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A Trial Comparing the Efficacy and Safety of Insulin Degludec/Liraglutide Versus Insulin Glargine in Subjects With Type 2 Diabetes Mellitus (DUAL™ V)

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ClinicalTrials.gov Identifier: NCT01952145
Recruitment Status : Completed
First Posted : September 27, 2013
Results First Posted : January 20, 2017
Last Update Posted : January 3, 2019
Sponsor:
Information provided by (Responsible Party):
Novo Nordisk A/S

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Diabetes
Diabetes Mellitus, Type 2
Interventions Drug: insulin degludec/liraglutide
Drug: insulin glargine
Enrollment 557
Recruitment Details The trial was conducted at 75 sites in 10 countries as follows: Argentina: 5 sites; Australia: 4 sites; Greece: 6 sites, Hungary: 4 sites; Mexico: 5 sites, Russian Federation: 11 sites; Slovakia: 11 sites, South Africa: 4 sites; Spain: 6 sites, United States: 19 sites.
Pre-assignment Details Subjects who were recruited had T2DM and were required to have been on treatment with stable daily dose of insulin glargine between 20 units and 50 units (both inclusive) for at least 56 days prior to screening in combination with a stable daily dose of metformin (≥1500 mg or max tolerated dose) for at least 90 days prior to screening.
Arm/Group Title Insulin Degludec/Liraglutide (IDegLira) Insulin Glargine (IGlar)
Hide Arm/Group Description Eligible subjects received IDegLira once daily (OD) subcutaneously for a duration of 26 weeks. The starting dose of IDegLira was 16 dose steps (16 units IDeg/0.6 mg liraglutide) and was titrated according to a predefined titration algorithm with a maximum dose of 50 dose steps (50 units IDeg/1.8 mg liraglutide). Adjustment of the dose was performed twice weekly based on the mean of 3 preceding daily fasting SMPG values on 3 consecutive days. Adjustments were made in increments or decrements of 2 dose steps, aiming at a fasting glycaemic target of 4.0−5.0 mmol/L (71−90 mg/dL). That is, the adjustments were +2 or -2 if the mean of 3 pre-breakfast SMPG values were >5.0 mmol/L (or >90 mg/dL) and <4.0 mmol/L (or <71 mg/dL) respectively. No adjustment was done when the mean of 3 pre-breakfast SMPG values were 4.0 - 5.0 mmol/L (or 71-90 mg/dL). The subjects continued with pre-trial doses of metformin, unless there was a safety concern. Eligible subjects received IGlar OD subcutaneously for a duration of 26 weeks. The treatment started with dose equal to the pre-trial daily dose (dose-to-dose switch), after which the dose was titrated according to the specified titration algorithm aiming at a fasting glycaemic target of 4.0−5.0 mmol/L (71−90 mg/dL). No predefined maximum dose was specified for IGlar. The subjects continued with pre-trial doses of metformin, unless there was a safety concern.
Period Title: Overall Study
Started 278 279
Completed 250 265
Not Completed 28 14
Reason Not Completed
Protocol Violation             2             1
Death             0             1
Adverse Event             9             0
Withdrawal Criteria             16             11
Unclassified             1             1
Arm/Group Title Insulin Degludec/Liraglutide (IDegLira) Insulin Glargine (IGlar) Total
Hide Arm/Group Description Eligible subjects received IDegLira once daily (OD) subcutaneously for a duration of 26 weeks. The starting dose of IDegLira was 16 dose steps (16 units IDeg/0.6 mg liraglutide) and was titrated according to a predefined titration algorithm with a maximum dose of 50 dose steps (50 units IDeg/1.8 mg liraglutide). Adjustment of the dose was performed twice weekly based on the mean of 3 preceding daily fasting SMPG values on 3 consecutive days. Adjustments were made in increments or decrements of 2 dose steps, aiming at a fasting glycaemic target of 4.0−5.0 mmol/L (71−90 mg/dL). That is, the adjustments were +2 or -2 if the mean of 3 pre-breakfast SMPG values were >5.0 mmol/L (or >90 mg/dL) and <4.0 mmol/L (or <71 mg/dL) respectively. No adjustment was done when the mean of 3 pre-breakfast SMPG values were 4.0 - 5.0 mmol/L (or 71-90 mg/dL). The subjects continued with pre-trial doses of metformin, unless there was a safety concern. Eligible subjects received IGlar OD subcutaneously for a duration of 26 weeks. The treatment started with dose equal to the pre-trial daily dose (dose-to-dose switch), after which the dose was titrated according to the specified titration algorithm aiming at a fasting glycaemic target of 4.0−5.0 mmol/L (71−90 mg/dL). No predefined maximum dose was specified for IGlar. The subjects continued with pre-trial doses of metformin, unless there was a safety concern. Total of all reporting groups
