Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Africa, Asia, Europe and North America. The purpose of the trial is to investigate the effect of insulin degludec (IDeg) in combination with liraglutide (Lira) and metformin (at least 1500 mg daily or maximum tolerated dose) in subjects with type 2 diabetes qualifying for treatment intensification.
Interventions
DRUGinsulin degludec
Administered s.c. (under the skin) once daily. Dose individually adjusted.
DRUGplacebo
Administered s.c. (under the skin) once daily. Dose individually adjusted.
DRUGliraglutide
Administered s.c. (under the skin) once daily. Dose: 1.8 mg.
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Type 2 diabetes * Insulin naïve * Ongoing treatment with metformin or metformin in combination with either sulphonylurea (SU), glinides, dipeptidyl peptidase-IV (DPP-IV) inhibitors or exenatide (only twice daily (BID)) * Glycosylated haemoglobin (HbA1c) (by central laboratory analysis): a. 7.5-10.0 % (both inclusive) for subjects on metformin monotherapy, b. 7.0-9.0 % (both inclusive) for subjects on metformin in combination with either SU, glinides, DPP-IV inhibitors or exenatide (only BID)
Exclusion criteria
* Treatment with glucose-lowering agent(s) other than stated in the inclusion criteria within 12 weeks * Calcitonin equal to or above 50 pg/mL * Stroke; heart failure New York Heart Association (NYHA) class III or IV; myocardial infarction; unstable angina pectoris; or coronary arterial bypass graft or angioplasty; all within 24 weeks * Current or past (within the last 5 years) malignant neoplasms (except basal cell and squamous cell carcinoma)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glycosylated Haemoglobin (HbA1c) (%) | Week 0, week 26 | Change from baseline in HbA1c after 26 weeks of treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Responders for HbA1c (Below 7.0 %) | After 26 weeks of randomised treatment. | Number of responders for HbA1c below 7.0%, after 26 weeks of randomised treatment. |
| Change From Baseline in Mean Pre-breakfast Measurements Used for Titration | Week 0, week 26 | Change from baseline after 26 weeks of treatment in the average of the pre-breakfast self measured plasma glucose (SMPG) measured on the day of the contact and the two days immediately prior to the contact. The least squares means presented are the estimated values after 26 weeks of treatment and the statistical analysis presents the treatment difference of the change from baseline values as the model is adjusted for baseline. |
| Change From Baseline in 8-point Profile | Week 0, week 26 | The change from baseline in the 8-point SMPG profile after 26 weeks of randomised treatment. The least squares means presented are the estimated values after 26 weeks of treatment and the statistical analysis presents the treatment difference of the change from baseline values as the model is adjusted for baseline. |
| Change From Baseline in Fasting Plasma Glucose (FPG) | Week 0, week 26 | Change from baseline in FPG after 26 weeks of treatment |
| Number of Hypoglycaemic Episodes | Weeks 0 - 26 | Number of confirmed hypoglycaemic episodes from week 0 to 26 weeks of randomised treatment. A hypoglycaemic episode was defined as treatment emergent if the onset of the episode occurred after the first administration of investigational medicinal product and no later than 7 days after the last day on trial product. Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia or minor hypoglycaemic episodes. |
| Number of Adverse Events | Weeks 0 - 26 | Number of treatment emergent AEs (TEAEs) from week 0 to week 26 of the randomised treatment. A 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. |
| Change From Baseline in Patient Reported Health-related Quality of Life Using the Short-Form 36 Health Survey Version 2 (SF-36®v2) | Week 0, week 26 | Change in subject's quality of life was evaluated using the Short-Form 36 Health Survey version 2 (SF-36®v2). Evaluations were performed at baseline and at the last treatment visit (week 26). SF-36 was assessed on a scale range of 0.65 to 80.73 for physical health and -8.81 to 81.65 for mental health respectively, where higher scores indicated a better quality of life. 0-100 scores from the SF-36 were converted to a norm-based score using a T-score transformation in order to obtain a direct interpretation in relation to the distribution of the scores in the 1998 U.S. general population. |
| Change From Baseline in Mean of the 8-point Profile | Week 0, week 26 | Change from baseline in mean of the 8-point profile after 26 weeks of randomised treatment. |
Countries
Canada, France, Germany, Israel, Italy, Serbia, South Africa, Ukraine, United Arab Emirates, United Kingdom, United States
Participant flow
Recruitment details
The trial was conducted at 129 sites in 11 countries randomised subjects: Canada (7), France (10), Germany (8), Israel (6), Italy (7), Serbia (7), South Africa (6), Ukraine (4), United Arab Emirates (3), United Kingdom (6), and United States (65).
