Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Europe, Oceania and the United States of America (USA). The aim of the trial is to investigate the efficacy of insulin degludec/liraglutide in controlling glycaemia in adults with type 2 diabetes inadequately controlled on glucagon-like peptide-1 (GLP-1) receptor agonist and OAD therapy.
Interventions
DRUGinsulin degludec/liraglutide
Injected subcutaneously (under the skin) once daily. Dose individually adjusted. Subjects will continue their pre-trial OAD treatment without changing the frequency or dose throughout the trial.
DRUGliraglutide
Subjects will continue on their pre-trial treatment of liraglutide (Victoza®) (GLP-1 receptor agonist) + OAD without changing the frequency or dose throughout the trial.
DRUGexenatide
Subjects will continue on their pre-trial treatment of exenatide (Byetta®) (GLP-1 receptor agonist) + OAD without changing the frequency or dose throughout the trial.
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
* Subjects with type 2 diabetes mellitus * Glycosylated haemoglobin (HbA1c) 7.0-9.0% (53-75 mmol/mol) (both inclusive) * Treatment with daily GLP-1 receptor agonist at maximum dose according to local label (i.e. 1.8 mg once daily (OD) Victoza® (liraglutide) or 10 microgram twice daily (BID) Byetta® (exenatide)) or documented maximum tolerated dose (i.e. 1.2 mg OD Victoza® (liraglutide) or 5 microgram BID Byetta® (exenatide)) in combination with a stable daily dose of metformin (equal to or above 1500 mg or documented maximum tolerated dose) for 90 days or more prior to screening visit (Visit 1) * BMI (body mass index) equal to or below 40 kg/m\^2
Exclusion criteria
* Any use of oral anti-diabetic drugs (OADs) (except for metformin, pioglitazone and sulphonylurea) for 90 days or less prior to screening visit (Visit 1) * Use of any drug (except metformin,pioglitazone, sulphonylurea and GLP-1 receptor agonist) which in the Investigator's opinion could interfere with the blood glucose level (e.g. systemic corticosteroids) * Treatment with any insulin regimen (short term treatment due to intercurrent illness including gestational diabetes is allowed at the discretion of the Investigator) * Screening calcitonin equal to or above 50 ng/l * Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia type 2 (MEN2) * Cardiovascular disorders defined as: congestive heart failure (New York Heart Association (NYHA) class III-IV), diagnosis of unstable angina pectoris, cerebral stroke and/or myocardial infarction within the past 52 weeks prior to screening visit (Visit 1) and/or planned coronary, carotid or peripheral artery revascularisation procedures * Proliferative retinopathy requiring acute treatment or maculopathy (macular oedema) according to the Investigator's opinion * Subjects with a clinically significant, active (during the past 12 months) disease of the gastrointestinal, pulmonary, endocrinological (except for the type 2 diabetes mellitus), neurological, genitourinary or haematological system that in the opinion of the Investigator may confound the results of the trial or pose additional risk in administering trial products * History of chronic pancreatitis or idiopathic acute pancreatitis
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change in Glycosylated Haemoglobin (HbA1c) From Baseline (Randomisation, Visit 2) | Week 0, week 26 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Responders Achieving Pre-defined Target: HbA1c Below or Equal to 6.5% (48 mmol/Mol) | Week 26 | Percentage of responders achieving pre-defined target for HbA1c - HbA1c ≤ 6.5% (48 mmol/mol). |
| Change From Baseline in Body Weight | Week 0, week 26 | Mean change in body weight after 26 weeks of treatment. |
| Change From Baseline in Fasting Plasma Glucose (FPG) | Week 0, week 26 | Mean change in fasting plasma glucose from baseline, after 26 weeks of treatment. |
| Responders Achieving Pre-defined Target: HbA1c Below 7.0% (53 mmol/Mol) | Week 26 | Percentage of subjects achieving HbA1c below 7.0% after 26 weeks of treatment. |
| Number of Adverse Events (AEs) | After 26 weeks of treatment | Rate (events per 100 exposure years) of treatment-emergent adverse events (an event that had onset date (or an increase in severity) on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment) which occurred during the 26 weeks of treatment. |
| Change From Baseline in Patient Reported Outcomes (PROs) Based on the Treatment Related Impact Measure - Diabetes (TRIM-D) | Week 0, week 26 | The patient related outcome is calculated based on TRIM-D questionnaire. The TRIM-D questionnaire consists of 5 sub-domains (treatment burden, daily life, diabetes management, compliance and psychological health), where each question is scored to a 1-5-point scale with a higher score indicating a better health state (less negative impact). Mean TRIM-D individual sub-domain scores and total score are later transformed to a 0-100 scale for analysis. The mean change in scores from baseline to 26 weeks for all the individual sub domains and total scores are presented here. |