Overall Number of Baseline Participants 278 279 557
Hide Baseline Analysis Population Description
Full analysis set (FAS) was used for baseline measurements. FAS included all randomised subjects.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 278 participants 279 participants 557 participants
58.4  (9.8) 59.1  (9.3) 58.8  (9.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 278 participants 279 participants 557 participants
Female
135
  48.6%
142
  50.9%
277
  49.7%
Male
143
  51.4%
137
  49.1%
280
  50.3%
Glycated hemoglobin (HbA1c)  
Mean (Standard Deviation)
Unit of measure:  Percentage (%)
Number Analyzed 278 participants 279 participants 557 participants
8.4  (0.9) 8.2  (0.9) 8.3  (0.9)
Body weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 278 participants 279 participants 557 participants
88.3  (17.5) 87.3  (15.8) 87.8  (16.6)
1.Primary Outcome
Title Change From Baseline in HbA1c (Glycosylated Haemoglobin)
Hide Description Change from baseline in HbA1c after 26 weeks of treatment
Time Frame Week 0, week 26
Hide Outcome Measure Data
Hide Analysis Population Description
FAS was used for analysis of this endpoint. And FAS included all randomised subjects. Missing values (including intermittent missing values) were imputed using the last observation carried forward (LOCF) method.
Arm/Group Title Insulin Degludec/Liraglutide (IDegLira) Insulin Glargine (IGlar)
Hide Arm/Group Description:
Eligible subjects received IDegLira once daily (OD) subcutaneously for a duration of 26 weeks. The starting dose of IDegLira was 16 dose steps (16 units IDeg/0.6 mg liraglutide) and was titrated according to a predefined titration algorithm with a maximum dose of 50 dose steps (50 units IDeg/1.8 mg liraglutide). Adjustment of the dose was performed twice weekly based on the mean of 3 preceding daily fasting SMPG values on 3 consecutive days. Adjustments were made in increments or decrements of 2 dose steps, aiming at a fasting glycaemic target of 4.0−5.0 mmol/L (71−90 mg/dL). That is, the adjustments were +2 or -2 if the mean of 3 pre-breakfast SMPG values were >5.0 mmol/L (or >90 mg/dL) and <4.0 mmol/L (or <71 mg/dL) respectively. No adjustment was done when the mean of 3 pre-breakfast SMPG values were 4.0 - 5.0 mmol/L (or 71-90 mg/dL). The subjects continued with pre-trial doses of metformin, unless there was a safety concern.
Eligible subjects received IGlar OD subcutaneously for a duration of 26 weeks. The treatment started with dose equal to the pre-trial daily dose (dose-to-dose switch), after which the dose was titrated according to the specified titration algorithm aiming at a fasting glycaemic target of 4.0−5.0 mmol/L (71−90 mg/dL). No predefined maximum dose was specified for IGlar. The subjects continued with pre-trial doses of metformin, unless there was a safety concern.
Overall Number of Participants Analyzed 278 279
Mean (Standard Deviation)
Unit of Measure: Percentage (%)
-1.81  (1.08) -1.13  (0.98)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Insulin Degludec/Liraglutide (IDegLira), Insulin Glargine (IGlar)
Comments This primary endpoint was analysed on the FAS using an ANCOVA model with treatment and region as fixed effects and baseline HbA1c value as covariate.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Non-inferiority of IDegLira versus IGlar was considered as confirmed, if the 95% confidence interval (CI) for the mean treatment difference was entirely below 0.30%.
Statistical Test of Hypothesis P-Value < 0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment contrast
Estimated Value -0.59
Confidence Interval (2-Sided) 95%
-0.74 to -0.45
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Change From Baseline in Body Weight
Hide Description Change from baseline in body weight after 26 weeks of treatment
Time Frame Week 0, week 26
Hide Outcome Measure Data
Hide Analysis Population Description
FAS which included all randomised subjects was used for analysis of this endpoint. Missing values (including intermittent missing values) were imputed using LOCF method.