Participants by arm
| Arm | Count |
|---|---|
| IDeg Liraglutide treatment was initiated on 0.6 mg daily for one week and increased further after the second week in the run-in period. In the randomized period, Insulin degludec (IDeg, 100 U/mL, in a 3 mL prefilled pen PDS290) treatment was recommended to be initiated and administered subcutaneously (under the skin) once daily (OD) with 10 units. After that it was titrated once weekly. If one or more of the pre-breakfast plasma glucose values were below a certain range, the subjects were to reduce the insulin dose. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period. | 174 |
| Placebo Placebo treatment (3 mL prefilled pen) in combination with Liraglutide (Lira,1.8 mg/daily, 3 mL prefilled pen) once daily was given subcutaneously (under the skin) in the thigh, abdomen or upper arm (deltoid) at any time of the day according to the subject's choice for 26 weeks of treatment period. Subjects continued on metformin (1500/day) treatment at the stable, pre-trial dose and maintained dosing frequency levels throughout the trial period. | 172 |
| Total | 346 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 3 |
| Overall Study | Protocol Violation | 3 | 5 |
| Overall Study | Unclassified | 5 | 29 |
| Overall Study | Withdrawal Criteria | 1 | 4 |
Baseline characteristics
| Characteristic | IDeg | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 57.0 years STANDARD_DEVIATION 10 | 57.3 years STANDARD_DEVIATION 9.4 | 57.2 years STANDARD_DEVIATION 9.7 |
| Fasting plasma glucose (FPG) | 8.7 mmol/L STANDARD_DEVIATION 2.1 | 9.1 mmol/L STANDARD_DEVIATION 2.2 | 8.9 mmol/L STANDARD_DEVIATION 2.2 |
| Glycosylated haemoglobin (HbA1c) | 7.5 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.6 | 7.6 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.6 | 7.6 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.6 |
| Sex: Female, Male Female | 76 Participants | 68 Participants | 144 Participants |
| Sex: Female, Male Male | 98 Participants | 104 Participants | 202 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 33 / 173 | 32 / 170 |
| serious Total, serious adverse events | 6 / 173 | 9 / 170 |
Outcome results
Primary
Change From Baseline in Glycosylated Haemoglobin (HbA1c) (%)
Change from baseline in HbA1c after 26 weeks of treatment
Time frame: Week 0, week 26
Population: The FAS included all randomised subjects and missing data was imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| IDeg | Change From Baseline in Glycosylated Haemoglobin (HbA1c) (%) | -0.99 percentage of glycosylated haemoglobin | Standard Error 0.08 |
| Placebo | Change From Baseline in Glycosylated Haemoglobin (HbA1c) (%) | -0.07 percentage of glycosylated haemoglobin | Standard Error 0.08 |
Secondary
Change From Baseline in 8-point Profile
The change from baseline in the 8-point SMPG profile after 26 weeks of randomised treatment. The least squares means presented are the estimated values after 26 weeks of treatment and the statistical analysis presents the treatment difference of the change from baseline values as the model is adjusted for baseline.
