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Completed

NCT Number: NCT01089556

A Study in Painful Diabetic Neuropathy

This study will investigate the efficacy of a combination treatment of duloxetine + pregabalin compared with the maximal dose of each drug in monotherapy, in patients with diabetic peripheral neuropathic pain (DPNP) who have not responded to the standard recommended dose of either drug. It will provide an answer to a common clinical question, namely, is it better to increase the dose of the current monotherapy or to combine both treatments early on, in patients who do not respond to standard doses of duloxetine or pregabalin.

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Key information

Conditions

Diabetic Neuropathy, Painful Diabetes Complications Diabetes Mellitus Diabetic Neuropathies Endocrine System Diseases Nervous System Diseases Neuromuscular Diseases Peripheral Nervous System Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician., Newcastle, New South Wales, Australia

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Pain due to bilateral peripheral neuropathy (caused by type 1 or type 2 diabetes mellitus. Pain must begin in the feet, with relatively symmetrical onset. Daily pain should be present for more than 3 months [assessed by questioning patient]).
  • Score of at least 4 on the 24-hour average pain severity score on an 11-point Likert scale [on Brief Pain Inventory (BPI) Modified Short Form] at screening and at randomization.
  • Patient is currently not receiving treatment for diabetic peripheral neuropathic pain (DPNP) or was receiving treatment for DPNP, with a drug other than pregabalin or duloxetine, and completed the required washout
  • Patient has never received treatment with duloxetine or pregabalin. (However, a short course of less than 15 days of treatment, at any time previously, will be allowed.)
  • Stable glycemic control, as assessed by a physician investigator, and hemoglobin A1c (HbA1c) less than or equal to 12% at screening.

Exclusion criteria

  • Have a known hypersensitivity to duloxetine or pregabalin or any of the inactive ingredients or have any contraindication for the use of duloxetine or pregabalin.
  • Have uncontrolled narrow-angle glaucoma.
  • Have received treatment with a monoamine oxidase inhibitor (MAOI) within 14 days prior to randomization, or have a potential need to use a MAOI during the study or within 5 days after discontinuation of study drug.
  • Have received fluoxetine within 30 days prior to randomization.
  • Have acute liver injury (such as hepatitis) or severe cirrhosis (Child-Pugh Class C).
  • Have a serum creatinine greater than or equal to 1.5 milligram per deciliter (mg/dL) or a creatinine clearance less than 60 milliliter per minute (mL/min), at screening.
  • Are judged clinically by the investigator to be at suicidal risk or as defined by a score of 2 or greater on Question 9 of the Beck Depression Inventory-II (BDI-II), at screening or randomization
  • Have a historical exposure to drugs known to cause neuropathy (for example, vincristine), or a history of a medical condition, including pernicious anemia and hypothyroidism, that could have been responsible for neuropathy.
  • Have pain that cannot be clearly differentiated from or conditions that interfere with the assessment of the DPNP.
  • Have serious or unstable cardiovascular, hepatic, renal, respiratory or hematological illness; symptomatic peripheral vascular disease; a history of seizure disorder; or other medical (including unstable hypertension and not clinically euthyroid) or psychological conditions that, in the opinion of the investigator, would compromise participation or be likely to require hospitalization during the course of the study.
  • Have received non-pharmacological treatment for pain within 14 days prior to randomization, or do not agree to abstain from non-pharmacological treatment during the study.
  • Have a history of frequent and/or severe allergic reactions with multiple medications.

Treatment and study plan

Duloxetine

Drug

Administered orally

Other names: Cymbalta, LY248686

Pregabalin

Drug

Administered orally

Placebo

Drug

Administered orally, daily as a blind for duloxetine and/or pregabalin for 8 or 16 weeks

Primary outcomes

  1. Change From Week 8 to Week 16 Endpoint in 24 Hour Average Pain Item Score on the Brief Pain Inventory (BPI) Modified Short Form

    Time frame: Week 8, Week 16

    BPI Modified Short Form 24-Hour average pain item score is a self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment*visit, baseline*visit and treatment in Study Period II.

Secondary outcomes

  1. Mean Change From Week 8 to Week 16 Endpoint in Items of the Brief Pain Inventory (BPI) Modified Short Form Worst Pain Score

    Time frame: Week 8, Week 16

    BPI Modified Short Form worst pain score is a self-reported scale that measures the severity of pain based on the worst pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment*visit, baseline*visit and treatment in Study Period II.

  2. Percentage of Participants With a Reduction of Greater Than or Equal to 30% on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 16 Endpoint

    Time frame: Week 8 through Week 16

    BPI Modified Short Form 24-Hour average pain item score is a self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine).