Arm/Group Title Insulin Degludec/Liraglutide (IDegLira) Insulin Glargine (IGlar)
Hide Arm/Group Description:
Eligible subjects received IDegLira once daily (OD) subcutaneously for a duration of 26 weeks. The starting dose of IDegLira was 16 dose steps (16 units IDeg/0.6 mg liraglutide) and was titrated according to a predefined titration algorithm with a maximum dose of 50 dose steps (50 units IDeg/1.8 mg liraglutide). Adjustment of the dose was performed twice weekly based on the mean of 3 preceding daily fasting SMPG values on 3 consecutive days. Adjustments were made in increments or decrements of 2 dose steps, aiming at a fasting glycaemic target of 4.0−5.0 mmol/L (71−90 mg/dL). That is, the adjustments were +2 or -2 if the mean of 3 pre-breakfast SMPG values were >5.0 mmol/L (or >90 mg/dL) and <4.0 mmol/L (or <71 mg/dL) respectively. No adjustment was done when the mean of 3 pre-breakfast SMPG values were 4.0 - 5.0 mmol/L (or 71-90 mg/dL). The subjects continued with pre-trial doses of metformin, unless there was a safety concern.
Eligible subjects received IGlar OD subcutaneously for a duration of 26 weeks. The treatment started with dose equal to the pre-trial daily dose (dose-to-dose switch), after which the dose was titrated according to the specified titration algorithm aiming at a fasting glycaemic target of 4.0−5.0 mmol/L (71−90 mg/dL). No predefined maximum dose was specified for IGlar. The subjects continued with pre-trial doses of metformin, unless there was a safety concern.
Overall Number of Participants Analyzed 278 279
Mean (Standard Deviation)
Unit of Measure: Kg
-1.4  (3.5) 1.8  (3.6)
3.Secondary Outcome
Title Number of Treatment Emergent Confirmed Hypoglycaemic Episodes
Hide Description Confirmed hypoglycaemic episodes were defined as either: Severe (i.e., an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions) or an episode biochemically confirmed by a plasma glucose value of <3.1 mmol/L (56 mg/dL), with or without symptoms consistent with hypoglycaemia.
Time Frame During 26 weeks of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set was used for analysis of this endpoint and this set included all subjects receiving at least one dose of trial product. Subjects contributed to the evaluation “as treated”. Confirmed hypoglycaemic episodes were reported by 79 subjects in IdegLira arm and by 137 subjects in IGlar arm.
Arm/Group Title Insulin Degludec/Liraglutide (IDegLira) Insulin Glargine (IGlar)
Hide Arm/Group Description:
Eligible subjects received IDegLira once daily (OD) subcutaneously for a duration of 26 weeks. The starting dose of IDegLira was 16 dose steps (16 units IDeg/0.6 mg liraglutide) and was titrated according to a predefined titration algorithm with a maximum dose of 50 dose steps (50 units IDeg/1.8 mg liraglutide). Adjustment of the dose was performed twice weekly based on the mean of 3 preceding daily fasting SMPG values on 3 consecutive days. Adjustments were made in increments or decrements of 2 dose steps, aiming at a fasting glycaemic target of 4.0−5.0 mmol/L (71−90 mg/dL). That is, the adjustments were +2 or -2 if the mean of 3 pre-breakfast SMPG values were >5.0 mmol/L (or >90 mg/dL) and <4.0 mmol/L (or <71 mg/dL) respectively. No adjustment was done when the mean of 3 pre-breakfast SMPG values were 4.0 - 5.0 mmol/L (or 71-90 mg/dL). The subjects continued with pre-trial doses of metformin, unless there was a safety concern.
Eligible subjects received IGlar OD subcutaneously for a duration of 26 weeks. The treatment started with dose equal to the pre-trial daily dose (dose-to-dose switch), after which the dose was titrated according to the specified titration algorithm aiming at a fasting glycaemic target of 4.0−5.0 mmol/L (71−90 mg/dL). No predefined maximum dose was specified for IGlar. The subjects continued with pre-trial doses of metformin, unless there was a safety concern.
Overall Number of Participants Analyzed 278 279
Measure Type: Number
Unit of Measure: Number of episodes
289 683
Time Frame Week 0 to week 27 (26-week treatment period and a follow-up visit 1 week after end of treatment)
Adverse Event Reporting Description All AEs described below are treatment-emergent. A treatment-emergent AE (TEAE) was defined as an event that had onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment. Analysis population: safety analysis set.
