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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/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
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"
Secondary ID [1] 0 0
F1J-EW-HMGQ
Secondary ID [2] 0 0
13084
Universal Trial Number (UTN)
Trial acronym
COMBO-DN
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diabetic Neuropathy, Painful 0 0
Condition category
Condition code
Neurological 0 0 0 0
Other neurological disorders
Metabolic and Endocrine 0 0 0 0
Diabetes

Intervention/exposure
Study type
Interventional
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

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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.
Timepoint [1] 0 0
Week 8, Week 16
Secondary outcome [1] 0 0
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.
Timepoint [1] 0 0
Week 8, Week 16
Secondary outcome [2] 0 0
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).
Timepoint [2] 0 0
Week 8 through Week 16
Secondary outcome [3] 0 0
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).
Timepoint [3] 0 0
Week 8 through Week 16
Secondary outcome [4] 0 0
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).
Timepoint [4] 0 0
Week 8 through Week 16
Secondary outcome [5] 0 0
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.
Timepoint [5] 0 0
Week 16
Secondary outcome [6] 0 0
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.
Timepoint [6] 0 0
Week 8, Week 16
Secondary outcome [7] 0 0
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.
Timepoint [7] 0 0
Week 8, Week 16
Secondary outcome [8] 0 0
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.
Timepoint [8] 0 0
Week 8, Week 16
Secondary outcome [9] 0 0
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.
Timepoint [9] 0 0
Week 8 through Week 16
Secondary outcome [10] 0 0
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.
Timepoint [10] 0 0
Week 16
Secondary outcome [11] 0 0
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.
Timepoint [11] 0 0
Week 8, Week 16
Secondary outcome [12] 0 0
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.
Timepoint [12] 0 0
Week 8, Week 16
Secondary outcome [13] 0 0
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.
Timepoint [13] 0 0
Week 8 through Week 16
Secondary outcome [14] 0 0
Number of Participants Who Discontinued From Study Between Week 8 and Week 16 Endpoint
Timepoint [14] 0 0
Week 8 through Week 16

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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
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
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA
Recruitment hospital [1] 0 0
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
Recruitment hospital [2] 0 0
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
Recruitment hospital [3] 0 0
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
Recruitment postcode(s) [1] 0 0
2292 - Newcastle
Recruitment postcode(s) [2] 0 0
2502 - Warrawong
Recruitment postcode(s) [3] 0 0
5112 - Elizabeth Vale
Recruitment outside Australia
Country [1] 0 0
Canada
State/province [1] 0 0
British Columbia
Country [2] 0 0
Canada
State/province [2] 0 0
Manitoba
Country [3] 0 0
Canada
State/province [3] 0 0
Nova Scotia
Country [4] 0 0
Canada
State/province [4] 0 0
Ontario
Country [5] 0 0
Canada
State/province [5] 0 0
Quebec
Country [6] 0 0
Croatia
State/province [6] 0 0
Osijek
Country [7] 0 0
Croatia
State/province [7] 0 0
Rijeka
Country [8] 0 0
Croatia
State/province [8] 0 0
Varazdin
Country [9] 0 0
Croatia
State/province [9] 0 0
Zagreb
Country [10] 0 0
France
State/province [10] 0 0
Angers
Country [11] 0 0
France
State/province [11] 0 0
Antibes Juan Les Pins
Country [12] 0 0
France
State/province [12] 0 0
Bourges
Country [13] 0 0
France
State/province [13] 0 0
Nevers
Country [14] 0 0
France
State/province [14] 0 0
Nimes
Country [15] 0 0
France
State/province [15] 0 0
Paris
Country [16] 0 0
France
State/province [16] 0 0
Valenciennes
Country [17] 0 0
France
State/province [17] 0 0
Vierzon
Country [18] 0 0
France
State/province [18] 0 0
Vieux Conde
Country [19] 0 0
Germany
State/province [19] 0 0
Dresden
Country [20] 0 0
Germany
State/province [20] 0 0
Schkeuditz
Country [21] 0 0
Greece
State/province [21] 0 0
Ampelokipoi
Country [22] 0 0
Greece
State/province [22] 0 0
Athens
Country [23] 0 0
Greece
State/province [23] 0 0
Melissia
Country [24] 0 0
Italy
State/province [24] 0 0
Catania
Country [25] 0 0
Italy
State/province [25] 0 0
Milano
Country [26] 0 0
Italy
State/province [26] 0 0
Napoli
Country [27] 0 0
Italy
State/province [27] 0 0
Rome
Country [28] 0 0
Korea, Republic of
State/province [28] 0 0
Seoul
Country [29] 0 0
Mexico
State/province [29] 0 0
Mexico City
Country [30] 0 0
Netherlands
State/province [30] 0 0
Eindhoven
Country [31] 0 0
Netherlands
State/province [31] 0 0
Maastricht
Country [32] 0 0
Poland
State/province [32] 0 0
Bialystok
Country [33] 0 0
Poland
State/province [33] 0 0
Lublin
Country [34] 0 0
Poland
State/province [34] 0 0
Szczecin
Country [35] 0 0
Poland
State/province [35] 0 0
Wroclaw
Country [36] 0 0
Spain
State/province [36] 0 0
Girona
Country [37] 0 0
Spain
State/province [37] 0 0
Valencia
Country [38] 0 0
Sweden
State/province [38] 0 0
Falkoping
Country [39] 0 0
Sweden
State/province [39] 0 0
Huddinge
Country [40] 0 0
Sweden
State/province [40] 0 0
Lund
Country [41] 0 0
Sweden
State/province [41] 0 0
Stockholm
Country [42] 0 0
Switzerland
State/province [42] 0 0
Zuerich
Country [43] 0 0
Turkey
State/province [43] 0 0
Ankara
Country [44] 0 0
Turkey
State/province [44] 0 0
Izmir
Country [45] 0 0
United Kingdom
State/province [45] 0 0
Greater Manchester
Country [46] 0 0
United Kingdom
State/province [46] 0 0
Scotland
Country [47] 0 0
United Kingdom
State/province [47] 0 0
Warwickshire
Country [48] 0 0
United Kingdom
State/province [48] 0 0
West Lothian
Country [49] 0 0
United Kingdom
State/province [49] 0 0
Ashton-Under-Lyne
Country [50] 0 0
United Kingdom
State/province [50] 0 0
Chorley

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Eli Lilly and Company
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Boehringer Ingelheim
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

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.
Trial website
https://clinicaltrials.gov/show/NCT01089556
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
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)
Address 0 0
Eli Lilly and Company
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications