Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Europe. The aim of the trial is to investigate the efficacy and safety of liraglutide versus lixisenatide as add-on to metformin in subjects with type 2 diabetes (T2DM).
Interventions
DRUGliraglutide
Starting dose of 0.6 mg/day, with weekly dose escalations of 0.6 mg/day until the maintenance dose of 1.8 mg/day is reached. Administered s.c. (subcutaneously, under the skin) once daily in addition to the subject's stable pre-trial metformin (equal to or above 1000 mg/day and up to 3000 mg/day).
DRUGlixisenatide
Starting dose of 10 microg to be administered s.c. once daily, within the hour prior to the first meal of the day or the evening meal in addition to subject's stable pre-trial metformin (equal to or above 1000mg/day and up to 3000mg/day). Dose escalation to 20 microg s.c. once daily from day 15 after randomization.
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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 * Subjects diagnosed with T2DM and on unchanged metformin treatment at the maximum tolerated dose (at least 1000 mg/day and up to 3000 mg/day) for at least 90 days prior to screening * HbA1c 7.5 - 10.5% (53 mmol/mol - 91 mmol/mol) (both inclusive) * Body Mass Index (BMI) equal to or above 20 kg/m\^2
Exclusion criteria
* Female of child-bearing potential who is pregnant, breast-feeding or intend to become pregnant or is not using adequate contraceptive methods. (Adequate contraceptive measures as required by local law or practice) * Treatment with glucose lowering agent(s) other than stated in the inclusion criteria in a period of 90 days prior to screening. Exception is short-term treatment (equal to or below 7 days in total) with insulin in connection with intercurrent illness * History of chronic pancreatitis or idiopathic acute pancreatitis * Screening calcitonin value equal to or above 50 ng/L * Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN 2) * Impaired liver function, defined as alanine aminotransferase (ALAT) equal to or above 2.5 times upper normal limit (UNL) * Impaired renal function defined as estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m\^2 per Modification of Diet in Renal Disease (MDRD) formula * Any episode of unstable angina, acute coronary event, cerebral stroke/transient ischemic attack (TIA) or other significant cardiovascular event as judged by the investigator within 90 days prior to screening * Heart failure, New York Heart Association (NYHA) class IV * Uncontrolled hypertension (defined as systolic blood pressure equal to or above 180 mmHg and/or diastolic blood pressure equal to or above 100 mmHg) * 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 in Glycosylated Haemoglobin (HbA1c) From Baseline | Week 0, week 26 | Change from baseline in HbA1c after 26 weeks of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Body Weight From Baseline | Week 0, week 26 | Change from baseline in body weight after 26 weeks of treatment. |
| Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) (American Diabetes Association (ADA) Target) (Yes/no) | After 26 weeks of treatment | Subjects who achieved HbA1c below 7.0% (53 mmol/mol) after 26 weeks of treatment (yes/no). |
| Change in Fasting Plasma Glucose (FPG) From Baseline | Week 0, week 26 | Change from baseline in FPG after 26 weeks of treatment. |
| Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) and no Weight Gain (Yes/no) | After 26 weeks of treatment | Subjects who achieved HbA1c below 7.0% (53 mmol/mol) and no weight gain after 26 weeks of treatment (yes/no). |
| Number of Treatment Emergent Adverse Events (TEAEs) | Weeks 0-26 | A Treatment Emergent Adverse Event (TEAE) was defined as an event that had onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment. Severity was assessed by investigator. |
| Subjects Who Achieve HbA1c Equal to or Below 6.5% (48 mmol/Mol) (American Association of Clinical Endocrinologists [AACE] Target) (Yes/no) | After 26 weeks of treatment | Subjects who achieved HbA1c below equal to or below 6.5% (48 mmol/mol) after 26 weeks of treatment (yes/no). |
Countries
Czechia, Finland, France, Germany, Hungary, Italy, Latvia, Lithuania, United Kingdom
Participant flow
Recruitment details
The trial was conducted at 56 sites in 9 countries; Czech Republic (5), Finland (4), France (6), Germany (8), Hungary (6), Italy (5), Latvia (6), Lithuania (5) and UK (11).
