Diabetes, Diabetes Mellitus, Type 1
Conditions
Brief summary
This trial is conducted globally. The aim of the trial is to confirm the efficacy and safety of liraglutide as adjunct therapy to insulin in the treatment of type 1 diabetes. The total trial duration per subject is approximately 58 weeks.
Interventions
DRUGliraglutide
Subjects randomised to 0.6 mg liraglutide treatment or liraglutide placebo as an add-on to their pre-trial insulin treatment will remain on this dose throughout the study (52 weeks). Administered subcutaneously (s.c., under the skin) once daily.
DRUGplacebo
Subjects randomised to 0.6 mg liraglutide treatment or liraglutide placebo as an add-on to their pre-trial insulin treatment will remain on this dose throughout the study (52 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 * \- Type 1 diabetes mellitus for 12 months or longer * \- Basal bolus or CSII (Continuous Subcutaneous Insulin Infusion, insulin pump) treatment for 6 months or longer * \- Stable insulin treatment for the last 3 months prior to Screening, as judged and documented by the investigator * \- HbA1c 7.0-10% (Diabetes Control and Complications Trial (DCCT)), both inclusive, (corresponding to 53-86 mmol/mol (International Federation of Clinical Chemistry (IFCC)) * \- Ability and willingness to comply with all protocol procedures e.g. correct handling of trial product, complete trial related questionnaires, diaries, self-monitoring of plasma glucose, self titration of insulin and attend all scheduled visits
Exclusion criteria
* \- Prior use of glucagon-like peptide-1 (GLP-1) receptor agonist or dipeptidyl peptidase IV (DPP-4) inhibitors * \- Use of any medication, which in the investigator's opinion could interfere with the glycaemic control 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 above 160 mmHg for systolic or above 100 mmHg for diastolic * \- History of acute or chronic pancreatitis * \- Screening calcitonin value equal to or above 50 ng/L * \- Personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia type 2 (MEN2) * \- Diagnosis of malignant neoplasm in the previous 5 years (except basal cell skin cancer or squamous cell skin cancer)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c (Glycosylated Haemoglobin) | Week 0, week 52 | Change from baseline in HbA1c at week 52. Missing values were handled by using a mixed model for repeated measurements (MMRM). |
| Change From Baseline in Body Weight | Week 0, week 52 | Change from baseline in body weight at week 52. Missing values were handled by using a MMRM. |
| Change From Baseline in Total Daily Insulin Dose | Week 0, week 52 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment-emergent Symptomatic Hypoglycaemic Episodes | Weeks 0-52 | 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. |
Countries
Argentina, Australia, Belgium, Canada, Finland, France, Germany, Ireland, Israel, Netherlands, Norway, Poland, Russia, Sweden, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
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
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 350 |
| 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. | 346 |
| 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. | 346 |
| 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. | 347 |
| Total | 1,389 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 15 | 41 | 49 | 14 |
| Overall Study | Met Withdrawal Criteria | 13 | 13 | 21 | 27 |
| Overall Study | Protocol Violation | 6 | 3 | 2 | 4 |
| Overall Study | Unclassified | 17 | 28 | 19 | 29 |
Baseline characteristics
| Characteristic | Total | Placebo | Liraglutide 0.6 mg | Liraglutide 1.8 mg | Liraglutide 1.2 mg |
|---|---|---|---|---|---|
| Age, Continuous | 43.7 years STANDARD_DEVIATION 12.93 | 43.4 years STANDARD_DEVIATION 12.57 | 43.6 years STANDARD_DEVIATION 12.78 | 43.7 years STANDARD_DEVIATION 13.33 | 43.9 years STANDARD_DEVIATION 13.06 |
| Body weight | 86.15 kg STANDARD_DEVIATION 17.397 | 86.41 kg STANDARD_DEVIATION 17.768 | 86.54 kg STANDARD_DEVIATION 17.338 | 86.27 kg STANDARD_DEVIATION 17.321 | 85.39 kg STANDARD_DEVIATION 17.21 |
| Gender Female | 726 Participants | 180 Participants | 186 Participants | 181 Participants | 179 Participants |
| Gender Male | 663 Participants | 167 Participants | 164 Participants | 165 Participants | 167 Participants |
| Glycosylated haemoglobin (HbA1c) | 8.16 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.746 | 8.15 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.728 | 8.18 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.738 | 8.14 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.74 | 8.16 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.779 |
| Total daily actual insulin dose-continuous subcutaneous insulin infusion | 50.65 units | 49.18 units | 52.97 units | 50.46 units | 50.73 units |
| Total daily actual insulin dose - Multiple daily injections | 60.94 units | 62.42 units | 59.54 units | 62.52 units | 59.61 units |
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 | 259 / 350 | 263 / 348 | 282 / 347 | 224 / 348 |
| serious Total, serious adverse events | 35 / 350 | 36 / 348 | 29 / 347 | 38 / 348 |
Outcome results
Primary
Change From Baseline in Body Weight
Change from baseline in body weight at week 52. Missing values were handled by using a MMRM.
