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A Study in Painful Diabetic Neuropathy (COMBO-DN)

Primary Purpose

Diabetic Neuropathy, Painful

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Duloxetine

Pregabalin

Placebo

About this trial

This is an interventional treatment trial for Diabetic Neuropathy, Painful

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Duloxetine

Pregabalin+Duloxetine

Pregabalin

Duloxetine + Pregabalin

Arm Description

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

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

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

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

Outcomes

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

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

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

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

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

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

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

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)

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)

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

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

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

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

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

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

Full Information

NCT ID

NCT01089556

First Posted

March 15, 2010

Last Updated

January 17, 2013

Sponsor

Eli Lilly and Company

Collaborators

Boehringer Ingelheim

1. Study Identification

Unique Protocol Identification Number

NCT01089556

Brief Title

A Study in Painful Diabetic Neuropathy

Acronym

COMBO-DN

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"

Study Type

Interventional

2. Study Status

Record Verification Date

January 2013

Overall Recruitment Status

Completed

Study Start Date

March 2010 (undefined)

Primary Completion Date

November 2011 (Actual)

Study Completion Date

November 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Eli Lilly and Company

Collaborators

Boehringer Ingelheim

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Diabetic Neuropathy, Painful

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

811 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Duloxetine

Arm Type

Experimental

Arm Description

Arm Title

Pregabalin+Duloxetine

Arm Type

Experimental

Arm Description

Arm Title

Pregabalin

Arm Type

Experimental

Arm Description

Arm Title

Duloxetine + Pregabalin

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Duloxetine

Other Intervention Name(s)

Cymbalta, LY248686

Intervention Description

Administered orally

Intervention Type

Drug

Intervention Name(s)

Pregabalin

Intervention Description

Administered orally

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

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

Primary Outcome Measure Information:

Title

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

Description

Time Frame

Week 8, Week 16

Secondary Outcome Measure Information:

Title

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

Description

Time Frame

Week 8, Week 16

Title

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

Description

Time Frame

Week 8 through Week 16

Title

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

Description

Time Frame

Week 8 through Week 16

Title

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

Description

Time Frame

Week 8 through Week 16

Title

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

Description

Time Frame

Week 16

Title

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

Description

Time Frame

Week 8, Week 16

Title

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

Description

Time Frame

Week 8, Week 16

Title

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

Description

Time Frame

Week 8, Week 16

Title

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

Description

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.

Time Frame

Week 8 through Week 16

Title

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

Description

Time Frame

Week 16

Title

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

Description

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

Time Frame

Week 8, Week 16

Title

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

Description

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

Time Frame

Week 8, Week 16

Title

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

Description

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

Time Frame

Week 8 through Week 16

Title

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

Time Frame

Week 8 through Week 16

Other Pre-specified Outcome Measures:

Title

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

Description

Time Frame

Baseline, Week 8

Title

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

Description

Time Frame

Baseline through Week 8

Title

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

Description

Time Frame

Baseline through Week 8

Title

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

Description

Time Frame

Baseline through Week 8

Title

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

Description

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.

Time Frame

Week 8

Title

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

Description

Time Frame

Baseline, Week 8

Title

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

Description

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.

Time Frame

Baseline, Week 8

Title

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

Description

Time Frame

Baseline, Week 8

Title

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

Description

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.

Time Frame

Baseline through Week 8

Title

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

Description

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

Time Frame

Baseline through Week 8

Title

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

Description

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

Time Frame

Week 8 through Week 16

Title

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

Description

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.

Time Frame

Week 8

Title

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

Description

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

Time Frame

Baseline, Week 8

Title

Mean Change in Heart Rate From Baseline to Week 8 Endpoint

Description

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

Time Frame

Baseline, Week 8

Title

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

Description

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

Time Frame

Baseline through Week 8

Title

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

Time Frame

Baseline through Week 8

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

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)

Organizational Affiliation

Eli Lilly and Company

Official's Role

Study Director

Facility Information:

Facility Name

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.

