A Study in Painful Diabetic Neuropathy (COMBO-DN)

This study has been completed.
Sponsor:
Collaborator:
Boehringer Ingelheim
Information provided by (Responsible Party):
Eli Lilly and Company
ClinicalTrials.gov Identifier:
NCT01089556
First received: March 15, 2010
Last updated: January 17, 2013
Last verified: January 2013
  Purpose

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.


Condition Intervention Phase
Diabetic Neuropathy, Painful
Drug: Duloxetine
Drug: Pregabalin
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official 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"

Resource links provided by NLM:


Further study details as provided by Eli Lilly and Company:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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).

  • 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 ] [ Designated as safety issue: No ]
    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).

  • 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 ] [ Designated as safety issue: No ]
    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).

  • Clinical Global Impression of Improvement (CGI-I) at Week 16 Endpoint [ Time Frame: Week 16 ] [ Designated as safety issue: No ]
    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.

  • Mean Change From Week 8 to Week 16 Endpoint on the Neuropathic Pain Symptom Inventory (NPSI) Questionnaire [ Time Frame: Week 8, Week 16 ] [ Designated as safety issue: No ]
    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.

  • Mean Change From Week 8 to Week 16 Endpoint in Sheehan Disability Scale (SDS) [ Time Frame: Week 8, Week 16 ] [ Designated as safety issue: No ]
    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.

  • Mean Change From Week 8 to Week 16 Endpoint in Hospital Anxiety and Depression Scale (HADS) [ Time Frame: Week 8, Week 16 ] [ Designated as safety issue: No ]
    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.

  • Resource Utilization (Number of Days Hospitalized, Number of Days of Sick Leave) Week 8 Through Week 16 [ Time Frame: Week 8 through Week 16 ] [ Designated as safety issue: No ]
    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.

  • Patient Global Impression of Improvement (PGI-I) Score at Week 16 Endpoint [ Time Frame: Week 16 ] [ Designated as safety issue: No ]
    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.

  • Mean Change in Blood Pressure (BP) From Week 8 to Week 16 Endpoint [ Time Frame: Week 8, Week 16 ] [ Designated as safety issue: Yes ]
    Least Squares (LS) mean values are controlled for treatment, site, baseline value, treatment*site and treatment in Study Period II.

  • Mean Change in Heart Rate From Week 8 to Week 16 Endpoint [ Time Frame: Week 8, Week 16 ] [ Designated as safety issue: Yes ]
    Least Squares (LS) mean values are controlled for treatment, site, baseline value, treatment*site and treatment in Study Period II.

  • Number of Participants With Treatment Emergent Adverse Events (TEAEs) Between Week 8 and Week 16 Endpoint [ Time Frame: Week 8 through Week 16 ] [ Designated as safety issue: Yes ]
    TEAEs in Study Period III are events that began or worsened after Week 8 compared with the period before Week 8.

  • Number of Participants Who Discontinued From Study Between Week 8 and Week 16 Endpoint [ Time Frame: Week 8 through Week 16 ] [ Designated as safety issue: Yes ]

Other Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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).

  • 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 ] [ Designated as safety issue: No ]
    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).

  • 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 ] [ Designated as safety issue: No ]
    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).

  • Clinical Global Impression of Improvement (CGI-I) at Week 8 Endpoint [ Time Frame: Week 8 ] [ Designated as safety issue: No ]
    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.

  • Mean Change From Baseline to Week 8 Endpoint on the Neuropathic Pain Symptom Inventory (NPSI) Questionnaire [ Time Frame: Baseline, Week 8 ] [ Designated as safety issue: No ]
    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.

  • Mean Change From Baseline to Week 8 Endpoint in Sheehan Disability Scale (SDS) [ Time Frame: Baseline, Week 8 ] [ Designated as safety issue: No ]
    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.

  • Mean Change From Baseline to Week 8 Endpoint in Hospital Anxiety and Depression Scale (HADS) [ Time Frame: Baseline, Week 8 ] [ Designated as safety issue: No ]
    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.

  • Resource Utilization (Number of Days Hospitalized, Number of Days of Sick Leave) Baseline Through Week 8 [ Time Frame: Baseline through Week 8 ] [ Designated as safety issue: No ]
    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.

  • Average Number of Hours Worked for Pay Per Week Baseline Through Week 8 [ Time Frame: Baseline through Week 8 ] [ Designated as safety issue: No ]
    Data presented are the average number of hours worked for pay per week during the last 8 weeks.

  • Average Number of Hours Worked for Pay Per Week Week 8 Through Week 16 [ Time Frame: Week 8 through Week 16 ] [ Designated as safety issue: No ]
    Data presented are the average number of hours worked for pay per week during the last 8 weeks.

  • Patient Global Impression of Improvement (PGI-I) Score at Week 8 Endpoint [ Time Frame: Week 8 ] [ Designated as safety issue: No ]
    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.

  • Mean Change in Blood Pressure (BP) From Baseline to Week 8 Endpoint [ Time Frame: Baseline, Week 8 ] [ Designated as safety issue: Yes ]
    Least Squares (LS) mean values are controlled for treatment, site, baseline value, and treatment*site.

  • Mean Change in Heart Rate From Baseline to Week 8 Endpoint [ Time Frame: Baseline, Week 8 ] [ Designated as safety issue: Yes ]
    Least Squares (LS) mean values are controlled for treatment, site, baseline value, and treatment*site.

  • Number of Participants With Treatment Emergent Adverse Events (TEAE) Between Baseline and Week 8 Endpoint [ Time Frame: Baseline through Week 8 ] [ Designated as safety issue: Yes ]
    TEAEs in Study Period II are events that began or worsened after Week 0 compared with the period before Week 0.

  • Number of Participants Who Discontinued From Study Between Baseline and Week 8 Endpoint [ Time Frame: Baseline through Week 8 ] [ Designated as safety issue: Yes ]

Enrollment: 811
Study Start Date: March 2010
Study Completion Date: November 2011
Primary Completion Date: November 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Duloxetine

Initial Treatment:

Duloxetine 30 milligram (mg) daily for 1 week

Duloxetine 60 mg daily for 7 weeks

Intensive Treatment:

Duloxetine 90 mg (60 mg in the morning, 30 mg in the evening) daily for 1 week

Duloxetine 120 mg (60 mg twice daily) daily for 7 weeks

Drug: Duloxetine
Administered orally
Other Names:
  • Cymbalta
  • LY248686
Drug: Placebo
Administered orally, daily as a blind for duloxetine and/or pregabalin for 8 or 16 weeks
Experimental: Pregabalin+Duloxetine

Initial Treatment:

Pregabalin 150 mg daily for 1 week

Pregabalin 300 mg (150 mg twice daily) daily for 7 weeks

Intensive Treatment:

Pregabalin 300 mg (150 mg twice daily) daily for 8 weeks

Duloxetine 30 mg daily for 1 week

Duloxetine 60 mg daily for 7 weeks

Drug: Duloxetine
Administered orally
Other Names:
  • Cymbalta
  • LY248686
Drug: Pregabalin
Administered orally
Drug: Placebo
Administered orally, daily as a blind for duloxetine and/or pregabalin for 8 or 16 weeks
Experimental: Pregabalin

Initial Treatment:

Pregabalin 150 mg daily for 1 week

Pregabalin 300 mg (150 mg twice daily) daily for 7 weeks

Intensive Treatment:

Pregabalin 450 mg (300 mg in the morning, 150 mg in the evening) daily for 1 week

Pregabalin 600 mg (300 mg twice daily) daily for 7 weeks

Drug: Pregabalin
Administered orally
Drug: Placebo
Administered orally, daily as a blind for duloxetine and/or pregabalin for 8 or 16 weeks
Experimental: Duloxetine + Pregabalin

Initial Treatment:

Duloxetine 30 mg daily for 1 week

Duloxetine 60 mg daily for 7 weeks

Intensive Treatment:

Duloxetine 60 mg daily for 8 weeks

Pregabalin 150 mg daily for 1 week

Pregabalin 300 mg (150 mg twice daily) daily for 7 weeks

Drug: Duloxetine
Administered orally
Other Names:
  • Cymbalta
  • LY248686
Drug: Pregabalin
Administered orally
Drug: Placebo
Administered orally, daily as a blind for duloxetine and/or pregabalin for 8 or 16 weeks

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01089556

  Show 54 Study Locations
Sponsors and Collaborators
Eli Lilly and Company
Boehringer Ingelheim
Investigators
Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5AM Eastern time (UTC/GMT - 5 hours, EST) Eli Lilly and Company
  More Information

No publications provided

Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT01089556     History of Changes
Other Study ID Numbers: 13084, F1J-EW-HMGQ
Study First Received: March 15, 2010
Results First Received: October 30, 2012
Last Updated: January 17, 2013
Health Authority: Australia: Human Research Ethics Committee
Canada: Health Canada
Croatia: Agency for Medicinal Product and Medical Devices
Croatia: Ethics Committee
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
France: Institutional Ethical Committee
Germany: Federal Institute for Drugs and Medical Devices
Germany: Ethics Commission
Greece: Ethics Committee
Greece: National Organization of Medicines
Italy: The Italian Medicines Agency
South Korea: Korea Food and Drug Administration (KFDA)
Mexico: Federal Commission for Sanitary Risks Protection
Netherlands: Medical Ethics Review Committee (METC)
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Spain: Ministry of Health
Sweden: Medical Products Agency
Switzerland: Swissmedic
Turkey: Ministry of Health
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Additional relevant MeSH terms:
Diabetic Neuropathies
Pain
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases
Nervous System Diseases
Neurologic Manifestations
Neuromuscular Diseases
Peripheral Nervous System Diseases
Signs and Symptoms
Duloxetine
Pregabalin
Adrenergic Agents
Adrenergic Uptake Inhibitors
Analgesics
Anticonvulsants
Antidepressive Agents
Calcium Channel Blockers
Cardiovascular Agents
Central Nervous System Agents
Dopamine Agents
Dopamine Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Neurotransmitter Uptake Inhibitors
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Psychotropic Drugs

ClinicalTrials.gov processed this record on October 23, 2014