| Change From Baseline in Patient Reported Outcomes (PROs) Based on Diabetes Treatment Satisfaction Questionnaire (DTSQ). | Week 0, week 26 | Mean change in diabetes treatment satisfaction questionnaire (DTSQs) scores from baseline. The scores ranged from 0 to 6. Higher total score on a 0-6 point scale indicates a general higher treatment satisfaction, whereas higher score on perceived frequency of hyperglycaemia and perceived frequency of hypoglycaemia indicate that blood glucose levels are out of the target range. |
| Number of Severe or Minor Hypoglycaemic Episodes | After 26 weeks of treatment | Rate (events per 100 patient years of exposure) of treatment-emergent confirmed hypoglycaemic episodes. The pool of severe and minor hypoglycaemic episodes was referred to as confirmed hypoglycaemic episodes. Severe hypoglycaemia was categorised as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes were defined as an episode with symptoms consistent with hypoglycaemia with confirmation by blood glucose \<2.8 mmol/L (50 mg/dL) or PG \<3.1 mmol/L (56 mg/dL), and which was handled by the subject himself/herself, or any asymptomatic blood glucose value \<2.8 mmol/L (50 mg/dL) or PG value \<3.1 mmol/L (56 mg/dL). |
Countries
Australia, France, Hungary, Slovakia, United States
Participant flow
Recruitment details
The trial was conducted at 81 sites in 5 countries as follows: Australia: 5 sites; France: 7 sites; Hungary: 4 sites; Slovakia 6 sites; United States: 59 sites.
Pre-assignment details
The duration of the screening period was 2 weeks. All subjects continued GLP-1 receptor agonist and metformin±pioglitazone±SU treatments in their pre-trial doses during the screening period.
Participants by arm
| Arm | Count |
|---|---|
| Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs) Subjects were treated with subcutaneous (under the skin) once daily (OD) insulin degludec/liraglutide. Treatment with insulin degludec/liraglutide was initiated at 16 dose steps containing 16 units of insulin degludec and 0.6 mg liraglutide. Adjustment of the insulin degludec/liraglutide dose was performed twice weekly based on the mean of 3 preceding daily fasting self measured plasma glucose (SMPG) values on 3 consecutive days. The aim was to achieve a fasting plasma glucose (FPG) target of 4.0-5.0 mmol/L (72-90 mg/dL) and the maximum allowed dose was 50 dose steps (50 units insulin degludec/1.8 mg liraglutide). Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) treatment without changing the frequency or dose throughout the trial, unless there was a safety concern. | 292 |
| Liraglutide or Exenatide + OADs Subjects continued on their pre-trial GLP-1 receptor agonist treatment with subcutaneous (under the skin) liraglutide (Victoza®) or exenatide (Byetta®) in stable pre-trial dose without changing the frequency or dose throughout the trial. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) without changing the frequency or dose throughout the trial, unless there was a safety concern. | 146 |
| Total | 438 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Protocol Violation | 9 | 3 |
| Overall Study | Unclassified | 4 | 10 |
| Overall Study | Withdrawal criteria | 2 | 14 |
Baseline characteristics
| Characteristic | Liraglutide or Exenatide + OADs | Total | Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs) |
|---|---|---|---|
| Age, Continuous | 58.4 years STANDARD_DEVIATION 8.8 | 58.3 years STANDARD_DEVIATION 9.5 | 58.3 years STANDARD_DEVIATION 9.9 |
| Body weight | 95.5 kg STANDARD_DEVIATION 17.3 | 95.5 kg STANDARD_DEVIATION 16.8 | 95.6 kg STANDARD_DEVIATION 16.6 |
| Fasting plasma glucose | 9.4 mmol/L STANDARD_DEVIATION 2.3 | 9.1 mmol/L STANDARD_DEVIATION 2.2 | 9 mmol/L STANDARD_DEVIATION 2.1 |
| HbA1c | 7.7 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.6 | 7.8 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.6 | 7.8 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.6 |
| Sex: Female, Male Female | 75 Participants | 214 Participants | 139 Participants |
| Sex: Female, Male Male | 71 Participants | 224 Participants | 153 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 88 / 291 | 39 / 145 |
| serious Total, serious adverse events | 9 / 291 | 3 / 145 |
Outcome results
Primary
Change in Glycosylated Haemoglobin (HbA1c) From Baseline (Randomisation, Visit 2)
Time frame: Week 0, week 26
Population: Full analysis set included all the randomised subjects. Missing values (including intermittent missing values) were imputed using the last observation carried forward (LOCF) method.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs) | Change in Glycosylated Haemoglobin (HbA1c) From Baseline (Randomisation, Visit 2) | -1.32 percentage of glycosylated haemoglobin | Standard Error 0.05 |
| Liraglutide or Exenatide + OADs | Change in Glycosylated Haemoglobin (HbA1c) From Baseline (Randomisation, Visit 2) | -0.37 percentage of glycosylated haemoglobin | Standard Error 0.07 |
p-value: <0.00195% CI: [-1.11, -0.78]ANCOVA
Secondary
Change From Baseline in Body Weight
Mean change in body weight after 26 weeks of treatment.