Time frame: Week 0, week 26
Population: The FAS included all randomised subjects. The subjects not analysed were 12, 45, 46, 44, 44, 54, 56 and 21 subjects for before breakfast, 90 mins after breakfast, before lunch, 90 mins after start of lunch, before main evening meal, 90 mins after main evening meal, before bedtime and before breakfast the following day time points respectively.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| IDeg | Change From Baseline in 8-point Profile | 90 min after breakfast, N=153, 148 | 7.65 mmol/L | Standard Error 0.24 |
| IDeg | Change From Baseline in 8-point Profile | Before lunch, N=151,149 | 6.33 mmol/L | Standard Error 0.18 |
| IDeg | Change From Baseline in 8-point Profile | 90 min after lunch, N=152,150 | 7.73 mmol/L | Standard Error 0.21 |
| IDeg | Change From Baseline in 8-point Profile | Before evening meal, N=154,148 | 6.77 mmol/L | Standard Error 0.2 |
| IDeg | Change From Baseline in 8-point Profile | 90 mins after evening meal, N=147,145 | 7.93 mmol/L | Standard Error 0.21 |
| IDeg | Change From Baseline in 8-point Profile | Before bedtime, N=148, 142 | 7.21 mmol/L | Standard Error 0.2 |
| IDeg | Change From Baseline in 8-point Profile | Before breakfast the next day, N=164,161 | 6.05 mmol/L | Standard Error 0.17 |
| IDeg | Change From Baseline in 8-point Profile | Before breakfast, N=170, 164 | 5.85 mmol/L | Standard Error 0.15 |
| Placebo | Change From Baseline in 8-point Profile | Before breakfast, N=170, 164 | 8.54 mmol/L | Standard Error 0.16 |
| Placebo | Change From Baseline in 8-point Profile | 90 min after breakfast, N=153, 148 | 9.75 mmol/L | Standard Error 0.25 |
| Placebo | Change From Baseline in 8-point Profile | 90 mins after evening meal, N=147,145 | 9.65 mmol/L | Standard Error 0.22 |
| Placebo | Change From Baseline in 8-point Profile | Before lunch, N=151,149 | 8.34 mmol/L | Standard Error 0.19 |
| Placebo | Change From Baseline in 8-point Profile | Before breakfast the next day, N=164,161 | 8.55 mmol/L | Standard Error 0.18 |
| Placebo | Change From Baseline in 8-point Profile | 90 min after lunch, N=152,150 | 9.67 mmol/L | Standard Error 0.21 |
| Placebo | Change From Baseline in 8-point Profile | Before bedtime, N=148, 142 | 8.95 mmol/L | Standard Error 0.21 |
| Placebo | Change From Baseline in 8-point Profile | Before evening meal, N=154,148 | 9.51 mmol/L | Standard Error 0.21 |
Comparison: The 8-point profile (SMPG) values after 26 weeks of treatment were analysed jointly using a linear mixed model with an un-structured residual covariance structure and with treatment, time-point and an interaction between treatment and time-point, region and sex as fixed effects, and age and baseline response per time-point as covariates. Missing data was imputed using LOCF. The treatment contrast estimated was IDeg - Placebo for the time point before breakfast.p-value: <0.000195% CI: [-3.04, -2.34]Mixed Models Analysis
Comparison: The 8-point profile (SMPG) values after 26 weeks of treatment were analysed jointly using a linear mixed model with an un-structured residual covariance structure and with treatment, time-point and an interaction between treatment and time-point, region and sex as fixed effects, and age and baseline response per time-point as covariates. Missing data was imputed using LOCF. The treatment contrast estimated was IDeg - Placebo for the time point 90 mins after breakfast.p-value: <0.000195% CI: [-2.71, -1.48]Mixed Models Analysis
Comparison: The 8-point profile (SMPG) values after 26 weeks of treatment were analysed jointly using a linear mixed model with an un-structured residual covariance structure and with treatment, time-point and an interaction between treatment and time-point, region and sex as fixed effects, and age and baseline response per time-point as covariates. Missing data was imputed using LOCF. The treatment contrast estimated was IDeg - Placebo for the time point before lunch.p-value: <0.000195% CI: [-2.47, -1.56]Mixed Models Analysis
Comparison: The 8-point profile (SMPG) values after 26 weeks of treatment were analysed jointly using a linear mixed model with an un-structured residual covariance structure and with treatment, time-point and an interaction between treatment and time-point, region and sex as fixed effects, and age and baseline response per time-point as covariates. Missing data was imputed using LOCF. The treatment contrast estimated was IDeg - Placebo for the time point 90 mins after start of lunch.p-value: <0.000195% CI: [-2.46, -1.4]Mixed Models Analysis
Comparison: The 8-point profile (SMPG) values after 26 weeks of treatment were analysed jointly using a linear mixed model with an un-structured residual covariance structure and with treatment, time-point and an interaction between treatment and time-point, region and sex as fixed effects, and age and baseline response per time-point as covariates. Missing data was imputed using LOCF. The treatment contrast estimated was IDeg - Placebo for the time point main evening meal.p-value: <0.000195% CI: [-2.25, -1.23]Mixed Models Analysis
Comparison: The 8-point profile (SMPG) values after 26 weeks of treatment were analysed jointly using a linear mixed model with an un-structured residual covariance structure and with treatment, time-point and an interaction between treatment and time-point, region and sex as fixed effects, and age and baseline response per time-point as covariates. Missing data was imputed using LOCF. The treatment contrast estimated was IDeg - Placebo for the time point 90 mins after main evening meal.p-value: <0.000195% CI: [-2.26, -1.18]Mixed Models Analysis
Comparison: The 8-point profile (SMPG) values after 26 weeks of treatment were analysed jointly using a linear mixed model with an un-structured residual covariance structure and with treatment, time-point and an interaction between treatment and time-point, region and sex as fixed effects, and age and baseline response per time-point as covariates. Missing data was imputed using LOCF. The treatment contrast estimated was IDeg - Placebo for the time point before bedtime.p-value: <0.000195% CI: [-2.27, -1.23]Mixed Models Analysis
Comparison: The 8-point profile (SMPG) values after 26 weeks of treatment were analysed jointly using a linear mixed model with an un-structured residual covariance structure and with treatment, time-point and an interaction between treatment and time-point, region and sex as fixed effects, and age and baseline response per time-point as covariates. Missing data was imputed using LOCF. The treatment contrast estimated was IDeg - Placebo for the time point before breakfast the following day.p-value: <0.000195% CI: [-2.91, -2.09]Mixed Models Analysis
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG)
Change from baseline in FPG after 26 weeks of treatment
Time frame: Week 0, week 26
Population: The FAS included all randomised subjects and missing data was imputed using LOCF. For 6 subjects FPG values were missing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg | Change From Baseline in Fasting Plasma Glucose (FPG) | -2.60 mmol/L | Standard Deviation 2.91 |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) | -0.28 mmol/L | Standard Deviation 2.44 |
Secondary
Change From Baseline in Mean of the 8-point Profile
Change from baseline in mean of the 8-point profile after 26 weeks of randomised treatment.
Time frame: Week 0, week 26
Population: The FAS included all randomised subjects and missing data is imputed using LOCF. Mean values were missing for 11 subjects.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg | Change From Baseline in Mean of the 8-point Profile | -2.3 mmol/L | Standard Deviation 1.8 |
| Placebo | Change From Baseline in Mean of the 8-point Profile | -0.5 mmol/L | Standard Deviation 1.7 |
Secondary
Change From Baseline in Mean Pre-breakfast Measurements Used for Titration
Change from baseline after 26 weeks of treatment in the average of the pre-breakfast self measured plasma glucose (SMPG) measured on the day of the contact and the two days immediately prior to the contact. The least squares means presented are the estimated values after 26 weeks of treatment and the statistical analysis presents the treatment difference of the change from baseline values as the model is adjusted for baseline.
Time frame: Week 0, week 26
Population: The FAS included all randomised subjects and missing data was imputed using LOCF. For 8 subjects the baseline values were missing
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| IDeg | Change From Baseline in Mean Pre-breakfast Measurements Used for Titration | 5.88 mmol/L | Standard Error 0.14 |
| Placebo | Change From Baseline in Mean Pre-breakfast Measurements Used for Titration | 8.23 mmol/L | Standard Error 0.15 |
Comparison: The pre-breakfast measures of SMPG values after 26 weeks of treatment were analysed an ANOVA method with treatment, region and sex as fixed effects, and age and baseline response as covariates.p-value: <0.000195% CI: [-2.67, -2.01]ANOVA
Secondary
Change From Baseline in Patient Reported Health-related Quality of Life Using the Short-Form 36 Health Survey Version 2 (SF-36®v2)
Change in subject's quality of life was evaluated using the Short-Form 36 Health Survey version 2 (SF-36®v2). Evaluations were performed at baseline and at the last treatment visit (week 26). SF-36 was assessed on a scale range of 0.65 to 80.73 for physical health and -8.81 to 81.65 for mental health respectively, where higher scores indicated a better quality of life. 0-100 scores from the SF-36 were converted to a norm-based score using a T-score transformation in order to obtain a direct interpretation in relation to the distribution of the scores in the 1998 U.S. general population.
Time frame: Week 0, week 26
Population: The FAS included all randomised subjects and missing data was imputed using LOCF. For 3 subjects PRO scores were missing at the baseline and did not contribute to the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IDeg | Change From Baseline in Patient Reported Health-related Quality of Life Using the Short-Form 36 Health Survey Version 2 (SF-36®v2) | Mental health | 0.6 T-scores | Standard Deviation 8.1 |
| IDeg | Change From Baseline in Patient Reported Health-related Quality of Life Using the Short-Form 36 Health Survey Version 2 (SF-36®v2) | Physical health | 0.5 T-scores | Standard Deviation 6.3 |
| Placebo | Change From Baseline in Patient Reported Health-related Quality of Life Using the Short-Form 36 Health Survey Version 2 (SF-36®v2) | Mental health | -0.7 T-scores | Standard Deviation 8.8 |
| Placebo | Change From Baseline in Patient Reported Health-related Quality of Life Using the Short-Form 36 Health Survey Version 2 (SF-36®v2) | Physical health | 0.0 T-scores | Standard Deviation 6.2 |
Secondary
Number of Adverse Events
Number of treatment emergent AEs (TEAEs) from week 0 to week 26 of the randomised treatment. A 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.
Time frame: Weeks 0 - 26
Population: The SAS included all subjects who received at least one dose of the investigational product or its comparator.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDeg | Number of Adverse Events | 285 events |
| Placebo | Number of Adverse Events | 252 events |
Secondary
Number of Hypoglycaemic Episodes
Number of confirmed hypoglycaemic episodes from week 0 to 26 weeks of randomised treatment. A hypoglycaemic episode was defined as treatment emergent if the onset of the episode occurred after the first administration of investigational medicinal product and no later than 7 days after the last day on trial product. Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia or minor hypoglycaemic episodes.
Time frame: Weeks 0 - 26
Population: The safety analysis set (SAS) included all subjects who received at least one dose of the investigational product or its comparator.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDeg | Number of Hypoglycaemic Episodes | 47 events |
| Placebo | Number of Hypoglycaemic Episodes | 9 events |
Secondary
Number of Responders for HbA1c (Below 7.0 %)
Number of responders for HbA1c below 7.0%, after 26 weeks of randomised treatment.
Time frame: After 26 weeks of randomised treatment.
Population: The FAS included all randomised subjects and missing data was imputed using LOCF.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDeg | Number of Responders for HbA1c (Below 7.0 %) | 77.6 percentage (%) of subjects |
| Placebo | Number of Responders for HbA1c (Below 7.0 %) | 35.5 percentage (%) of subjects |