Clinical Trial Results:
DUAL™ III - GLP-1 switch: The efficacy of insulin degludec/liraglutide in controlling glycaemia in adults with type 2 diabetes inadequately controlled on GLP-1 receptor agonist and OAD therapy
Summary
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EudraCT number |
2012-000209-63 |
Trial protocol |
SK HU |
Global end of trial date |
11 Mar 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
15 Mar 2016
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First version publication date |
28 Jul 2015
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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 |
NN9068-3851
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01676116 | ||
WHO universal trial number (UTN) |
U1111-1127-1321 | ||
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) |
No
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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 |
27 Aug 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
11 Mar 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
11 Mar 2014
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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 superiority of insulin degludec/liraglutide versus unchanged glucagon-like peptide-1 (GLP-1) receptor agonist therapy in controlling glycaemia in insulin naïve subjects with type 2 diabetes mellitus (T2DM) inadequately controlled on GLP-1 receptor agonist therapy in combination with metformin±pioglitazone±sulphonylurea.
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Protection of trial subjects |
The trial was conducted in accordance with the Declaration of Helsinki (59th WMA Assembly, October 2008) and ICH Good Clinical Practice (May 1996) and 21 CFR 312.120.
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Background therapy |
Subjects continued with the OADs Metformin, pioglitazone and sulphonylurea in stable pre-trial doses. | ||
Evidence for comparator |
Not applicable. | ||
Actual start date of recruitment |
29 Aug 2012
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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 |
Australia: 41
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Country: Number of subjects enrolled |
United States: 262
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Country: Number of subjects enrolled |
Slovakia: 60
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Country: Number of subjects enrolled |
France: 40
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Country: Number of subjects enrolled |
Hungary: 35
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Worldwide total number of subjects |
438
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EEA total number of subjects |
135
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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) |
326
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From 65 to 84 years |
112
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85 years and over |
0
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Recruitment
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Recruitment details |
The trial was conducted at 81 sites in 5 countries as follows: Australia: 5 sites; France: 7 sites; Hungary: 4 sites; Slovakia 6 sites; United States: 59 sites. | ||||||||||||||||||||||||
Pre-assignment
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Screening details |
The duration of the screening period was 2-weeks. All subjects continued GLP-1 receptor agonist and metformin±pioglitazone±SU treatments in their pre-trial doses during the screening period. | ||||||||||||||||||||||||
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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Insulin degludec/liraglutide + OADs | ||||||||||||||||||||||||
Arm description |
Subjects were treated with subcutaneous (under the skin) once daily (OD) insulin degludec/liraglutide. Insulin degludec/liraglutide was dosed on an individual basis. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) treatment without changing the frequency or dose throughout the trial, unless there was a safety concern. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Insulin degludec/liraglutide PDS290
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Investigational medicinal product code |
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Other name |
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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 |
Insulin degludec/liraglutide in a fixed insulin degludec/liraglutide ratio of 100 units/3.6 mg per mL was supplied in a 3 mL prefilled PDS290 pen-injector. Insulin degludec/liraglutide was injected s.c. in the thigh, upper arm (deltoid region) or abdomen once daily preferably at the same time every day. The insulin degludec/liraglutide dosing unit is defined as a dose step, where 1 insulin degludec/liraglutide dose step consists of 1 unit insulin degludec and 0.036 mg liraglutide. Treatment with insulin degludec/liraglutide was initiated at 16 dose steps containing 16 units insulin degludec and 0.6 mg liraglutide. Adjustment of the insulin degludec/liraglutide dose performed twice weekly based on the mean of 3 preceding daily fasting SMPG values on 3 consecutive days. The maximum allowed dose was 50 dose steps (50 units insulin degludec/1.8 mg liraglutide).
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Arm title
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Liraglutide or exenatide + OADs | ||||||||||||||||||||||||
Arm description |
Subjects continued on their pre-trial treatment with subcutaneous (under the skin) liraglutide (Victoza®) (GLP-1 receptor agonist) or exenatide (Byetta®) (GLP-1 receptor agonist) without changing the frequency or dose throughout the trial. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) without changing the frequency or dose throughout the trial, unless there was a safety concern. | ||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||
Investigational medicinal product name |
Liraglitide or Exenatide
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Investigational medicinal product code |
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Other name |
Victoza or Byetta
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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 |
The subjects continued their pre-trial GLP-1 receptor agonist treatment either with liraglutide or exenatide with the dose and treatment schedule unchanged throughout the trial period. Subjects also continued with the OADs - metformin, pioglitazone and SU - in stable pre-trial doses (unless there was a safety concern).
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Baseline characteristics reporting groups
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Reporting group title |
Insulin degludec/liraglutide + OADs
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Reporting group description |
Subjects were treated with subcutaneous (under the skin) once daily (OD) insulin degludec/liraglutide. Insulin degludec/liraglutide was dosed on an individual basis. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) treatment without changing the frequency or dose throughout the trial, unless there was a safety concern. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Liraglutide or exenatide + OADs
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Reporting group description |
Subjects continued on their pre-trial treatment with subcutaneous (under the skin) liraglutide (Victoza®) (GLP-1 receptor agonist) or exenatide (Byetta®) (GLP-1 receptor agonist) without changing the frequency or dose throughout the trial. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) without changing the frequency or dose throughout the trial, unless there was a safety concern. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Insulin degludec/liraglutide + OADs
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Reporting group description |
Subjects were treated with subcutaneous (under the skin) once daily (OD) insulin degludec/liraglutide. Insulin degludec/liraglutide was dosed on an individual basis. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) treatment without changing the frequency or dose throughout the trial, unless there was a safety concern. | ||
Reporting group title |
Liraglutide or exenatide + OADs
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Reporting group description |
Subjects continued on their pre-trial treatment with subcutaneous (under the skin) liraglutide (Victoza®) (GLP-1 receptor agonist) or exenatide (Byetta®) (GLP-1 receptor agonist) without changing the frequency or dose throughout the trial. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) without changing the frequency or dose throughout the trial, unless there was a safety concern. |
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End point title |
Change in glycosylated haemoglobin (HbA1c) from baseline (randomisation, Visit 2). | ||||||||||||
End point description |
The mean change from baseline in HbA1c, after 26 weeks of treatment.
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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 |
Statistical Analysis | ||||||||||||
Statistical analysis description |
The primary endpoint was analysed using an analysis of covariance (ANCOVA) model with treatment, pre-trial GLP-1 receptor agonist (Victoza® or Byetta®) and region as fixed factors and baseline HbA1c value as covariate.
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Comparison groups |
Insulin degludec/liraglutide + OADs v Liraglutide or exenatide + OADs
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Number of subjects included in analysis |
438
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Treatment Contrast | ||||||||||||
Point estimate |
-0.94
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.11 | ||||||||||||
upper limit |
-0.78 |
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End point title |
Responders (Yes/No) achieving pre-defined target for HbA1c - HbA1c < 7.0% (53 mmol/mol). | ||||||||||||
End point description |
Proportion of subjects achieving HbA1c below 7.0% after 24 weeks of treatment.
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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 |
Responders (Yes/No) achieving pre-defined target for HbA1c - HbA1c ≤ 6.5% (48 mmol/mol). | ||||||||||||
End point description |
Proportion of responders achieving pre-defined target for HbA1c - HbA1c ≤ 6.5% (48 mmol/mol).
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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 |
Change from baseline in body weight. | ||||||||||||
End point description |
Mean change in body weight after 26 weeks of treatment.
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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 |
Change from baseline in fasting plasma glucose (FPG). | ||||||||||||
End point description |
Mean change in fasting plasma glucose from baseline, after 26 weeks of treatment.
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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 |
Number of treatment-emergent (confirmed) hypoglycaemic episodes. | ||||||||||||
End point description |
Rate (event rate per 100 patient years of exposure) of treatment-emergent confirmed hypoglycaemic episodes. The pool of severe and minor hypoglycaemic episodes was referred to as confirmed hypoglycaemic episodes.
Severe hypoglycaemia was categorised as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes were defined as an episode with symptoms consistent with hypoglycaemia with confirmation by blood glucose <2.8 mmol/L (50 mg/dL) or PG <3.1 mmol/L (56 mg/dL), and which was handled by the subject himself/herself, or any asymptomatic blood glucose value <2.8 mmol/L (50 mg/dL) or PG value <3.1 mmol/L (56 mg/dL).
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End point type |
Secondary
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End point timeframe |
During 26 weeks of treatment.
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No statistical analyses for this end point |
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End point title |
Number of treatment-emergent adverse events (AEs) | ||||||||||||
End point description |
Rate (event rate per 100 exposure years) of treatment-emergent adverse events (an event that had onset date (or an increase in severity) on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment) which occurred during the 26 weeks of treatment .
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End point type |
Secondary
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End point timeframe |
During 26 weeks of treatment.
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No statistical analyses for this end point |
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End point title |
Change from baseline in patient reported outcomes (PROs):-Treatment related impact measure – diabetes (TRIM-D). | ||||||||||||||||||||||||||||||
End point description |
The mean change from baseline on the ‘Treatment related impact measure for diabetes’ (TRIM-D), after 26 weeks of treatment. A higher score on the 1–5 point TRIM-D scale indicates a better health state (less negative impact). The mean change in scores for all the sub domains (treatment burden, daily life, diabetes management, compliance and psychological health) and total scores were analysed. Sub-domain scores were calculated by summing across items in the same domain and total score was calculated by adding scores from all the domains.
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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 |
Change from baseline in patient reported outcomes (PROs):-Diabetes treatment satisfaction questionnaire (DTSQ). | |||||||||||||||||||||
End point description |
Mean change in diabetes treatment satisfaction questionnaire (DTSQs) scores from baseline. Higher total score on a 0–6 point scale indicates a general higher treatment satisfaction (items 1, 4, 5, 6, 7 and 8), whereas higher score on perceived frequency of hyperglycaemia (item 2) and perceived frequency of hypoglycaemia (item 3) indicate that blood glucose levels are out of the target range.
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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 |
Adverse events from the first trial-related activity after the subject had signed the informed consent until the end of the post-treatment follow-up period are reported.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.1
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Reporting groups
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Reporting group title |
Liraglutide or exenatide + OADs
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Reporting group description |
Subjects continued on their pre-trial treatment with subcutaneous (under the skin) liraglutide (Victoza®) (GLP-1 receptor agonist) or exenatide (Byetta®) (GLP-1 receptor agonist) without changing the frequency or dose throughout the trial. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) without changing the frequency or dose throughout the trial, unless there was a safety concern. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Insulin degludec/liraglutide +OADs
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Reporting group description |
Subjects were treated with subcutaneous (under the skin) once daily (OD) insulin degludec/liraglutide. Insulin degludec/liraglutide was dosed on an individual basis. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) treatment without changing the frequency or dose throughout the trial, unless there was a safety concern. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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? Yes | |||
Date |
Amendment |
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04 Feb 2013 |
The global amendment included:
a) Changes in the pre-trial medication from GLP-1 and metformin therapy to allow GLP-1 in combination with OADs (metformin±pioglitazone±SU) due to recruitment facilitation and reflection of current diabetic patient population on GLP-1 receptor agonists.
b) Changes to the endpoints and statistical sections as described in Section 9.8.2 of this CTR.
c) Update of withdrawal criterion no. 1. Updates of the list of participating countries (Hungary added), recruitment timelines, blood volume to be drawn, protocol title, version and date of all appendices.
d) Update of the following MESI’s based on the learning’s from previous insulin degludec/liraglutide trials:
– Acute coronary syndrome (myocardial infarction [MI] or hospitalisation for unstable angina), incl. AMI caused by stent thrombosis: The wording “, incl. AMI caused by stent thrombosis” was deleted, as this information was already provided under Definitions in Appendix D.
– Hospitalisation for cardiac arrhythmia: The word “hospitalisation” was removed, as reporting of hospitalisation for cardiac arrhythmia was not always applicable. Cardiac arrhythmia was still to be reported as a MESI.
– Elevated lipase and/or amylase: Confirmatory testing removed. The single elevation >3xUNR of lipase/amylase was to be reported as a MESI.
– Elevated calcitonin: Protocol text clarified and aligned to match Appendix D of the protocol.
e) Removal of the initial aim to recruit approximately 50% of each type of GLP-1 receptor agonist.
f) Update of the ICF regarding blood to be drawn and increased heart rate according to the recent investigator’s brochure for liraglutide. |
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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. | |||
Not applicable |