A Study in Painful Diabetic Neuropathy (COMBO-DN)

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

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

Diabetic neuropathy

Study Type

Interventional

Study Design

Randomized, Dose Comparison, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Parallel Assignment, Treatment, Efficacy Study

Further Details

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: 8 weeks, 16 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

• Mean change from week 8 to week 16 endpoint in items of the BPI Modified Short Form Severity and Interference portions [ Time Frame: 8 weeks, 16 weeks ] [ Designated as safety issue: No ]
• Clinical Global Impression of Improvement (CGI-I) at 16 week endpoint
  [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
• Proportion of patients with a Reduction of greater than or equal to 30% on BPI Modified Short Form 24-Hour average Pain Item Score at 16 weeks endpoint [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
• Mean change from week 8 to week 16 endpoint on the Neuropathic Pain Symptom Inventory (NPSI) questionnaire
  [ Time Frame: 8 weeks, 16 weeks ] [ Designated as safety issue: No ]
• Mean change from week 8 to week 16 endpoint in Hospital Anxiety and Depression (HADS) Scale
  [ Time Frame: 8 weeks, 16 weeks ] [ Designated as safety issue: No ]
• Mean change from week 8 to week 16 endpoint in Sheehan Disability Scale (SDS)
  [ Time Frame: 8 weeks, 16 weeks ] [ Designated as safety issue: No ]
• Resource utilisation (number of days hospitalised, number of days of sick leave)
  [ Time Frame: 8 weeks through 16 weeks ] [ Designated as safety issue: No ]
• Patient Global Impression of Improvement (PGI-I) Score at 16 Weeks Endpoint
  [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
• Proportion of patients with a Reduction of greater than or equal to50% on BPI Modified Short Form 24-Hour average Pain Item Score at 16 weeks endpoint [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
• Proportion of patients with a Decrease of greater than or equal to 2 points on BPI Modified Short Form 24-Hour average Pain Item Score at 16 weeks endpoint [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
• Mean change in Blood pressure from week 8 to week 16 endpoint
  [ Time Frame: 8 weeks, 16 weeks ] [ Designated as safety issue: Yes ]
• Mean change in Heart Rate from week 8 to week 16 endpoint
  [ Time Frame: 8 weeks, 16 weeks ] [ Designated as safety issue: Yes ]
• Number of patients discontinued between week 8 and week 16 endpoint
  [ Time Frame: 8 weeks, 16 weeks ] [ Designated as safety issue: Yes ]
• Number of Treatment Emergent Adverse Events between week 8 and week 16 endpoint
  [ Time Frame: 8 weeks, 16 weeks ] [ Designated as safety issue: Yes ]
• 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: 8 weeks, 16 weeks ] [ Designated as safety issue: No ]

 

Secondary Outcome Measures:

• Mean change from week 8 to week 16 endpoint in items of the BPI Modified Short Form Severity and Interference portions [ Time Frame: 8 weeks, 16 weeks ] [ Designated as safety issue: No ]
• Clinical Global Impression of Improvement (CGI-I) at 16 week endpoint
  [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
• Proportion of patients with a Reduction of greater than or equal to 30% on BPI Modified Short Form 24-Hour average Pain Item Score at 16 weeks endpoint [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
• Mean change from week 8 to week 16 endpoint on the Neuropathic Pain Symptom Inventory (NPSI) questionnaire
  [ Time Frame: 8 weeks, 16 weeks ] [ Designated as safety issue: No ]
• Mean change from week 8 to week 16 endpoint in Hospital Anxiety and Depression (HADS) Scale
  [ Time Frame: 8 weeks, 16 weeks ] [ Designated as safety issue: No ]
• Mean change from week 8 to week 16 endpoint in Sheehan Disability Scale (SDS)
  [ Time Frame: 8 weeks, 16 weeks ] [ Designated as safety issue: No ]
• Resource utilisation (number of days hospitalised, number of days of sick leave)
  [ Time Frame: 8 weeks through 16 weeks ] [ Designated as safety issue: No ]
• Patient Global Impression of Improvement (PGI-I) Score at 16 Weeks Endpoint
  [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
• Proportion of patients with a Reduction of greater than or equal to50% on BPI Modified Short Form 24-Hour average Pain Item Score at 16 weeks endpoint [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
• Proportion of patients with a Decrease of greater than or equal to 2 points on BPI Modified Short Form 24-Hour average Pain Item Score at 16 weeks endpoint [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
• Mean change in Blood pressure from week 8 to week 16 endpoint
  [ Time Frame: 8 weeks, 16 weeks ] [ Designated as safety issue: Yes ]
• Mean change in Heart Rate from week 8 to week 16 endpoint
  [ Time Frame: 8 weeks, 16 weeks ] [ Designated as safety issue: Yes ]
• Number of patients discontinued between week 8 and week 16 endpoint
  [ Time Frame: 8 weeks, 16 weeks ] [ Designated as safety issue: Yes ]
• Number of Treatment Emergent Adverse Events between week 8 and week 16 endpoint
  [ Time Frame: 8 weeks, 16 weeks ] [ Designated as safety issue: Yes ]

 

Arms	Assigned Interventions
Duloxetine: Experimental Initial Treatment: Duloxetine 30 mg daily for 1 week Duloxetine 60 mg daily for 7 weeks Intensive Treatment: Duloxetine 90 mg (60 mg a.m., 30 mg p.m.) daily for 1 week Duloxetine 120 mg (60 mg twice daily) daily for 7 weeks	Drug: Duloxetine Administered orally Drug: Placebo Administered orally, daily as a blind for duloxetine and/or pregabalin for 8 or 16 weeks
Pregabalin+Duloxetine: Experimental 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 Drug: Pregabalin Administered orally Drug: Placebo Administered orally, daily as a blind for duloxetine and/or pregabalin for 8 or 16 weeks
Pregabalin: Experimental 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 am, 150 mg pm) 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
Duloxetine + Pregabalin: Experimental  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 Drug: Pregabalin Administered orally Drug: Placebo Administered orally, daily as a blind for duloxetine and/or pregabalin for 8 or 16 weeks

Study Start

March 2010 – November 2011

Eligibility & Criteria

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

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 BPI Modified Short Form) at screening and at randomization.
• Patient is currently not receiving treatment for 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 mg/dL or a creatinine clearance less than 60 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 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.

Total Enrolment

800

Contact Details

There may be multiple sites in this clinical trial.
1-877-285-4559 or
1-317-615-4559

 

Australia, New South Wales
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, 2292
Contact: Eli Lilly
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.
Warrawong, New South Wales, Australia, 2502
Contact: Eli Lilly
Australia, South Australia
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.
Daw Park, South Australia, Australia, 5041
Contact: Eli Lilly
Australia, Victoria
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.
Box Hill, Victoria, Australia, 3128
Contact: Eli Lilly