City

Newcastle

State/Province

New South Wales

ZIP/Postal Code

2292

Country

Australia

Facility Name

City

Warrawong

State/Province

New South Wales

ZIP/Postal Code

2502

Country

Australia

Facility Name

City

Elizabeth Vale

State/Province

South Australia

ZIP/Postal Code

5112

Country

Australia

Facility Name

City

Kelowna

State/Province

British Columbia

ZIP/Postal Code

V1Y 1Z9

Country

Canada

Facility Name

City

Vancouver

State/Province

British Columbia

ZIP/Postal Code

V6H 3X8

Country

Canada

Facility Name

City

Winnipeg

State/Province

Manitoba

ZIP/Postal Code

R3P 3P4

Country

Canada

Facility Name

City

Halifax

State/Province

Nova Scotia

ZIP/Postal Code

B3H 3A7

Country

Canada

Facility Name

City

Cambridge

State/Province

Ontario

ZIP/Postal Code

N1R 7L6

Country

Canada

Facility Name

City

Laval

State/Province

Quebec

ZIP/Postal Code

H7T 2P5

Country

Canada

Facility Name

City

Osijek

ZIP/Postal Code

31000

Country

Croatia

Facility Name

City

Rijeka

ZIP/Postal Code

HR-51000

Country

Croatia

Facility Name

City

Varazdin

ZIP/Postal Code

42000

Country

Croatia

Facility Name

City

Zagreb

ZIP/Postal Code

10000

Country

Croatia

Facility Name

City

Angers

ZIP/Postal Code

49933

Country

France

Facility Name

City

Antibes Juan Les Pins

ZIP/Postal Code

06600

Country

France

Facility Name

City

Bourges

ZIP/Postal Code

18000

Country

France

Facility Name

City

Nevers

ZIP/Postal Code

58000

Country

France

Facility Name

City

Nimes

ZIP/Postal Code

30029

Country

France

Facility Name

City

Paris

ZIP/Postal Code

75018

Country

France

Facility Name

City

Valenciennes

ZIP/Postal Code

59322

Country

France

Facility Name

City

Vierzon

ZIP/Postal Code

18100

Country

France

Facility Name

City

Vieux Conde

ZIP/Postal Code

59690

Country

France

Facility Name

City

Dresden

ZIP/Postal Code

01307

Country

Germany

Facility Name

City

Schkeuditz

ZIP/Postal Code

04435

Country

Germany

Facility Name

City

Ampelokipoi

ZIP/Postal Code

11527

Country

Greece

Facility Name

City

Athens

ZIP/Postal Code

11521

Country

Greece

Facility Name

City

Melissia

ZIP/Postal Code

15126

Country

Greece

Facility Name

City

Catania

ZIP/Postal Code

95100

Country

Italy

Facility Name

City

Milano

ZIP/Postal Code

20162

Country

Italy

Facility Name

City

Napoli

ZIP/Postal Code

80131

Country

Italy

Facility Name

City

Rome

ZIP/Postal Code

00161

Country

Italy

Facility Name

City

Seoul

ZIP/Postal Code

138-736

Country

Korea, Republic of

Facility Name

City

Mexico City

ZIP/Postal Code

38000

Country

Mexico

Facility Name

City

Eindhoven

ZIP/Postal Code

5623 EJ

Country

Netherlands

Facility Name

City

Maastricht

ZIP/Postal Code

6229 HX

Country

Netherlands

Facility Name

City

Bialystok

ZIP/Postal Code

15-445

Country

Poland

Facility Name

City

Lublin

ZIP/Postal Code

20-538

Country

Poland

Facility Name

City

Szczecin

ZIP/Postal Code

70-506

Country

Poland

Facility Name

City

Wroclaw

ZIP/Postal Code

50-127

Country

Poland

Facility Name

City

Girona

ZIP/Postal Code

17007

Country

Spain

Facility Name

City

Valencia

ZIP/Postal Code

46010

Country

Spain

Facility Name

City

Falkoping

ZIP/Postal Code

SE 52143

Country

Sweden

Facility Name

City

Huddinge

ZIP/Postal Code

SE 141 86

Country

Sweden

Facility Name

City

Lund

ZIP/Postal Code

22185

Country

Sweden

Facility Name

City

Stockholm

ZIP/Postal Code

11522

Country

Sweden

Facility Name

City

Zuerich

ZIP/Postal Code

CH-8091

Country

Switzerland

Facility Name

City

Ankara

ZIP/Postal Code

06100

Country

Turkey

Facility Name

City

Izmir

ZIP/Postal Code

35340

Country

Turkey

Facility Name

City

Manchester

State/Province

Greater Manchester

ZIP/Postal Code

M13 0JE

Country

United Kingdom

Facility Name

City

Ayrshire

State/Province

Scotland

ZIP/Postal Code

KA6 6DX

Country

United Kingdom

Facility Name

City

Nuneaton

State/Province

Warwickshire

ZIP/Postal Code

CV10 7BL

Country

United Kingdom

Facility Name

City

Livingston

State/Province

West Lothian

ZIP/Postal Code

EH54 6PP

Country

United Kingdom

Facility Name

City

Ashton-Under-Lyne

ZIP/Postal Code

OL6 9RW

Country

United Kingdom

Facility Name

City

Chorley

ZIP/Postal Code

PR7 1PP

Country

United Kingdom

12. IPD Sharing Statement

Learn more about this trial

A Study in Painful Diabetic Neuropathy

We'll reach out to this number within 24 hrs