Clinical Trial Results:
DUAL™VII - Insulin degludec/liraglutide (IDegLira) vs. basal-bolus therapy: A clinical trial comparing efficacy and safety of insulin degludec/liraglutide (IDegLira) versus basal-bolus therapy in subjects with type 2 diabetes mellitus
Summary
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EudraCT number |
2014-003621-18 |
Trial protocol |
HU SK GR ES CZ FR |
Global end of trial date |
05 Oct 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
19 Oct 2017
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First version publication date |
19 Oct 2017
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
NN9068-4185
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02420262 | ||
WHO universal trial number (UTN) |
U1111-1160-6923 | ||
Sponsors
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Sponsor organisation name |
Novo Nordisk A/S
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Sponsor organisation address |
Novo Allé, Bagsvaerd, Denmark, 2880
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Public contact |
Global Clinical Registry (GCR, 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
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Scientific contact |
Global Clinical Registry (GCR, 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
30 May 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
05 Oct 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
05 Oct 2016
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To confirm the efficacy of insulin degludec/liraglutide (IDegLira) in terms of glycaemic control in subjects with type 2 diabetes mellitus on previous treatment with insulin glargine (IGlar) and metformin. This was done by comparing the difference in change in HbA1c from baseline after 26 weeks of treatment to a non-inferiority limit of 0.30% for once daily IDegLira versus basal-bolus therapy with once daily IGlar plus prandial insulin aspart (IAsp), both arms in combination with metformin.
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Protection of trial subjects |
The trial was conducted in accordance with the Declaration of Helsinki (64th WMA Assembly) and ICH Good Clinical Practice (May 1996) and 21 CFR 312.120.
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Background therapy |
All subjects were to continue with metformin at the stable pre-trial dose level, unless there was a safety concern. | ||
Evidence for comparator |
Not applicable | ||
Actual start date of recruitment |
26 Jul 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Argentina: 45
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Country: Number of subjects enrolled |
Czech Republic: 37
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Country: Number of subjects enrolled |
France: 16
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Country: Number of subjects enrolled |
Greece: 44
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Country: Number of subjects enrolled |
Hungary: 37
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Country: Number of subjects enrolled |
Israel: 30
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Country: Number of subjects enrolled |
Mexico: 46
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Country: Number of subjects enrolled |
Russian Federation: 50
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Country: Number of subjects enrolled |
Slovakia: 36
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Country: Number of subjects enrolled |
Spain: 45
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Country: Number of subjects enrolled |
Turkey: 40
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Country: Number of subjects enrolled |
United States: 80
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Worldwide total number of subjects |
506
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EEA total number of subjects |
215
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
382
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From 65 to 84 years |
123
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85 years and over |
1
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Recruitment
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Recruitment details |
The trial was conducted at 89 sites in 12 countries: Argentina (3 sites), Czech Republic (5 sites), France (3 sites), Greece (6 sites), Hungary (3 sites), Israel (6 sites), Mexico (3 sites), Russia (7 sites), Slovakia (5 sites), Spain (6 sites), Turkey (5 sites) and United States (37 sites). | ||||||||||||||||||||||||
Pre-assignment
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Screening details |
Subjects with type 2 diabetes mellitus were on treatment with stable daily dose of insulin glargine (IGlar) 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 maximum tolerated dose) for at least 90 days prior to screening. | ||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||
Blinding implementation details |
Not applicable
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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IDegLira | ||||||||||||||||||||||||
Arm description |
Insulin Degludec/Liraglutide (IDegLira) was administered once daily (OD) for a duration of 26 weeks. IDegLira treatment was initiated at starting dose 16 dose steps and was titrated according to a predefined titration algorithm. The maximum daily dose was 50 dose steps. All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose), unless there was a safety concern. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Insulin degludec liraglutide
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Investigational medicinal product code |
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Other name |
Xultophy®
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
IDegLira was supplied in a 3 mL pre-filled PDS290 pen-injector with a fixed IDeg/liraglutide ratio of 100 units/3.6 mg per mL solution. IDegLira treatment was initiated at 16 dose steps (containing 16 units IDeg /0.6 mg liraglutide) and adjusted twice weekly based on the mean of three pre-breakfast self-measured plasma glucose (SMPG) values measured on the days of the titration and the two days prior to the titration (target SMPG: 4.0-5.0 mmol/L [72- 90 mg/dL]). The maximum daily dose was 50 dose steps (50U IDeg /1.8 mg Lira).
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Arm title
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IGlar + IAsp | ||||||||||||||||||||||||
Arm description |
Subjects received insulin glargine plus prandial insulin aspart (IGlar + IAsp) for a duration of 26 weeks. A stable pre-trial OD dose of IGlar was continued with metformin therapy (≥ 1500 mg or the maximum tolerated dose). IAsp was added to the IGlar therapy with a start dose of 4U as prandial insulin treatment before each main meal and was titrated in a treat-to-target fashion in accordance with a predefined titration algorithm. There was no maximum dose specified for IGlar or IAsp. | ||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||
Investigational medicinal product name |
Insulin Glargine
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Investigational medicinal product code |
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Other name |
Lantus®
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
A stable pre- trial OD dose of IGlar (20-50 units, in a 3 mL pre-filled Solostar®. The dose of IGlar was adjusted twice weekly based on the mean of three pre-breakfast SMPG values measured on the days of the titration and the two days prior to the titration (target SMPG: 4.0-5.0 mmol/L [72- 90 mg/dL]).
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Investigational medicinal product name |
Insulin Aspart
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Investigational medicinal product code |
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Other name |
NovoRapid®
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
IAsp was added to the IGlar therapy with a start dose of 4U using a 3 mL pre-filled FlexPen®, as prandial insulin treatment before each main meal. The dose of IAsp was titrated twice weekly based on pre-prandial and bedtime SMPGs, obtained on the three previous days (target SMPG: 4.0 – 6.0 mmol/L).
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Baseline characteristics reporting groups
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Reporting group title |
IDegLira
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Reporting group description |
Insulin Degludec/Liraglutide (IDegLira) was administered once daily (OD) for a duration of 26 weeks. IDegLira treatment was initiated at starting dose 16 dose steps and was titrated according to a predefined titration algorithm. The maximum daily dose was 50 dose steps. All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose), unless there was a safety concern. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
IGlar + IAsp
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Reporting group description |
Subjects received insulin glargine plus prandial insulin aspart (IGlar + IAsp) for a duration of 26 weeks. A stable pre-trial OD dose of IGlar was continued with metformin therapy (≥ 1500 mg or the maximum tolerated dose). IAsp was added to the IGlar therapy with a start dose of 4U as prandial insulin treatment before each main meal and was titrated in a treat-to-target fashion in accordance with a predefined titration algorithm. There was no maximum dose specified for IGlar or IAsp. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
IDegLira
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Reporting group description |
Insulin Degludec/Liraglutide (IDegLira) was administered once daily (OD) for a duration of 26 weeks. IDegLira treatment was initiated at starting dose 16 dose steps and was titrated according to a predefined titration algorithm. The maximum daily dose was 50 dose steps. All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose), unless there was a safety concern. | ||
Reporting group title |
IGlar + IAsp
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Reporting group description |
Subjects received insulin glargine plus prandial insulin aspart (IGlar + IAsp) for a duration of 26 weeks. A stable pre-trial OD dose of IGlar was continued with metformin therapy (≥ 1500 mg or the maximum tolerated dose). IAsp was added to the IGlar therapy with a start dose of 4U as prandial insulin treatment before each main meal and was titrated in a treat-to-target fashion in accordance with a predefined titration algorithm. There was no maximum dose specified for IGlar or IAsp. |
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End point title |
Change from baseline in HbA1c (glycosylated haemoglobin) | ||||||||||||
End point description |
Change from baseline in HbA1c values after 26 weeks of treatment. The analysis of this efficacy endpoint was based on the full analysis set (FAS). The FAS included all randomised subjects. The statistical evaluation of the FAS followed the intention-to-treat (ITT) principle and subjects contributed to the evaluation “as randomised”. 14 subjects in IDegLira and 21 subjects in IGlar + IAsp arm did not contribute to the analysis for this endpoint.
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End point type |
Primary
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End point timeframe |
After 26 weeks of treatment
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Statistical analysis title |
Primary statistical analysis | ||||||||||||
Statistical analysis description |
Change from baseline in HbA1c was analysed using a mixed model for repeated measurements with an unstructured covariance matrix. The model included treatment, visit and region as fixed factors and baseline HbA1c as covariate. Interactions between visit and all factors and the covariate were also included in the model.
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Comparison groups |
IGlar + IAsp v IDegLira
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Number of subjects included in analysis |
489
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Treatment contrast | ||||||||||||
Point estimate |
-0.02
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.16 | ||||||||||||
upper limit |
0.12 | ||||||||||||
Notes [1] - Non-inferiority for IDegLira vs basal-bolus (IGlar + IAsp) was considered confirmed if the upper boundary of the two-sided 95% confidence interval was strictly below 0.30% or equivalent for non-inferiority using one-sided test for null hypothesis (H0): D ≥0.30% against alternative hypothesis (HA): D <0.30% was less than or equal to 2.5%, where D is the mean treatment difference (IDegLira minus basal-bolus). |
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End point title |
Number of treatment emergent severe or blood glucose confirmed symptomatic hypoglycaemic episodes | |||||||||
End point description |
Severe or blood glucose (BG) confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe and/or BG confirmed by a plasma glucose value of <56 mg/dL (3.1 mmol/L), with symptoms consistent with hypoglycaemia. The safety analysis set (SAS) included all subjects receiving at least one dose of the investigational product or comparator. Subjects in the safety set contributed to the evaluation “as treated”. One subject in IGlar + IAsp arm did not contribute to the analysis for this endpoint.
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End point type |
Secondary
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End point timeframe |
During 26 weeks of treatment
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Statistical analysis title |
Confirmatory secondary statistical analysis | |||||||||
Statistical analysis description |
Hypoglycaemic episodes were analysed using a negative binomial regression. The model included treatment and region as fixed factors and logarithm of the time period in which a hypoglycaemic episode considered treatment emergent as offset.
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Comparison groups |
IDegLira v IGlar + IAsp
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Number of subjects included in analysis |
505
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Analysis specification |
Pre-specified
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Analysis type |
superiority [2] | |||||||||
P-value |
< 0.0001 | |||||||||
Method |
Negative binomial regression model | |||||||||
Parameter type |
Treatment ratio | |||||||||
Point estimate |
0.11
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.08 | |||||||||
upper limit |
0.17 | |||||||||
Notes [2] - Superiority for IDegLira vs basal-bolus was considered confirmed if the 95% confidence interval for the treatment rate ratio was entirely below 1.0. The test for superiority of the confirmatory secondary endpoints was carried out only if non-inferiority of IDegLira vs basal-bolus for primary endpoint was confirmed. |
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End point title |
Change from baseline in body weight | ||||||||||||
End point description |
Change from baseline in body weight after 26 weeks of treatment. The analysis of this efficacy endpoint was based on the full analysis set (FAS). The FAS included all randomised subjects. The statistical evaluation of the FAS followed the intention-to-treat (ITT) principle and subjects contributed to the evaluation “as randomised”. 08 subjects in both IDegLira and IGlar + IAsp arm did not contribute to the analysis for this endpoint.
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End point type |
Secondary
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End point timeframe |
After 26 weeks of treatment
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Statistical analysis title |
Confirmatory secondary statistical analysis | ||||||||||||
Statistical analysis description |
Body weight measurements were analysed using a linear mixed model with an unstructured covariance matrix. The model included treatment, visit and region as fixed factors and baseline bodyweight as covariate. Interactions between visit and all factors and the covariate were also included in the model.
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Comparison groups |
IDegLira v IGlar + IAsp
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Number of subjects included in analysis |
490
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Treatment difference | ||||||||||||
Point estimate |
-3.57
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-4.19 | ||||||||||||
upper limit |
-2.95 | ||||||||||||
Notes [3] - Superiority for IDegLira vs basal-bolus was considered confirmed if the 95% confidence interval for the treatment difference was below 0 or equal to 0. |
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End point title |
Responder for HbA1c below 7.0% | |||||||||||||||
End point description |
Number of subjects with HbA1c below 7% after 26 weeks of treatment. The analysis of this efficacy endpoint was based on the full analysis set (FAS). The FAS included all randomised subjects. The statistical evaluation of the FAS followed the intention-to-treat (ITT) principle and subjects contributed to the evaluation “as randomised”. 14 subjects in IDegLira and 21 subjects in IGlar + IAsp arm did not contribute to the analysis for this endpoint.
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End point type |
Secondary
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End point timeframe |
After 26 weeks of treatment
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No statistical analyses for this end point |
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End point title |
Responder for HbA1c below or equal to 6.5 % | |||||||||||||||
End point description |
Number of subjects with HbA1c below 7% after 26 weeks of treatment. The analysis of this efficacy endpoint was based on the full analysis set (FAS). The FAS included all randomised subjects. The statistical evaluation of the FAS followed the intention-to-treat (ITT) principle and subjects contributed to the evaluation “as randomised”. 14 subjects in IDegLira and 21 subjects in IGlar + IAsp arm did not contribute to the analysis for this endpoint.
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End point type |
Secondary
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End point timeframe |
After 26 weeks of treatment
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Until 26 weeks+ follow-up contact (comprising of 7 days) after end of randomised treatment.
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Adverse event reporting additional description |
A treatment emergent adverse event was defined as an event that had onset time after the first day of exposure to randomised treatment and no later than seven days after the last day of randomised treatment (26 weeks + 7 days of follow-up). Analysis was performed using SAS, included all subjects receiving at least one dose of trial product.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19
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Reporting groups
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Reporting group title |
IDegLira
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Reporting group description |
Insulin Degludec/Liraglutide (IDegLira) was administered once daily (OD) for a duration of 26 weeks. IDegLira treatment was initiated at starting dose 16 dose steps and was titrated according to a predefined titration algorithm. The maximum daily dose was 50 dose steps. All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose), unless there was a safety concern. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
IGlar + IAsp
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Reporting group description |
Subjects received insulin glargine plus prandial insulin aspart (IGlar + IAsp) for a duration of 26 weeks. A stable pre-trial OD dose of IGlar was continued with metformin therapy (≥ 1500 mg or the maximum tolerated dose). IAsp was added to the IGlar therapy with a start dose of 4U as prandial insulin treatment before each main meal and was titrated in a treat-to-target fashion in accordance with a predefined titration algorithm. There was no maximum dose specified for IGlar or IAsp. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |