli.org/ourmember/daiichi-sankyo/
Keywords provided by Daiichi Sankyo, Inc.:
Keywords: pain, diabetes, neuropathy
Additional relevant MeSH terms:
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Peripheral Nervous System Diseases
Neuralgia
Diabetic Neuropathies
Neuromuscular Diseases
Nervous System Diseases
Pain
Neurologic Manifestations
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases
Pregabalin
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anticonvulsants
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Calcium-Regulating Hormones and Agents
Anti-Anxiety Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs