Trial Outcomes & Findings for The Efficacy and Safety of Liraglutide as Adjunct Therapy to Insulin in the Treatment of Type 1 Diabetes (NCT NCT01836523)

Last Updated: 2017-03-06

Results Overview

Change from baseline in HbA1c at week 52. Missing values were handled by using a mixed model for repeated measurements (MMRM).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1398 participants

Primary outcome timeframe

Week 0, week 52

Results posted on

2017-03-06

Participant Flow

The trial was conducted at 177 sites in 17 countries: Argentina: 6, Australia: 5, Belgium: 4, Canada: 14, Germany: 8, Finland: 6, France: 13, United Kingdom: 10, Ireland: 5, Israel: 6, Netherlands: 6, Norway: 5, Poland: 5, Russia: 5, Sweden: 4, Ukraine: 5, United States: 70

Eligible subjects were randomised in a 3:3:3:1:1:1 manner to receive liraglutide (0.6 mg, 1.2 mg or 1.8 mg) or placebo (0.1 mL, 0.2 mL or 0.3 mL), both adjunct to insulin treatment.

Participant milestones

Participant milestones
Measure	Liraglutide 0.6 mg Subjects received liraglutide 0.6 mg once daily (OD) subcutaneously for 52 weeks in addition to their pre-trial insulin treatment.	Liraglutide 1.2 mg Subjects received liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Liraglutide 1.8 mg Liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously for 2 weeks (weeks 2-4) followed by 1.8 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Placebo Subjects received placebo (matched to liraglutide 0.6, 1.2 and 1.8 mg) OD subcutaneously as an add-on to their pre-trial insulin treatment. Placebo 0.1 mL (placebo matched to liraglutide 0.6 mg): Subjects received 0.1 mL liraglutide placebo for 52 weeks. Placebo 0.2 mL (placebo matched to liraglutide 1.2 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL up to week 52. Placebo 0.3 mL (placebo matched to liraglutide 1.8 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL for next 2 weeks and 0.3 mL up to week 52. All the 3 placebo doses were pooled for data analysis.
Overall Study STARTED	351	350	349	348
Overall Study Exposed	350	348	347	348
Overall Study COMPLETED	300	265	258	274
Overall Study NOT COMPLETED	51	85	91	74

Reasons for withdrawal

Reasons for withdrawal
Measure	Liraglutide 0.6 mg Subjects received liraglutide 0.6 mg once daily (OD) subcutaneously for 52 weeks in addition to their pre-trial insulin treatment.	Liraglutide 1.2 mg Subjects received liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Liraglutide 1.8 mg Liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously for 2 weeks (weeks 2-4) followed by 1.8 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Placebo Subjects received placebo (matched to liraglutide 0.6, 1.2 and 1.8 mg) OD subcutaneously as an add-on to their pre-trial insulin treatment. Placebo 0.1 mL (placebo matched to liraglutide 0.6 mg): Subjects received 0.1 mL liraglutide placebo for 52 weeks. Placebo 0.2 mL (placebo matched to liraglutide 1.2 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL up to week 52. Placebo 0.3 mL (placebo matched to liraglutide 1.8 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL for next 2 weeks and 0.3 mL up to week 52. All the 3 placebo doses were pooled for data analysis.
Overall Study Adverse Event	15	41	49	14
Overall Study Protocol Violation	6	3	2	4
Overall Study Met Withdrawal Criteria	13	13	21	27
Overall Study Unclassified	17	28	19	29

Baseline Characteristics

The Efficacy and Safety of Liraglutide as Adjunct Therapy to Insulin in the Treatment of Type 1 Diabetes

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Liraglutide 0.6 mg n=350 Participants Subjects received liraglutide 0.6 mg once daily (OD) subcutaneously for 52 weeks in addition to their pre-trial insulin treatment.	Liraglutide 1.2 mg n=346 Participants Subjects received liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Liraglutide 1.8 mg n=346 Participants Liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously for 2 weeks (weeks 2-4) followed by 1.8 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Placebo n=347 Participants Subjects received placebo (matched to liraglutide 0.6, 1.2 and 1.8 mg) OD subcutaneously as an add-on to their pre-trial insulin treatment. Placebo 0.1 mL (placebo matched to liraglutide 0.6 mg): Subjects received 0.1 mL liraglutide placebo for 52 weeks. Placebo 0.2 mL (placebo matched to liraglutide 1.2 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL up to week 52. Placebo 0.3 mL (placebo matched to liraglutide 1.8 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL for next 2 weeks and 0.3 mL up to week 52. All the 3 placebo doses were pooled for data analysis.	Total n=1389 Participants Total of all reporting groups
Age, Continuous	43.6 years STANDARD_DEVIATION 12.78 • n=5 Participants	43.9 years STANDARD_DEVIATION 13.06 • n=7 Participants	43.7 years STANDARD_DEVIATION 13.33 • n=5 Participants	43.4 years STANDARD_DEVIATION 12.57 • n=4 Participants	43.7 years STANDARD_DEVIATION 12.93 • n=21 Participants
Gender Female	186 Participants n=5 Participants	179 Participants n=7 Participants	181 Participants n=5 Participants	180 Participants n=4 Participants	726 Participants n=21 Participants
Gender Male	164 Participants n=5 Participants	167 Participants n=7 Participants	165 Participants n=5 Participants	167 Participants n=4 Participants	663 Participants n=21 Participants
Glycosylated haemoglobin (HbA1c)	8.18 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.738 • n=5 Participants	8.16 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.779 • n=7 Participants	8.14 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.740 • n=5 Participants	8.15 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.728 • n=4 Participants	8.16 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.746 • n=21 Participants
Body weight	86.54 kg STANDARD_DEVIATION 17.338 • n=5 Participants	85.39 kg STANDARD_DEVIATION 17.210 • n=7 Participants	86.27 kg STANDARD_DEVIATION 17.321 • n=5 Participants	86.41 kg STANDARD_DEVIATION 17.768 • n=4 Participants	86.15 kg STANDARD_DEVIATION 17.397 • n=21 Participants
Total daily actual insulin dose-continuous subcutaneous insulin infusion	52.97 units n=5 Participants	50.73 units n=7 Participants	50.46 units n=5 Participants	49.18 units n=4 Participants	50.65 units n=21 Participants
Total daily actual insulin dose - Multiple daily injections	59.54 units n=5 Participants	59.61 units n=7 Participants	62.52 units n=5 Participants	62.42 units n=4 Participants	60.94 units n=21 Participants

PRIMARY outcome

Timeframe: Week 0, week 52

Population: Full analysis set. Number of subjects analysed=subjects with any post-baseline HbA1c data.

Change from baseline in HbA1c at week 52. Missing values were handled by using a mixed model for repeated measurements (MMRM).

Outcome measures

Outcome measures
Measure	Liraglutide 0.6 mg n=334 Participants Subjects received liraglutide 0.6 mg once daily (OD) subcutaneously for 52 weeks in addition to their pre-trial insulin treatment.	Liraglutide 1.2 mg n=312 Participants Subjects received liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Liraglutide 1.8 mg n=305 Participants Liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously for 2 weeks (weeks 2-4) followed by 1.8 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Placebo n=324 Participants Subjects received placebo (matched to liraglutide 0.6, 1.2 and 1.8 mg) OD subcutaneously as an add-on to their pre-trial insulin treatment. Placebo 0.1 mL (placebo matched to liraglutide 0.6 mg): Subjects received 0.1 mL liraglutide placebo for 52 weeks. Placebo 0.2 mL (placebo matched to liraglutide 1.2 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL up to week 52. Placebo 0.3 mL (placebo matched to liraglutide 1.8 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL for next 2 weeks and 0.3 mL up to week 52. All the 3 placebo doses were pooled for data analysis.
Change From Baseline in HbA1c (Glycosylated Haemoglobin)	-0.45 percentage of glycosylated haemoglobin Standard Deviation 0.741	-0.50 percentage of glycosylated haemoglobin Standard Deviation 0.767	-0.54 percentage of glycosylated haemoglobin Standard Deviation 0.729	-0.34 percentage of glycosylated haemoglobin Standard Deviation 0.707

PRIMARY outcome

Timeframe: Week 0, week 52

Population: Full analysis set. Number of subjects analysed=subjects with any post-baseline body weight data.

Change from baseline in body weight at week 52. Missing values were handled by using a MMRM.

Outcome measures

Outcome measures
Measure	Liraglutide 0.6 mg n=324 Participants Subjects received liraglutide 0.6 mg once daily (OD) subcutaneously for 52 weeks in addition to their pre-trial insulin treatment.	Liraglutide 1.2 mg n=300 Participants Subjects received liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Liraglutide 1.8 mg n=298 Participants Liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously for 2 weeks (weeks 2-4) followed by 1.8 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Placebo n=311 Participants Subjects received placebo (matched to liraglutide 0.6, 1.2 and 1.8 mg) OD subcutaneously as an add-on to their pre-trial insulin treatment. Placebo 0.1 mL (placebo matched to liraglutide 0.6 mg): Subjects received 0.1 mL liraglutide placebo for 52 weeks. Placebo 0.2 mL (placebo matched to liraglutide 1.2 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL up to week 52. Placebo 0.3 mL (placebo matched to liraglutide 1.8 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL for next 2 weeks and 0.3 mL up to week 52. All the 3 placebo doses were pooled for data analysis.
Change From Baseline in Body Weight	-1.34 kg Standard Deviation 4.183	-2.73 kg Standard Deviation 4.524	-4.02 kg Standard Deviation 4.873	0.94 kg Standard Deviation 3.828

PRIMARY outcome

Timeframe: Week 0, week 52

Population: Full analysis set. Number of subjects analysed=subjects with any post-baseline total insulin daily dose data.

Change from baseline in total daily insulin dose at week 52. Change from baseline was represented in terms of ratio to baseline for insulin dose i.e. Total daily insulin dose at week 52/total daily insulin dose at baseline. Missing values were handled by using a MMRM.

Outcome measures

Outcome measures
Measure	Liraglutide 0.6 mg n=337 Participants Subjects received liraglutide 0.6 mg once daily (OD) subcutaneously for 52 weeks in addition to their pre-trial insulin treatment.	Liraglutide 1.2 mg n=328 Participants Subjects received liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Liraglutide 1.8 mg n=331 Participants Liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously for 2 weeks (weeks 2-4) followed by 1.8 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Placebo n=341 Participants Subjects received placebo (matched to liraglutide 0.6, 1.2 and 1.8 mg) OD subcutaneously as an add-on to their pre-trial insulin treatment. Placebo 0.1 mL (placebo matched to liraglutide 0.6 mg): Subjects received 0.1 mL liraglutide placebo for 52 weeks. Placebo 0.2 mL (placebo matched to liraglutide 1.2 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL up to week 52. Placebo 0.3 mL (placebo matched to liraglutide 1.8 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL for next 2 weeks and 0.3 mL up to week 52. All the 3 placebo doses were pooled for data analysis.
Change From Baseline in Total Daily Insulin Dose	1.04 ratio Geometric Coefficient of Variation 23.75	0.98 ratio Geometric Coefficient of Variation 26.66	0.95 ratio Geometric Coefficient of Variation 24.21	1.04 ratio Geometric Coefficient of Variation 26.69

SECONDARY outcome

Timeframe: Weeks 0-52

Population: The safety analysis set included all randomised subjects exposed to at least one dose of liraglutide or placebo.

This is a confirmatory secondary endpoint. Symptomatic hypoglycaemic episodes were defined as: 1) Severe according to the American Diabetes Association (ADA) classification: An episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. OR 2) Self-monitoring of plasma glucose value of \<3.1 mmol/L, with symptoms consistent with hypoglycaemia. A treatment emergent episode is defined as an episode with onset date (or increase in severity) on or after first day of exposure to randomised treatment and up to last dose + 7 days.

Outcome measures

Outcome measures
Measure	Liraglutide 0.6 mg n=350 Participants Subjects received liraglutide 0.6 mg once daily (OD) subcutaneously for 52 weeks in addition to their pre-trial insulin treatment.	Liraglutide 1.2 mg n=348 Participants Subjects received liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Liraglutide 1.8 mg n=347 Participants Liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously for 2 weeks (weeks 2-4) followed by 1.8 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.	Placebo n=348 Participants Subjects received placebo (matched to liraglutide 0.6, 1.2 and 1.8 mg) OD subcutaneously as an add-on to their pre-trial insulin treatment. Placebo 0.1 mL (placebo matched to liraglutide 0.6 mg): Subjects received 0.1 mL liraglutide placebo for 52 weeks. Placebo 0.2 mL (placebo matched to liraglutide 1.2 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL up to week 52. Placebo 0.3 mL (placebo matched to liraglutide 1.8 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL for next 2 weeks and 0.3 mL up to week 52. All the 3 placebo doses were pooled for data analysis.
Number of Treatment-emergent Symptomatic Hypoglycaemic Episodes	4954 episodes	4602 episodes	4614 episodes	3654 episodes

Adverse Events

Liraglutide 0.6 mg

Serious events: 35 serious events

Other events: 259 other events

Deaths: 0 deaths

Liraglutide 1.2 mg

Serious events: 36 serious events

Other events: 263 other events

Deaths: 0 deaths

Liraglutide 1.8 mg

Serious events: 29 serious events

Other events: 282 other events

Deaths: 0 deaths

Placebo

Serious events: 38 serious events

Other events: 224 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Public Access to Clinical Trials

Novo Nordisk A/S

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Novo Nordisk commits to communicating, and otherwise making available for public disclosure, results of trials regardless of outcome.At the end of the trial, one or more public disclosures 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.
Publication restrictions are in place

Restriction type: OTHER