Diabetes, Diabetes Mellitus, Type 1
Conditions
Brief summary
This trial is conducted in Africa, Europe and North America. The purpose of the trial is to investigate the efficacy and safety of liraglutide adjunct to insulin treatment in type 1 diabetes.
Interventions
DRUGliraglutide
Subjects randomised to 1.8 mg liraglutide treatment as an add-on to their pre-trial insulin treatment will receive 0.6 mg liraglutide for 2 weeks followed by 1.2 mg liraglutide for 2 weeks. After 4 weeks of treatment subjects will receive 1.8 mg liraglutide for 22 weeks. Administered subcutaneously (s.c., under the skin) once daily.
DRUGplacebo
Subjects randomised to 0.3 mL liraglutide placebo as an add-on to their pre-trial insulin treatment will receive 0.1 mL for 2 weeks followed by 0.2 mL for 2 weeks. After 4 weeks of liraglutide placebo, subjects will receive 0.3 mL for 22 weeks. Administered subcutaneously (s.c., under the skin) once daily.
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial * Male or female, aged equal to or greater than 18 years at the time of signing informed consent * Type 1 diabetes mellitus (as diagnosed clinically) 12 months or longer prior to Visit 1 (i.e. screening) * Treatment with basal bolus or CSII (continuous subcutaneous insulin infusion, insulin pump) treatment 6 months or longer prior to Visit 1 (i.e. screening) * Stable insulin treatment 3 months or longer prior to Visit 1 (i.e. screening), as judged and documented by the investigator * HbA1c 7.0-10.0 percent (Diabetes Control and Complications Trial (DCCT)), both inclusive, by central laboratory analysis (Visit 1, screening) corresponding to 53-86 mmol/mol (International Federation of Clinical Chemistry (IFCC))
Exclusion criteria
* Prior use of glucagon-like peptide-1 (GLP-1) receptor agonist or dipeptidyl peptidase IV (DPPIV) inhibitors * Use of any medication, which in the investigator's opinion could interfere with the glycaemic control (e.g. systemic corticosteroids, pramlintide (Symlin®)) or affect the subject's safety. Premix insulin is not allowed * Known proliferative retinopathy or maculopathy requiring acute treatment * Severe neuropathy, in particular autonomic neuropathy, i.e. gastroparesis, as judged by the investigator * Uncontrolled/untreated blood pressure at screening (Visit 1) (after resting for 5 minutes) while sitting greater than 160 mmHg for systolic or greater than 100 mmHg for diastolic (repeated measurement at Visit 2 (prior to performing the trial related activities) is allowed to exclude white-coat hypertension) * History of acute or chronic pancreatitis * Screening (Visit 1) calcitonin value equal to or greater than 50 ng/L
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glycosylated Haemoglobin (HbA1c) | Week 0, Week 26 | Change from baseline in glycosylated haemoglobin (HbA1c), after 26 weeks of treatment. Full analysis set (FAS = 831) included all randomised subjects who had received at least one dose and had any post-randomisation data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Body Weight | Week 0, Week 26 | Change from baseline body weight, after 26 weeks of treatment. Full analysis set (FAS = 831) included all randomised subjects who had received at least one dose and had any post-randomisation data. |
| Number of Treatment-emergent Symptomatic Hypoglycaemic Episodes | Weeks 0-26 | Number of treatment-emergent symptomatic hypoglycaemic episodes during 26 weeks of treatment. Symptomatic hypoglycaemic episodes were defined as episodes that were severe according to the American Diabetes Association (ADA) classification or a self-measured plasma glucose (SMPG) value of \<3.1 mmol/L (56 mg/dL), with symptoms consistent with hypoglycaemia. Severe hypoglycaemia as per ADA classification is defined as an episode that required assistance of another person to actively administer carbohydrate, glucagon or take other corrective actions. |
Countries
Austria, Belgium, Bulgaria, Canada, Denmark, Finland, France, Italy, Netherlands, South Africa, Spain, Sweden, United States
Participant flow
Recruitment details
Subjects were randomised at 113 sites in 13 countries: Austria 2 sites, Belgium 9 sites, Bulgaria 5 sites, Canada 9 sites, Denmark 4 sites, Finland 6 sites, France 9 sites, Italy 7 sites, Netherlands 5 sites, South Africa 2 sites, Spain 5 sites, Sweden 5 sites, United States 45 sites.
