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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT01089556
Registration number
NCT01089556
Ethics application status
Date submitted
15/03/2010
Date registered
18/03/2010
Date last updated
24/01/2013
Titles & IDs
Public title
A Study in Painful Diabetic Neuropathy
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Scientific 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"
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Secondary ID [1]
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F1J-EW-HMGQ
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Secondary ID [2]
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13084
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Universal Trial Number (UTN)
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Trial acronym
COMBO-DN
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Diabetic Neuropathy, Painful
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Condition category
Condition code
Metabolic and Endocrine
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Diabetes
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Neurological
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Other neurological disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Duloxetine
Treatment: Drugs - Pregabalin
Treatment: Drugs - Placebo
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
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
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
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
Treatment: Drugs: Duloxetine
Administered orally
Treatment: Drugs: Pregabalin
Administered orally
Treatment: Drugs: Placebo
Administered orally, daily as a blind for duloxetine and/or pregabalin for 8 or 16 weeks
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Change From Week 8 to Week 16 Endpoint in 24 Hour Average Pain Item Score on the Brief Pain Inventory (BPI) Modified Short Form
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Assessment method [1]
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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.
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Timepoint [1]
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Week 8, Week 16
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Secondary outcome [1]
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Mean Change From Week 8 to Week 16 Endpoint in Items of the Brief Pain Inventory (BPI) Modified Short Form Worst Pain Score
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Assessment method [1]
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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.
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Timepoint [1]
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Week 8, Week 16
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Secondary outcome [2]
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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
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Assessment method [2]
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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).
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Timepoint [2]
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Week 8 through Week 16
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Secondary outcome [3]
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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
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Assessment method [3]
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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).
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Timepoint [3]
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Week 8 through Week 16
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Secondary outcome [4]
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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
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Assessment method [4]
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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).
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Timepoint [4]
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Week 8 through Week 16
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Secondary outcome [5]
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Clinical Global Impression of Improvement (CGI-I) at Week 16 Endpoint
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Assessment method [5]
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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.
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Timepoint [5]
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Week 16
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Secondary outcome [6]
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Mean Change From Week 8 to Week 16 Endpoint on the Neuropathic Pain Symptom Inventory (NPSI) Questionnaire
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Assessment method [6]
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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.
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Timepoint [6]
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Week 8, Week 16
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Secondary outcome [7]
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Mean Change From Week 8 to Week 16 Endpoint in Sheehan Disability Scale (SDS)
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Assessment method [7]
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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.
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Timepoint [7]
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Week 8, Week 16
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Secondary outcome [8]
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Mean Change From Week 8 to Week 16 Endpoint in Hospital Anxiety and Depression Scale (HADS)
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Assessment method [8]
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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.
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Timepoint [8]
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Week 8, Week 16
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Secondary outcome [9]
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Resource Utilization (Number of Days Hospitalized, Number of Days of Sick Leave) Week 8 Through Week 16
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Assessment method [9]
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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.
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Timepoint [9]
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Week 8 through Week 16
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Secondary outcome [10]
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Patient Global Impression of Improvement (PGI-I) Score at Week 16 Endpoint
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Assessment method [10]
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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.
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Timepoint [10]
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Week 16
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Secondary outcome [11]
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Mean Change in Blood Pressure (BP) From Week 8 to Week 16 Endpoint
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Assessment method [11]
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Least Squares (LS) mean values are controlled for treatment, site, baseline value, treatment*site and treatment in Study Period II.
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Timepoint [11]
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Week 8, Week 16
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Secondary outcome [12]
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Mean Change in Heart Rate From Week 8 to Week 16 Endpoint
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Assessment method [12]
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Least Squares (LS) mean values are controlled for treatment, site, baseline value, treatment*site and treatment in Study Period II.
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Timepoint [12]
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Week 8, Week 16
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Secondary outcome [13]
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Number of Participants With Treatment Emergent Adverse Events (TEAEs) Between Week 8 and Week 16 Endpoint
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Assessment method [13]
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TEAEs in Study Period III are events that began or worsened after Week 8 compared with the period before Week 8.
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Timepoint [13]
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Week 8 through Week 16
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Secondary outcome [14]
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Number of Participants Who Discontinued From Study Between Week 8 and Week 16 Endpoint
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Assessment method [14]
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Timepoint [14]
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Week 8 through Week 16
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Eligibility
Key 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.
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/03/2010
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
1/11/2011
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Sample size
Target
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Accrual to date
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Final
811
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Recruitment in Australia
Recruitment state(s)
NSW,SA
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Recruitment hospital [1]
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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
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Recruitment hospital [2]
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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
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Recruitment hospital [3]
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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. - Elizabeth Vale
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Recruitment postcode(s) [1]
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2292 - Newcastle
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Recruitment postcode(s) [2]
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2502 - Warrawong
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Recruitment postcode(s) [3]
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5112 - Elizabeth Vale
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Recruitment outside Australia
Country [1]
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Canada
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British Columbia
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Canada
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Manitoba
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Canada
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Nova Scotia
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Canada
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Ontario
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Canada
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Quebec
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Croatia
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Osijek
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Croatia
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Rijeka
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Croatia
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Varazdin
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Croatia
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Zagreb
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France
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Angers
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France
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Antibes Juan Les Pins
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France
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Bourges
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France
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Nevers
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France
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Nimes
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France
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Paris
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France
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Valenciennes
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France
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Vierzon
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France
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Vieux Conde
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Germany
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Dresden
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Germany
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Schkeuditz
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Greece
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Ampelokipoi
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Greece
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Athens
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Greece
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Melissia
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Italy
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Catania
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Italy
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Milano
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Italy
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Napoli
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Italy
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Rome
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Korea, Republic of
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Seoul
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Mexico
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Mexico City
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Netherlands
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Eindhoven
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Netherlands
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Maastricht
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Bialystok
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Lublin
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Szczecin
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Wroclaw
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Spain
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Girona
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Spain
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Valencia
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Sweden
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Falkoping
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Sweden
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Huddinge
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Sweden
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Lund
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Stockholm
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Switzerland
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Zuerich
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Turkey
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Ankara
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Turkey
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Izmir
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United Kingdom
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Greater Manchester
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United Kingdom
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Scotland
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United Kingdom
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Warwickshire
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United Kingdom
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West Lothian
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United Kingdom
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Ashton-Under-Lyne
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United Kingdom
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Chorley
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Eli Lilly and Company
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Address
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Other collaborator category [1]
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Commercial sector/Industry
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Name [1]
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Boehringer Ingelheim
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Address [1]
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT01089556
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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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)
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Address
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Eli Lilly and Company
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT01089556
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