 
Arm/Group Title Insulin Degludec/Liraglutide (IDegLira) Insulin Glargine (IGlar)
Hide Arm/Group Description Eligible subjects received IDegLira once daily (OD) subcutaneously for a duration of 26 weeks. The starting dose of IDegLira was 16 dose steps (16 units IDeg/0.6 mg liraglutide) and was titrated according to a predefined titration algorithm with a maximum dose of 50 dose steps (50 units IDeg/1.8 mg liraglutide). Adjustment of the dose was performed twice weekly based on the mean of 3 preceding daily fasting SMPG values on 3 consecutive days. Adjustments were made in increments or decrements of 2 dose steps, aiming at a fasting glycaemic target of 4.0−5.0 mmol/L (71−90 mg/dL). That is, the adjustments were +2 or -2 if the mean of 3 pre-breakfast SMPG values were >5.0 mmol/L (or >90 mg/dL) and <4.0 mmol/L (or <71 mg/dL) respectively. No adjustment was done when the mean of 3 pre-breakfast SMPG values were 4.0 - 5.0 mmol/L (or 71-90 mg/dL). The subjects continued with pre-trial doses of metformin, unless there was a safety concern. Eligible subjects received IGlar OD subcutaneously for a duration of 26 weeks. The treatment started with dose equal to the pre-trial daily dose (dose-to-dose switch), after which the dose was titrated according to the specified titration algorithm aiming at a fasting glycaemic target of 4.0−5.0 mmol/L (71−90 mg/dL). No predefined maximum dose was specified for IGlar. The subjects continued with pre-trial doses of metformin, unless there was a safety concern.
All-Cause Mortality
Insulin Degludec/Liraglutide (IDegLira) Insulin Glargine (IGlar)
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Hide Serious Adverse Events
Insulin Degludec/Liraglutide (IDegLira) Insulin Glargine (IGlar)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   5/278 (1.80%)      9/279 (3.23%)    
Cardiac disorders     
Acute coronary syndrome  1  0/278 (0.00%)  0 1/279 (0.36%)  1
Arrhythmia  1  0/278 (0.00%)  0 1/279 (0.36%)  1
Cardiac failure  1  0/278 (0.00%)  0 1/279 (0.36%)  1
Ear and labyrinth disorders     
Auricular perichondritis  1  0/278 (0.00%)  0 1/279 (0.36%)  1
Hepatobiliary disorders     
Biliary colic  1  0/278 (0.00%)  0 1/279 (0.36%)  1
Cholecystitis acute  1  0/278 (0.00%)  0 1/279 (0.36%)  1
Cholelithiasis  1  1/278 (0.36%)  1 0/279 (0.00%)  0
Infections and infestations     
Appendicitis  1  0/278 (0.00%)  0 1/279 (0.36%)  1
Metabolism and nutrition disorders     
Hypoglycaemia  1  0/278 (0.00%)  0 1/279 (0.36%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Prostate cancer  1  1/278 (0.36%)  1 0/279 (0.00%)  0
Rectal adenocarcinoma  1  1/278 (0.36%)  1 0/279 (0.00%)  0
Nervous system disorders     
Haemorrhagic stroke  1  0/278 (0.00%)  0 1/279 (0.36%)  1
Vertebrobasilar insufficiency  1  1/278 (0.36%)  1 0/279 (0.00%)  0
Reproductive system and breast disorders     
Postmenopausal haemorrhage  1  1/278 (0.36%)  1 0/279 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Insulin Degludec/Liraglutide (IDegLira) Insulin Glargine (IGlar)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   52/278 (18.71%)      22/279 (7.89%)    
Gastrointestinal disorders     
Diarrhoea  1  20/278 (7.19%)  23 7/279 (2.51%)  10
Nausea  1  26/278 (9.35%)  34 3/279 (1.08%)  3
Vomiting  1  14/278 (5.04%)  22 5/279 (1.79%)  5
Nervous system disorders     
Headache  1  11/278 (3.96%)  12 14/279 (5.02%)  28
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or communication for up to 60 days to protect intellectual property.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Global Clinical Registry (GCR, 1452)
Organization: Novo Nordisk A/S
EMail: clinicaltrials@novonordisk.com
Publications of Results:
Layout table for additonal information
Responsible Party: Novo Nordisk A/S
ClinicalTrials.gov Identifier: NCT01952145    
Other Study ID Numbers: NN9068-3952
2012-004413-14 ( EudraCT Number )
U1111-1135-1003 ( Other Identifier: WHO )
First Submitted: September 24, 2013
First Posted: September 27, 2013
Results First Submitted: November 23, 2016
Results First Posted: January 20, 2017
Last Update Posted: January 3, 2019