Participants by arm
| Arm | Count |
|---|---|
| Liraglutide 0.6 mg Subjects randomised to 0.6 mg liraglutide treatment as an add-on to their pre-trial insulin treatment and remained on this dose throughout the trial (26 weeks). Administered subcutaneously (s.c., under the skin) once daily. | 211 |
| Liraglutide 1.2 mg Subjects randomised to 1.2 mg liraglutide treatment as an add-on to their pre-trial insulin treatment received 0.6 mg liraglutide for 2 weeks followed by 1.2 mg liraglutide for 24 weeks. Administered subcutaneously (s.c., under the skin) once daily. | 209 |
| Liraglutide 1.8 mg Subjects randomised to 1.8 mg liraglutide treatment as an add-on to their pre-trial insulin treatment received 0.6 mg liraglutide for 2 weeks followed by 1.2 mg liraglutide for 2 weeks. After 4 weeks of treatment subjects received 1.8 mg liraglutide for 22 weeks. Administered subcutaneously (s.c., under the skin) once daily. | 205 |
| Liraglutide Placebo Subjects randomised to 3 different placebo arms as an add-on to their pre-trial insulin treatment. Administered subcutaneously (s.c., under the skin) once daily. All the 3 arms were pooled together for data analysis.
1. Placebo 0.1 mL arm: Subjects received 0.1 mL placebo throughout the trial.
2. Placebo 0.2 mL arm: Subjects received 0.1 mL placebo for 2 weeks followed by 0.2 mL for 24 weeks.
3. Placebo 0.3 mL arm: Subjects received 0.1 mL placebo for 2 weeks followed by 0.2 mL for 2 weeks and 0.3 mL for next 22 weeks of the trial period. | 206 |
| Total | 831 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 12 | 19 | 34 | 2 |
| Overall Study | Lost to Follow-up | 2 | 1 | 0 | 3 |
| Overall Study | Protocol Violation | 2 | 2 | 0 | 7 |
| Overall Study | Unclassified | 0 | 0 | 3 | 2 |
| Overall Study | Withdrawal by Subject | 10 | 10 | 5 | 13 |
Baseline characteristics
| Characteristic | Liraglutide 0.6 mg | Liraglutide 1.2 mg | Liraglutide 1.8 mg | Liraglutide Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 43.9 years STANDARD_DEVIATION 12.88 | 42.8 years STANDARD_DEVIATION 13.31 | 43.2 years STANDARD_DEVIATION 12.9 | 42.7 years STANDARD_DEVIATION 12.97 | 43.2 years STANDARD_DEVIATION 13 |
| Body Weight | 83.10 kg STANDARD_DEVIATION 16.137 | 84.69 kg STANDARD_DEVIATION 18.155 | 83.64 kg STANDARD_DEVIATION 17.62 | 84.20 kg STANDARD_DEVIATION 16.539 | 83.91 kg STANDARD_DEVIATION 17.109 |
| Gender Female | 118 Participants | 106 Participants | 113 Participants | 112 Participants | 449 Participants |
| Gender Male | 93 Participants | 103 Participants | 92 Participants | 94 Participants | 382 Participants |
| Glycosylated Haemoglobin (HbA1c) | 8.09 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.743 | 8.07 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.731 | 8.04 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.736 | 8.12 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.723 | 8.08 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.732 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 137 / 211 | 164 / 209 | 162 / 206 | 125 / 206 |
| serious Total, serious adverse events | 20 / 211 | 21 / 209 | 14 / 206 | 14 / 206 |
Outcome results
Primary
Change From Baseline in Glycosylated Haemoglobin (HbA1c)
Change from baseline in glycosylated haemoglobin (HbA1c), after 26 weeks of treatment. Full analysis set (FAS = 831) included all randomised subjects who had received at least one dose and had any post-randomisation data.
Time frame: Week 0, Week 26
Population: Out of the 831 subjects in FAS, 22 subjects in lira 0.6 mg arm, 33 subjects in lira 1.2 mg arm, 35 subjects in lira 1.8 mg arm and 16 in placebo arm did not contribute to this analysis. Missing data imputed from a mixed model for repeated measurements (MMRM) method.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide 0.6 mg | Change From Baseline in Glycosylated Haemoglobin (HbA1c) | -0.23 Percent (%) glycosylated haemoglobin | Standard Deviation 0.744 |
| Liraglutide 1.2 mg | Change From Baseline in Glycosylated Haemoglobin (HbA1c) | -0.23 Percent (%) glycosylated haemoglobin | Standard Deviation 0.731 |
| Liraglutide 1.8 mg | Change From Baseline in Glycosylated Haemoglobin (HbA1c) | -0.32 Percent (%) glycosylated haemoglobin | Standard Deviation 0.73 |
| Liraglutide Placebo | Change From Baseline in Glycosylated Haemoglobin (HbA1c) | 0.01 Percent (%) glycosylated haemoglobin | Standard Deviation 0.674 |
Comparison: Superiority of liraglutide 1.8 mg versus placebo was planned to be concluded if and only if the upper limit of the two-sided 95% confidence interval for the estimated difference in HbA1c was less than zero.p-value: <0.000195% CI: [-0.5, -0.2]Mixed Models Analysis
Comparison: Superiority of liraglutide 1.2 mg was planned to be evaluated only if superiority for liraglutide 1.8 mg was concluded.p-value: =0.002195% CI: [-0.38, -0.08]Mixed Models Analysis
Comparison: Superiority of liraglutide 0.6 mg versus placebo was planned to be evaluated only if superiority of liraglutide 1.2 mg was concluded.p-value: =0.001195% CI: [-0.39, -0.1]Mixed Models Analysis
Secondary
Change From Baseline in Body Weight
Change from baseline body weight, after 26 weeks of treatment. Full analysis set (FAS = 831) included all randomised subjects who had received at least one dose and had any post-randomisation data.
Time frame: Week 0, Week 26
Population: Of the 831 subjects in FAS, 27 subjects in lira 0.6 mg arm, 38 subjects in lira 1.2 mg arm, 35 subjects in lira 1.8 mg arm and 26 in placebo arm did not contribute to the analysis. Missing data imputed from a mixed model for repeated measurements (MMRM) method.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide 0.6 mg | Change From Baseline in Body Weight | -2.37 kg | Standard Deviation 3.015 |
| Liraglutide 1.2 mg | Change From Baseline in Body Weight | -4.03 kg | Standard Deviation 3.677 |
| Liraglutide 1.8 mg | Change From Baseline in Body Weight | -5.1 kg | Standard Deviation 3.787 |
| Liraglutide Placebo | Change From Baseline in Body Weight | -0.26 kg | Standard Deviation 2.782 |
Secondary
Number of Treatment-emergent Symptomatic Hypoglycaemic Episodes
Number of treatment-emergent symptomatic hypoglycaemic episodes during 26 weeks of treatment. Symptomatic hypoglycaemic episodes were defined as episodes that were severe according to the American Diabetes Association (ADA) classification or a self-measured plasma glucose (SMPG) value of \<3.1 mmol/L (56 mg/dL), with symptoms consistent with hypoglycaemia. Severe hypoglycaemia as per ADA classification is defined as an episode that required assistance of another person to actively administer carbohydrate, glucagon or take other corrective actions.
Time frame: Weeks 0-26
Population: Safety analysis set (SAS) included all subjects exposed to at least one dose of randomised liraglutide or placebo (SAS = 832 subjects). Symptomatic hypoglycaemic episodes were reported by 166 subjects in liraglutide 0.6 mg arm, 175 subjects in liraglutide 1.2 mg, 160 subjects in liraglutide 1.8 mg arm and 162 subjects in liraglutide placebo arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Liraglutide 0.6 mg | Number of Treatment-emergent Symptomatic Hypoglycaemic Episodes | 1437 episodes |
| Liraglutide 1.2 mg | Number of Treatment-emergent Symptomatic Hypoglycaemic Episodes | 1943 episodes |
| Liraglutide 1.8 mg | Number of Treatment-emergent Symptomatic Hypoglycaemic Episodes | 1490 episodes |
| Liraglutide Placebo | Number of Treatment-emergent Symptomatic Hypoglycaemic Episodes | 1567 episodes |