  3. Percentage of Participants With a Reduction of Greater Than or Equal to 50% on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 16 Endpoint

    Time frame: Week 8 through Week 16

    BPI Modified Short Form 24-Hour average pain item score is a self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine).

  4. Percentage of Participants With a Decrease of Greater Than or Equal to 2 Points on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 16 Endpoint

    Time frame: Week 8 through Week 16

    BPI Modified Short Form 24-Hour average pain item score is a self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine).

  5. Clinical Global Impression of Improvement (CGI-I) at Week 16 Endpoint

    Time frame: Week 16

    Measures clinician's perception of participant improvement at the time of assessment compared with the start of treatment for Study Period III. Scores range from 1 (very much better) to 7 (very much worse). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment*visit, baseline*visit and treatment in Study Period II.

  6. Mean Change From Week 8 to Week 16 Endpoint on the Neuropathic Pain Symptom Inventory (NPSI) Questionnaire

    Time frame: Week 8, Week 16

    The NPSI is a 12-item self-administered questionnaire to assess 5 different dimensions of neuropathic pain: superficial spontaneous burning pain, deep spontaneous pressing pain, paroxysmal pain, evoked pains, and paresthesias/dysesthesias. A total score ranges from 0 to 100. Higher score indicates a greater intensity of pain. Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment*visit, baseline*visit and treatment in Study Period II.

  7. Mean Change From Week 8 to Week 16 Endpoint in Sheehan Disability Scale (SDS)

    Time frame: Week 8, Week 16

    The SDS is completed by the participant and is used to assess the effect of the participant's symptoms on their work (Item 1), social (Item 2), and family life (Item 3). Each item is measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. Total scores is the sum of the 3 items and range from 0 to 30 with higher values indicating greater disruption in the participant's work/social/family life. Least Squares (LS) Mean values are controlled for treatment, site, baseline value, treatment*site and treatment in Study Period II.

  8. Mean Change From Week 8 to Week 16 Endpoint in Hospital Anxiety and Depression Scale (HADS)

    Time frame: Week 8, Week 16

    A 14-item questionnaire with 2 subscales: anxiety and depression. Each item is rated on a 4-point scale (0-3), giving maximum scores of 21 for anxiety and for depression. Scores of 11 or more on either subscale are considered to be a significant case of psychological morbidity, while scores of 8-10 represent 'borderline' and 0-7 represent 'normal.' Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment*visit, baseline*visit and treatment in Study Period II.

  9. Resource Utilization (Number of Days Hospitalized, Number of Days of Sick Leave) Week 8 Through Week 16

    Time frame: Week 8 through Week 16

    Data presented are the number of days hospitalized and work/school missed (sick leave) due to diabetic peripheral neuropathic pain (DPNP) during the last 8 weeks.

  10. Patient Global Impression of Improvement (PGI-I) Score at Week 16 Endpoint

    Time frame: Week 16

    Measures participant's perception of improvement at the time of assessment compared with the start of treatment for Study Period III. The score ranges from 1 (very much better) to 7 (very much worse). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment*visit, baseline*visit and treatment in Study Period II.

  11. Mean Change in Blood Pressure (BP) From Week 8 to Week 16 Endpoint

    Time frame: Week 8, Week 16

    Least Squares (LS) mean values are controlled for treatment, site, baseline value, treatment*site and treatment in Study Period II.

  12. Mean Change in Heart Rate From Week 8 to Week 16 Endpoint

    Time frame: Week 8, Week 16

    Least Squares (LS) mean values are controlled for treatment, site, baseline value, treatment*site and treatment in Study Period II.

  13. Number of Participants With Treatment Emergent Adverse Events (TEAEs) Between Week 8 and Week 16 Endpoint

    Time frame: Week 8 through Week 16

    TEAEs in Study Period III are events that began or worsened after Week 8 compared with the period before Week 8.

  14. Number of Participants Who Discontinued From Study Between Week 8 and Week 16 Endpoint

    Time frame: Week 8 through Week 16

Other outcomes

  1. Mean Change From Baseline to Week 8 Endpoint in 24 Hour Average Pain Item Score on the Brief Pain Inventory (BPI) Modified Short Form

    Time frame: Baseline, Week 8

    BPI Modified Short Form 24-Hour average pain item score is a self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment*visit and baseline*visit.

  2. Percentage of Participants With a Reduction of Greater Than or Equal to 30% on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 8 Endpoint

    Time frame: Baseline through Week 8

    BPI Modified Short Form 24-Hour average pain item score is a self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine).

  3. Percentage of Participants With a Reduction of Greater Than or Equal to 50% on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 8 Endpoint

    Time frame: Baseline through Week 8

    BPI Modified Short Form 24-Hour average pain item score is a self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine).

  4. Percentage of Participants With a Decrease of Greater Than or Equal to 2 Points on Brief Pain Inventory (BPI) Modified Short Form 24-Hour Average Pain Item Score at Week 8 Endpoint

    Time frame: Baseline through Week 8

    BPI Modified Short Form 24-Hour average pain item score is a self-reported scale that measures the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine).

  5. Clinical Global Impression of Improvement (CGI-I) at Week 8 Endpoint

    Time frame: Week 8

    Measures clinician's perception of participant improvement at the time of assessment compared with the start of treatment. Scores range from 1 (very much better) to 7 (very much worse). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, visit, and treatment*visit.

  6. Mean Change From Baseline to Week 8 Endpoint on the Neuropathic Pain Symptom Inventory (NPSI) Questionnaire

    Time frame: Baseline, Week 8

    The NPSI is a 12-item self-administered questionnaire to assess 5 different dimensions of neuropathic pain: superficial spontaneous burning pain, deep spontaneous pressing pain, paroxysmal pain, evoked pains, and paresthesias/dysesthesias. A total score ranges from 0 to 100. Higher score indicates a greater intensity of pain. Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment*visit and baseline*visit.

  7. Mean Change From Baseline to Week 8 Endpoint in Sheehan Disability Scale (SDS)

    Time frame: Baseline, Week 8

    The SDS is completed by the participant and is used to assess the effect of the participant's symptoms on their work (Item 1), social (Item 2), and family life (Item 3). Each item is measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. Total scores is the sum of the 3 items and range from 0 to 30 with higher values indicating greater disruption in the participant's work/social/family life. Least Squares (LS) mean values are controlled for treatment, site, baseline value and treatment*site.

  8. Mean Change From Baseline to Week 8 Endpoint in Hospital Anxiety and Depression Scale (HADS)

    Time frame: Baseline, Week 8

    A 14-item questionnaire with 2 subscales: anxiety and depression. Each item is rated on a 4-point scale (0-3), giving maximum scores of 21 for anxiety and for depression. Scores of 11 or more on either subscale are considered to be a significant case of psychological morbidity, while scores of 8-10 represent 'borderline' and 0-7 represent 'normal.' Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, baseline value, visit, treatment*visit and baseline*visit.

  9. Resource Utilization (Number of Days Hospitalized, Number of Days of Sick Leave) Baseline Through Week 8

    Time frame: Baseline through Week 8

    Data presented are the number of days hospitalized and work/school missed (sick leave) due to diabetic peripheral neuropathic pain (DPNP) during the last 8 weeks.

  10. Average Number of Hours Worked for Pay Per Week Baseline Through Week 8

    Time frame: Baseline through Week 8

    Data presented are the average number of hours worked for pay per week during the last 8 weeks.

  11. Average Number of Hours Worked for Pay Per Week Week 8 Through Week 16

    Time frame: Week 8 through Week 16

    Data presented are the average number of hours worked for pay per week during the last 8 weeks.

  12. Patient Global Impression of Improvement (PGI-I) Score at Week 8 Endpoint

    Time frame: Week 8

    Measures participant's perception of improvement at the time of assessment compared with the start of treatment. The score ranges from 1 (very much better) to 7 (very much worse). Mixed-effects model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) Mean and 95% Confidence Interval (CI). LS Mean values are controlled for treatment, site, visit, and treatment*visit.

  13. Mean Change in Blood Pressure (BP) From Baseline to Week 8 Endpoint

    Time frame: Baseline, Week 8

    Least Squares (LS) mean values are controlled for treatment, site, baseline value, and treatment*site.

  14. Mean Change in Heart Rate From Baseline to Week 8 Endpoint

    Time frame: Baseline, Week 8

    Least Squares (LS) mean values are controlled for treatment, site, baseline value, and treatment*site.

  15. Number of Participants With Treatment Emergent Adverse Events (TEAE) Between Baseline and Week 8 Endpoint

    Time frame: Baseline through Week 8

    TEAEs in Study Period II are events that began or worsened after Week 0 compared with the period before Week 0.

  16. Number of Participants Who Discontinued From Study Between Baseline and Week 8 Endpoint

    Time frame: Baseline through Week 8

Sponsors and collaborators

Lead sponsor

Eli Lilly and Company

Industry

Collaborators

  • Boehringer Ingelheim

Registry information

Official study title

Use of Duloxetine or Pregabalin in Monotherapy Versus Combination Therapy of Both Drugs in Patients With Painful Diabetic Neuropathy "The COMBO - DN (COmbination vs Monotherapy of pregaBalin and dulOxetine in Diabetic Neuropathy) Study"

Acronym: COMBO-DN

Important dates

Study start
2010
Primary completion
2011
Study completion
2011
First posted
Mar 18, 2010
Registry last updated
Jan 24, 2013

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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