Time frame: Week 0, week 52
Population: Full analysis set. Number of subjects analysed=subjects with any post-baseline body weight data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide 0.6 mg | Change From Baseline in Body Weight | -1.34 kg | Standard Deviation 4.183 |
| Liraglutide 1.2 mg | Change From Baseline in Body Weight | -2.73 kg | Standard Deviation 4.524 |
| Liraglutide 1.8 mg | Change From Baseline in Body Weight | -4.02 kg | Standard Deviation 4.873 |
| Placebo | Change From Baseline in Body Weight | 0.94 kg | Standard Deviation 3.828 |
Comparison: Analysis was performed using MMRMs where all post-baseline measurements for the specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as the dependent variable, and visit, treatment, country and the stratification variable (4 levels: HbA1c \< 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and \>27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate.p-value: <0.000195% CI: [-5.65, -4.16]Mixed Models Analysis
Comparison: Analysis was performed using MMRMs where all post-baseline measurements for the specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as the dependent variable, and visit, treatment, country and the stratification variable (4 levels: HbA1c \< 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and \>27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate.p-value: <0.000195% CI: [-4.29, -2.81]Mixed Models Analysis
Comparison: Analysis was performed using MMRMs where all post-baseline measurements for the specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as the dependent variable, and visit, treatment, country and the stratification variable (4 levels: HbA1c \< 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and \>27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate.p-value: <0.000195% CI: [-2.91, -1.47]Mixed Models Analysis
Primary
Change From Baseline in HbA1c (Glycosylated Haemoglobin)
Change from baseline in HbA1c at week 52. Missing values were handled by using a mixed model for repeated measurements (MMRM).
Time frame: Week 0, week 52
Population: Full analysis set. Number of subjects analysed=subjects with any post-baseline HbA1c data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide 0.6 mg | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | -0.45 percentage of glycosylated haemoglobin | Standard Deviation 0.741 |
| Liraglutide 1.2 mg | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | -0.50 percentage of glycosylated haemoglobin | Standard Deviation 0.767 |
| Liraglutide 1.8 mg | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | -0.54 percentage of glycosylated haemoglobin | Standard Deviation 0.729 |
| Placebo | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | -0.34 percentage of glycosylated haemoglobin | Standard Deviation 0.707 |
Comparison: Analysis was performed using MMRMs where all post-baseline measurements for the specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as the dependent variable, and visit, treatment, country and the stratification variable (4 levels: HbA1c \< 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and \>27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate.95% CI: [-0.32, -0.07]
Comparison: Analysis was performed using MMRMs where all post-baseline measurements for the specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as the dependent variable, and visit, treatment, country and the stratification variable (4 levels: HbA1c \< 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and \>27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate.95% CI: [-0.27, -0.03]
Comparison: Analysis was performed using MMRMs where all post-baseline measurements for the specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as the dependent variable, and visit, treatment, country and the stratification variable (4 levels: HbA1c \< 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and \>27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate.95% CI: [-0.21, 0.03]
Primary
Change From Baseline in Total Daily Insulin Dose
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.
Time frame: Week 0, week 52
Population: Full analysis set. Number of subjects analysed=subjects with any post-baseline total insulin daily dose data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide 0.6 mg | Change From Baseline in Total Daily Insulin Dose | 1.04 ratio | Geometric Coefficient of Variation 23.75 |
| Liraglutide 1.2 mg | Change From Baseline in Total Daily Insulin Dose | 0.98 ratio | Geometric Coefficient of Variation 26.66 |
| Liraglutide 1.8 mg | Change From Baseline in Total Daily Insulin Dose | 0.95 ratio | Geometric Coefficient of Variation 24.21 |
| Placebo | Change From Baseline in Total Daily Insulin Dose | 1.04 ratio | Geometric Coefficient of Variation 26.69 |
Comparison: Analysis was done using MMRMs where all post-baseline measurements for specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as dependent variable, and visit, treatment, country and stratification variable (4 levels: HbA1c \< 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and \>27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate. The measurements were log-transformed before analysisp-value: <0.000195% CI: [0.88, 0.96]Mixed Models Analysis
Comparison: Analysis was done using MMRMs where all post-baseline measurements for specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as dependent variable, and visit, treatment, country and stratification variable (4 levels: HbA1c \< 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and \>27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate. The measurements were log-transformed before analysisp-value: 0.014895% CI: [0.91, 0.99]Mixed Models Analysis
Comparison: Analysis was done using MMRMs where all post-baseline measurements for specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as dependent variable, and visit, treatment, country and stratification variable (4 levels: HbA1c \< 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and \>27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate. The measurements were log-transformed before analysisp-value: 0.961595% CI: [0.96, 1.04]Mixed Models Analysis
Secondary
Number of Treatment-emergent Symptomatic Hypoglycaemic Episodes
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.
Time frame: Weeks 0-52
Population: The safety analysis set included all randomised subjects exposed to at least one dose of liraglutide or placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Liraglutide 0.6 mg | Number of Treatment-emergent Symptomatic Hypoglycaemic Episodes | 4954 episodes |
| Liraglutide 1.2 mg | Number of Treatment-emergent Symptomatic Hypoglycaemic Episodes | 4602 episodes |
| Liraglutide 1.8 mg | Number of Treatment-emergent Symptomatic Hypoglycaemic Episodes | 4614 episodes |
| Placebo | Number of Treatment-emergent Symptomatic Hypoglycaemic Episodes | 3654 episodes |
Comparison: The endpoint was analysed using a negative binomial regression model with a log-link function and the log of the time period in which an occurrence of a hypoglycaemic episode was considered treatment emergent as offset. The model included fixed factors (treatment, country, stratification group) and a covariate (baseline HbA1c).p-value: 0.008195% CI: [1.07, 1.59]Negative binomial regression
Comparison: The endpoint was analysed using a negative binomial regression model with a log-link function and the log of the time period in which an occurrence of a hypoglycaemic episode was considered treatment emergent as offset. The model included fixed factors (treatment, country, stratification group) and a covariate (baseline HbA1c).p-value: 0.021995% CI: [1.03, 1.55]Negative binomial regression
Comparison: The endpoint was analysed using a negative binomial regression model with a log-link function and the log of the time period in which an occurrence of a hypoglycaemic episode was considered treatment emergent as offset. The model included fixed factors (treatment, country, stratification group) and a covariate (baseline HbA1c).p-value: 0.107995% CI: [0.97, 1.43]Negative binomial regression