Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Europe and the United States of America (USA). The aim of this trial is to investigate the efficacy and safety of liraglutide in subjects with type 2 diabetes and moderate renal impairment. The trial medication will be add-on to the subject's stable pre-trial OAD and/or insulin regimen.
Interventions
DRUGliraglutide
1.8 mg administered once daily subcutaneously (s.c., under the skin) as add-on to the subject's stable pre-trial oral antidiabetic drug (OAD) and/or insulin regimen.
DRUGplacebo
Administered once daily subcutaneously (s.c., under the skin) as add-on to the subject's stable pre-trial oral antidiabetic drug (OAD) and/or insulin regimen.
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 80 Years
Healthy volunteers
No
Inclusion criteria
* Subjects diagnosed with type 2 diabetes with stable diabetes treatment (unchanged medication and unchanged dose) for 90 days prior to the screening visit including: Monotherapy or any duo-combinations of metformin and/or SUs and/or pioglitazone. Metformin should be used with caution in subjects with moderate renal failure and must be used in accordance with local metformin labelling or guidelines. Or Monotherapy or any combinations of metformin and/or pioglitazone and/or basal or premix insulin. Insulin adjustments (total daily dose) below or equal to 10% within 90 days prior to the screening visit as confirmed by the investigator are acceptable. Metformin should be used with caution in subjects with moderate renal failure and must be used in accordance with local metformin labelling or guidelines. Combination of pioglitazone and insulin should be used with caution and according to local labelling or guidelines * HbA1c 7-10% (both inclusive) * Moderate renal impairment diagnosed more than 90 days prior to the screening visit and confirmed by an eGFR (glomerular filtration rate) of 30-59 mL/min/1.73 m2 per MDRD (modification of diet in renal disease) formula at the screening visit * Body Mass Index (BMI) 20-45 kg/m\^2 (both inclusive)
Exclusion criteria
* Recurrent severe hypoglycaemia or hypoglycaemic unawareness as judged by the investigator * Treatment with antidiabetic medication(s) other than stated in the inclusion criteria in a period of 90 days prior to screening. Previous short-term (below or equal to 7 days in total) treatment with rapid-or short-acting insulin in connection with intercurrent illness is allowed at the discretion of the investigator * Impaired liver function, defined as ALAT (alanine aminotransferase) above or equal to 2.5 times upper normal limit * History of chronic pancreatitis or idiopathic acute pancreatitis * Within the past 180 days any of the following: Episode of unstable angina, acute coronary event, cerebral stroke/transient ischemic attack (TIA) or other significant cardiovascular event (including e.g. arrhythmias or conduction delays on ECG (electrocardiogram)) * Heart failure defined as New York Heart Association (NYHA) class IV * A systolic blood pressure above or equal to 180 mmHg or a diastolic blood pressure above or equal to 100 mmHg * Rapidly progressing renal disease (e.g., acute glomerulonephritis) at the discretion of the investigator * Use of immunosuppressive treatment within 90 days prior to screening * Diagnosis or treatment for cancer in the previous 5 years (except basal cell skin cancer or squamous cell skin cancer) * Proliferative retinopathy or maculopathy requiring acute treatment as judged by the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Estimated Mean From the Statistical Model and Standard Deviation From Observed Data For Change From Baseline to Week 26 in HbA1c (%) (Glycosylated Haemoglobin) | Week 0, Week 26 | Calculated as the estimated mean change from baseline in HbA1c (%) after 26 Weeks of treatment based on the statistical model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Estimated Proportion of Responders Achieving HbA1c <7.0% and no Weight Gain After 26 Weeks of Treatment | At week 26 | Calculated as estimated percentage of subjects achieving HbA1c \<7.0% and no weight gain after 26 weeks of treatment based on the statistical model. |
| Estimated Proportion of Responders Achieving HbA1c <7.0% and no Minor or Severe Hypoglycaemic Episodes After 26 Weeks of Treatment | At week 26 | Calculated as estimated percentage of subjects achieving HbA1c \<7.0% and no minor or severe hypoglycaemic episodes observed within 26 weeks of treatment based on the statistical model. |
| Estimated Mean From the Statistical Model and Standard Deviation From Observed Data For Change From Baseline to Week 26 in Self-measured Plasma Glucose (SMPG) 7-point Profiles | Week 0, week 26 | SMPG was measured before and 90 minutes after breakfast, lunch and dinner and at bedtime at Week 0, 12 and 26. A summary measure of the 7 values was derived for each applicable visit as the area under the curve divided by the period of time elapsed between the first and last measurement. The change from baseline to week 26 was estimated using the statistical model. |
| Estimated Mean From the Statistical Model and Standard Deviation From Observed Data For Change From Baseline to Week 26 in Body Mass Index (BMI) | Week 0, week 26 | Calculated as estimated mean change in BMI (kg/m˄2) from baseline to Week 26 based on the statistical model. |
| Estimated Mean Ratio to Baseline and Observed Coefficient of Variation in Renal Function-estimated Glomerular Filtration Rate (eGFR) (to Check How Well the Kidneys Are Functioning Using Modification of Diet in Renal Disease (MDRD) Formula) | Week 0, week 26 | Calculated as the estimated ratio to baseline in eGFR (mL/min/1.73m˄2) after 26 Weeks of treatment based on the statistical model. |
Countries
France, Poland, Russia, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
This trial was conducted in France, Poland, Russian Federation, Ukraine, United Kingdom, and the United States of America.
Participants by arm
| Arm | Count |
|---|---|
| Lira 1.8 mg Subjects received subcutaneous (s.c) liraglutide 1.8 mg once daily, applying a 3-4 week dose escalation regimen with weekly increments of 0.6 mg until the maintenance dose of 1.8 mg was reached, as an add-on to the subject's stable pre-trial oral antidiabetic drug (OAD) and/or insulin regimen (monotherapy or any duo-combinations of metformin and/or sulphonylureas and/or pioglitazone; or monotherapy of basal or premix insulin or combination with metformin and/or pioglitazone). | 140 |
| Placebo Subjects received s.c placebo 1.8 mg once daily, applying a 3-4 week dose escalation regimen with weekly increments of 0.6 mg until the maintenance dose of 1.8 mg was reached, as an add-on to the subject's stable pre-trial OAD and/or insulin regimen (monotherapy or any duo-combinations of metformin and/or sulphonylureas and/or pioglitazone; or monotherapy of basal or premix insulin or combination with metformin and/or pioglitazone). | 137 |
| Total | 277 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 17 | 4 |
| Overall Study | Protocol Violation | 0 | 3 |
| Overall Study | Unclassified | 1 | 2 |
| Overall Study | Withdrawal Criteria | 17 | 25 |
Baseline characteristics
| Characteristic | Placebo | Total | Lira 1.8 mg |
|---|---|---|---|
| Age, Continuous | 66.3 years STANDARD_DEVIATION 8 | 67.2 years STANDARD_DEVIATION 8.2 | 68.0 years STANDARD_DEVIATION 8.3 |
| Fasting plasma glucose (FPG) | 9.27 mmol/L STANDARD_DEVIATION 2.842 | 9.38 mmol/L STANDARD_DEVIATION 3.061 | 9.48 mmol/L STANDARD_DEVIATION 3.27 |
| Glycosylated haemoglobin (%)(HbA1c) | 8.00 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.853 | 8.04 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.823 | 8.08 Percent (%) glycosylated haemoglobin STANDARD_DEVIATION 0.792 |
| Sex: Female, Male Female | 72 Participants | 137 Participants | 65 Participants |
| Sex: Female, Male Male | 65 Participants | 140 Participants | 75 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 73 / 140 | 49 / 137 |
| serious Total, serious adverse events | 14 / 140 | 15 / 137 |
Outcome results
Primary
Estimated Mean From the Statistical Model and Standard Deviation From Observed Data For Change From Baseline to Week 26 in HbA1c (%) (Glycosylated Haemoglobin)
Calculated as the estimated mean change from baseline in HbA1c (%) after 26 Weeks of treatment based on the statistical model.
Time frame: Week 0, Week 26
Population: The full analysis set (FAS) included all randomised subjects that received at least one dose of the study medication. A total of 14 subjects in the FAS did not contribute to the analysis due to missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lira 1.8 mg | Estimated Mean From the Statistical Model and Standard Deviation From Observed Data For Change From Baseline to Week 26 in HbA1c (%) (Glycosylated Haemoglobin) | -1.05 percentage (%) | Standard Deviation 0.8944 |
| Placebo | Estimated Mean From the Statistical Model and Standard Deviation From Observed Data For Change From Baseline to Week 26 in HbA1c (%) (Glycosylated Haemoglobin) | -0.38 percentage (%) | Standard Deviation 0.8797 |
Comparison: The null hypothesis of no treatment difference was tested using a two-sided test based on a mixed model repeated measurement (MMRM) analysis. The model included treatment, country, stratification groups (6 groups from cross-classifying renal function category (2 levels: eGFR\<45 and ≥45 mL/min) and the background insulin treatment category (3 levels: basal, premix or no insulin)) as fixed effects factors and baseline HbA1c as a covariate, all nested within week.p-value: <0.000195% CI: [-0.9, -0.43]Mixed Models Analysis
Secondary
Estimated Mean From the Statistical Model and Standard Deviation From Observed Data For Change From Baseline to Week 26 in Body Mass Index (BMI)
Calculated as estimated mean change in BMI (kg/m˄2) from baseline to Week 26 based on the statistical model.
Time frame: Week 0, week 26
Population: The FAS included all randomised subjects that received at least one dose of study medication. A total of 14 subjects in the FAS did not contribute to the analysis due to missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lira 1.8 mg | Estimated Mean From the Statistical Model and Standard Deviation From Observed Data For Change From Baseline to Week 26 in Body Mass Index (BMI) | -0.88 kg/m^2 | Standard Deviation 1.3214 |
| Placebo | Estimated Mean From the Statistical Model and Standard Deviation From Observed Data For Change From Baseline to Week 26 in Body Mass Index (BMI) | -0.38 kg/m^2 | Standard Deviation 1.1679 |
Comparison: Change from baseline in BMI (kg/m˄2) after 26 weeks treatment was analysed separately using an MMRM analysis model with treatment, country and stratification groups as fixed effects and baseline as a covariate, all nested within visit.p-value: =0.002295% CI: [-0.83, -0.18]Mixed Models Analysis
Secondary
Estimated Mean From the Statistical Model and Standard Deviation From Observed Data For Change From Baseline to Week 26 in Self-measured Plasma Glucose (SMPG) 7-point Profiles
SMPG was measured before and 90 minutes after breakfast, lunch and dinner and at bedtime at Week 0, 12 and 26. A summary measure of the 7 values was derived for each applicable visit as the area under the curve divided by the period of time elapsed between the first and last measurement. The change from baseline to week 26 was estimated using the statistical model.
Time frame: Week 0, week 26
Population: The FAS included all randomised subjects that received at least one dose of study medication. A total of 46 subjects in the FAS did not contribute to the analysis due to missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lira 1.8 mg | Estimated Mean From the Statistical Model and Standard Deviation From Observed Data For Change From Baseline to Week 26 in Self-measured Plasma Glucose (SMPG) 7-point Profiles | -1.59 mmol/L | Standard Deviation 2.48 |
| Placebo | Estimated Mean From the Statistical Model and Standard Deviation From Observed Data For Change From Baseline to Week 26 in Self-measured Plasma Glucose (SMPG) 7-point Profiles | -0.51 mmol/L | Standard Deviation 2.391 |
Comparison: Mean change from baseline in the 7-point profile (SMPG) after 26 weeks treatment was analysed using an MMRM model with treatment, country and stratification groups as fixed effects and baseline as a covariate, all nested within visit.p-value: <0.000195% CI: [-1.58, -0.58]Mixed Models Analysis
Secondary
Estimated Mean Ratio to Baseline and Observed Coefficient of Variation in Renal Function-estimated Glomerular Filtration Rate (eGFR) (to Check How Well the Kidneys Are Functioning Using Modification of Diet in Renal Disease (MDRD) Formula)
Calculated as the estimated ratio to baseline in eGFR (mL/min/1.73m˄2) after 26 Weeks of treatment based on the statistical model.
Time frame: Week 0, week 26
Population: Safety analysis set included all subjects receiving at least one dose of the trial product. A total of 8 subjects in the safety analysis set did not contribute to the analysis due to missing data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Lira 1.8 mg | Estimated Mean Ratio to Baseline and Observed Coefficient of Variation in Renal Function-estimated Glomerular Filtration Rate (eGFR) (to Check How Well the Kidneys Are Functioning Using Modification of Diet in Renal Disease (MDRD) Formula) | 0.99 mL/min/1.73m˄2 | Geometric Coefficient of Variation 0.17 |
| Placebo | Estimated Mean Ratio to Baseline and Observed Coefficient of Variation in Renal Function-estimated Glomerular Filtration Rate (eGFR) (to Check How Well the Kidneys Are Functioning Using Modification of Diet in Renal Disease (MDRD) Formula) | 1.01 mL/min/1.73m˄2 | Geometric Coefficient of Variation 0.19 |
Comparison: The ratio to baseline in eGFR (mL/min/1.73m˄2) after 26 weeks treatment was estimated based on log-transformed data for changes from baseline. The responses were analysed using an MMRM model with treatment, country and stratification groups as fixed effects and log-transformed baseline as a covariate, all nested within visit. The resulting estimates were back-transformed to the original scale.p-value: =0.357595% CI: [0.94, 1.02]Mixed Models Analysis
Secondary
Estimated Proportion of Responders Achieving HbA1c <7.0% and no Minor or Severe Hypoglycaemic Episodes After 26 Weeks of Treatment
Calculated as estimated percentage of subjects achieving HbA1c \<7.0% and no minor or severe hypoglycaemic episodes observed within 26 weeks of treatment based on the statistical model.
Time frame: At week 26
Population: The FAS included all randomised subjects that received at least one dose of study medication. A total of 14 subjects in the FAS did not contribute to the analysis due to missing data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lira 1.8 mg | Estimated Proportion of Responders Achieving HbA1c <7.0% and no Minor or Severe Hypoglycaemic Episodes After 26 Weeks of Treatment | 33.23 percentage of patients |
| Placebo | Estimated Proportion of Responders Achieving HbA1c <7.0% and no Minor or Severe Hypoglycaemic Episodes After 26 Weeks of Treatment | 11.23 percentage of patients |
Comparison: Analysed by a logistic regression model with treatment, country and stratification groups as fixed effects and HbA1c at baseline as covariates.p-value: <0.000195% CI: [2.12, 7.3]Regression, Logistic
Secondary
Estimated Proportion of Responders Achieving HbA1c <7.0% and no Weight Gain After 26 Weeks of Treatment
Calculated as estimated percentage of subjects achieving HbA1c \<7.0% and no weight gain after 26 weeks of treatment based on the statistical model.
Time frame: At week 26
Population: The FAS included all randomised subjects that received at least one dose of study medication. A total of 14 subjects in the FAS did not contribute to the analysis due to missing data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lira 1.8 mg | Estimated Proportion of Responders Achieving HbA1c <7.0% and no Weight Gain After 26 Weeks of Treatment | 46.03 percentage of patients |
| Placebo | Estimated Proportion of Responders Achieving HbA1c <7.0% and no Weight Gain After 26 Weeks of Treatment | 15.99 percentage of patients |
Comparison: Analysed by a logistic regression model with treatment, country and stratification groups as fixed effects and HbA1c and body weight at baseline as covariates. No weight gain was defined as change from baseline to Week 26 in body weight ≤0 kg.p-value: <0.000195% CI: [2.46, 8.18]Regression, Logistic