A Study in Painful Diabetic Neuropathy

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Diabetic Neuropathy, Painful

Intervention / Treatment
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* Drug: Duloxetine
* Drug: Pregabalin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Duloxetine<br>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<br>* Administered orally<br>* Other names: LY248686;Drug: Placebo<br>* Administered orally, daily as a blind for duloxetine and/or pregabalin for 8 or 16 weeks<br>|
| Experimental: Pregabalin+Duloxetine<br>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<br>* Administered orally<br>* Other names: LY248686;Drug: Pregabalin<br>* Administered orally<br>Drug: Placebo<br>* Administered orally, daily as a blind for duloxetine and/or pregabalin for 8 or 16 weeks<br>|
| Experimental: Pregabalin<br>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<br>* Administered orally<br>Drug: Placebo<br>* Administered orally, daily as a blind for duloxetine and/or pregabalin for 8 or 16 weeks<br>|
| Experimental: Duloxetine + Pregabalin<br>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<br>* Administered orally<br>* Other names: LY248686;Drug: Pregabalin<br>* Administered orally<br>Drug: Placebo<br>* Administered orally, daily as a blind for duloxetine and/or pregabalin for 8 or 16 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Week 8, Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Week 8, Week 16 | 
| 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 | 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). | Week 8 through Week 16 | 
| 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 | 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). | Week 8 through Week 16 | 
| 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 | 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). | Week 8 through Week 16 | 
| 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. | Week 16 | 
| 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. | Week 8, Week 16 | 
| 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. | Week 8, Week 16 | 
| 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. | Week 8, Week 16 | 
| 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. | Week 8 through Week 16 | 
| 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. | Week 16 | 
| 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. | Week 8, Week 16 | 
| 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. | Week 8, Week 16 | 
| 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. | Week 8 through Week 16 | 
| Number of Participants Who Discontinued From Study Between Week 8 and Week 16 Endpoint |  | Week 8 through Week 16 |