Participants by arm
| Arm | Count |
|---|---|
| Liraglutide Liraglutide was administered subcutaneously (s.c.; under the skin) once daily in addition to the subject's stable pre-trial metformin (maximum tolerated dose, equal to or above 1000 mg/day and up to 3000 mg/day) for a total duration of 26 weeks. Starting dose of liraglutide was 0.6 mg/day, with weekly dose escalations of 0.6 mg/day until the maintenance dose of 1.8 mg/day was reached. | 202 |
| Lixisenatide Lixisenatide was administered s.c. once daily, within the hour prior to the first meal of the day or the evening meal in addition to subject's stable pre-trial metformin (maximum tolerated dose, equal to or above 1000mg/day and up to 3000mg/day) for a total duration of 26 weeks. Starting dose of lixisenatide was 10 µg once daily, the dose was escalated to 20 µg once daily from day 15 after randomisation. | 202 |
| Total | 404 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | unclassified | 2 | 1 |
| Overall Study | Withdrawal by Subject | 7 | 9 |
Baseline characteristics
| Characteristic | Liraglutide | Lixisenatide | Total |
|---|---|---|---|
| Age, Continuous | 56.3 years STANDARD_DEVIATION 10.6 | 56.1 years STANDARD_DEVIATION 10 | 56.2 years STANDARD_DEVIATION 10.3 |
| Body Weight | 101.89 kg STANDARD_DEVIATION 23.344 | 100.58 kg STANDARD_DEVIATION 19.949 | 101.24 kg STANDARD_DEVIATION 21.696 |
| Fasting plasma glucose (FPG) | 10.47 mmol/L STANDARD_DEVIATION 2.368 | 10.25 mmol/L STANDARD_DEVIATION 2.254 | 10.36 mmol/L STANDARD_DEVIATION 2.312 |
| Gender Female | 70 Participants | 90 Participants | 160 Participants |
| Gender Male | 132 Participants | 112 Participants | 244 Participants |
| Glycosylated Haemoglobin (HbA1c) | 8.40 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.723 | 8.43 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.785 | 8.41 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.754 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 90 / 202 | 83 / 202 |
| serious Total, serious adverse events | 12 / 202 | 7 / 202 |
Outcome results
Primary
Change in Glycosylated Haemoglobin (HbA1c) From Baseline
Change from baseline in HbA1c after 26 weeks of treatment.
Time frame: Week 0, week 26
Population: The full analysis set (FAS) included all randomised subjects. Missing values were imputed using predicted values from the mixed model for repeated measurements (MMRM) model. Due to missing HbA1c post baseline data, 194 and 191 subjects in liraglutide and lixisenatide treatment group, respectively were included in the HbA1c analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide | Change in Glycosylated Haemoglobin (HbA1c) From Baseline | -1.809 Percent (%) glycosylated haemoglobin | Standard Deviation 0.9159 |
| Lixisenatide | Change in Glycosylated Haemoglobin (HbA1c) From Baseline | -1.238 Percent (%) glycosylated haemoglobin | Standard Deviation 1.0085 |
Secondary
Change in Body Weight From Baseline
Change from baseline in body weight after 26 weeks of treatment.
Time frame: Week 0, week 26
Population: The FAS included all randomised subjects. Missing values were imputed using predicted values from the MMRM model. Due to missing body weight post baseline data, 194 and 191 subjects in liraglutide and lixisenatide treatment group, respectively were included in the body weight analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide | Change in Body Weight From Baseline | -4.24 kg | Standard Deviation 4.273 |
| Lixisenatide | Change in Body Weight From Baseline | -3.69 kg | Standard Deviation 4.746 |
Secondary
Change in Fasting Plasma Glucose (FPG) From Baseline
Change from baseline in FPG after 26 weeks of treatment.
Time frame: Week 0, week 26
Population: The FAS included all randomised subjects. Missing values were imputed using predicted values from the MMRM model. Due to missing FPG post baseline data, 194 and 189 subjects in liraglutide and lixisenatide treatment group, respectively were included in the FPG analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide | Change in Fasting Plasma Glucose (FPG) From Baseline | -2.904 mmol/L | Standard Deviation 2.2309 |
| Lixisenatide | Change in Fasting Plasma Glucose (FPG) From Baseline | -1.644 mmol/L | Standard Deviation 2.1511 |
Secondary
Number of Treatment Emergent Adverse Events (TEAEs)
A Treatment Emergent Adverse Event (TEAE) was defined as an event that had onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment. Severity was assessed by investigator.
Time frame: Weeks 0-26
Population: The safety analysis set (SAS) included all subjects who received at least one dose of any of the trial products.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Liraglutide | Number of Treatment Emergent Adverse Events (TEAEs) | Serious | 13 events |
| Liraglutide | Number of Treatment Emergent Adverse Events (TEAEs) | Moderate | 109 events |
| Liraglutide | Number of Treatment Emergent Adverse Events (TEAEs) | Severe | 10 events |
| Liraglutide | Number of Treatment Emergent Adverse Events (TEAEs) | Mild | 421 events |
| Liraglutide | Number of Treatment Emergent Adverse Events (TEAEs) | Events | 540 events |
| Lixisenatide | Number of Treatment Emergent Adverse Events (TEAEs) | Mild | 348 events |
| Lixisenatide | Number of Treatment Emergent Adverse Events (TEAEs) | Events | 435 events |
| Lixisenatide | Number of Treatment Emergent Adverse Events (TEAEs) | Serious | 7 events |
| Lixisenatide | Number of Treatment Emergent Adverse Events (TEAEs) | Severe | 3 events |
| Lixisenatide | Number of Treatment Emergent Adverse Events (TEAEs) | Moderate | 84 events |
Secondary
Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) (American Diabetes Association (ADA) Target) (Yes/no)
Subjects who achieved HbA1c below 7.0% (53 mmol/mol) after 26 weeks of treatment (yes/no).
Time frame: After 26 weeks of treatment
Population: The FAS included all randomised subjects. Missing values were imputed using predicted values from the MMRM model. Due to missing HbA1c post baseline data, 194 and 191 subjects in liraglutide and lixisenatide treatment group, respectively were included in the HbA1c analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Liraglutide | Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) (American Diabetes Association (ADA) Target) (Yes/no) | Yes | 74.2 percentage (%) of subjects |
| Liraglutide | Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) (American Diabetes Association (ADA) Target) (Yes/no) | No | 25.8 percentage (%) of subjects |
| Lixisenatide | Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) (American Diabetes Association (ADA) Target) (Yes/no) | Yes | 45.5 percentage (%) of subjects |
| Lixisenatide | Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) (American Diabetes Association (ADA) Target) (Yes/no) | No | 54.5 percentage (%) of subjects |
Secondary
Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) and no Weight Gain (Yes/no)
Subjects who achieved HbA1c below 7.0% (53 mmol/mol) and no weight gain after 26 weeks of treatment (yes/no).
Time frame: After 26 weeks of treatment
Population: The FAS included all randomised subjects. Missing values were imputed using predicted values from the MMRM model. Due to missing HbA1c post-baseline data, 194 and 191 subjects in liraglutide and lixisenatide treatment group, respectively were included in the HbA1c analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Liraglutide | Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) and no Weight Gain (Yes/no) | Yes | 66.5 percentage (%) of subjects |
| Liraglutide | Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) and no Weight Gain (Yes/no) | No | 33.5 percentage (%) of subjects |
| Lixisenatide | Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) and no Weight Gain (Yes/no) | Yes | 41.9 percentage (%) of subjects |
| Lixisenatide | Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) and no Weight Gain (Yes/no) | No | 58.1 percentage (%) of subjects |
Secondary
Subjects Who Achieve HbA1c Equal to or Below 6.5% (48 mmol/Mol) (American Association of Clinical Endocrinologists [AACE] Target) (Yes/no)
Subjects who achieved HbA1c below equal to or below 6.5% (48 mmol/mol) after 26 weeks of treatment (yes/no).
Time frame: After 26 weeks of treatment
Population: The FAS included all randomised subjects. Missing values were imputed using predicted values from the MMRM model. Due to missing HbA1c post baseline data, 194 and 191 subjects in liraglutide and lixisenatide treatment group, respectively were included in the HbA1c analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Liraglutide | Subjects Who Achieve HbA1c Equal to or Below 6.5% (48 mmol/Mol) (American Association of Clinical Endocrinologists [AACE] Target) (Yes/no) | Yes | 54.6 percentage (%) of subjects |
| Liraglutide | Subjects Who Achieve HbA1c Equal to or Below 6.5% (48 mmol/Mol) (American Association of Clinical Endocrinologists [AACE] Target) (Yes/no) | No | 45.4 percentage (%) of subjects |
| Lixisenatide | Subjects Who Achieve HbA1c Equal to or Below 6.5% (48 mmol/Mol) (American Association of Clinical Endocrinologists [AACE] Target) (Yes/no) | Yes | 26.2 percentage (%) of subjects |
| Lixisenatide | Subjects Who Achieve HbA1c Equal to or Below 6.5% (48 mmol/Mol) (American Association of Clinical Endocrinologists [AACE] Target) (Yes/no) | No | 73.8 percentage (%) of subjects |