Time frame: Week 0, week 26
Population: Full analysis set included all randomised subjects. Missing values (including intermittent missing values) were imputed using the last observation carried forward (LOCF) method.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs) | Change From Baseline in Body Weight | 2 kg | Standard Deviation 3.9 |
| Liraglutide or Exenatide + OADs | Change From Baseline in Body Weight | -0.8 kg | Standard Deviation 3 |
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG)
Mean change in fasting plasma glucose from baseline, after 26 weeks of treatment.
Time frame: Week 0, week 26
Population: Full analysis set included all randomised subjects. A total of 430 subjects contributed to the analysis. Missing values (including intermittent missing values) were imputed using the last observation carried forward (LOCF) method.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs) | Change From Baseline in Fasting Plasma Glucose (FPG) | -2.98 mmol/L | Standard Deviation 2.28 |
| Liraglutide or Exenatide + OADs | Change From Baseline in Fasting Plasma Glucose (FPG) | -0.6 mmol/L | Standard Deviation 2.74 |
Secondary
Change From Baseline in Patient Reported Outcomes (PROs) Based on Diabetes Treatment Satisfaction Questionnaire (DTSQ).
Mean change in diabetes treatment satisfaction questionnaire (DTSQs) scores from baseline. The scores ranged from 0 to 6. Higher total score on a 0-6 point scale indicates a general higher treatment satisfaction, whereas higher score on perceived frequency of hyperglycaemia and perceived frequency of hypoglycaemia indicate that blood glucose levels are out of the target range.
Time frame: Week 0, week 26
Population: Full analysis set included all randomised subjects. A total of 436 subjects contributed to the analysis. Missing values (including intermittent missing values) were imputed using the last observation carried forward (LOCF) method.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs) | Change From Baseline in Patient Reported Outcomes (PROs) Based on Diabetes Treatment Satisfaction Questionnaire (DTSQ). | Treatment satisfaction scale total | 3.1 Scores on a scale | Standard Deviation 5.6 |
| Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs) | Change From Baseline in Patient Reported Outcomes (PROs) Based on Diabetes Treatment Satisfaction Questionnaire (DTSQ). | Hyperglycaemia | -1.8 Scores on a scale | Standard Deviation 2.1 |
| Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs) | Change From Baseline in Patient Reported Outcomes (PROs) Based on Diabetes Treatment Satisfaction Questionnaire (DTSQ). | Hypoglycaemia | 0.2 Scores on a scale | Standard Deviation 1.7 |
| Liraglutide or Exenatide + OADs | Change From Baseline in Patient Reported Outcomes (PROs) Based on Diabetes Treatment Satisfaction Questionnaire (DTSQ). | Treatment satisfaction scale total | 1.1 Scores on a scale | Standard Deviation 5 |
| Liraglutide or Exenatide + OADs | Change From Baseline in Patient Reported Outcomes (PROs) Based on Diabetes Treatment Satisfaction Questionnaire (DTSQ). | Hyperglycaemia | -0.6 Scores on a scale | Standard Deviation 1.9 |
| Liraglutide or Exenatide + OADs | Change From Baseline in Patient Reported Outcomes (PROs) Based on Diabetes Treatment Satisfaction Questionnaire (DTSQ). | Hypoglycaemia | -0.1 Scores on a scale | Standard Deviation 1.5 |
Secondary
Change From Baseline in Patient Reported Outcomes (PROs) Based on the Treatment Related Impact Measure - Diabetes (TRIM-D)
The patient related outcome is calculated based on TRIM-D questionnaire. The TRIM-D questionnaire consists of 5 sub-domains (treatment burden, daily life, diabetes management, compliance and psychological health), where each question is scored to a 1-5-point scale with a higher score indicating a better health state (less negative impact). Mean TRIM-D individual sub-domain scores and total score are later transformed to a 0-100 scale for analysis. The mean change in scores from baseline to 26 weeks for all the individual sub domains and total scores are presented here.
Time frame: Week 0, week 26
Population: Full analysis set included all randomised subjects. A total of 436 subjects contributed to the analysis. Missing values (including intermittent missing values) were imputed using the last observation carried forward (LOCF) method.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs) | Change From Baseline in Patient Reported Outcomes (PROs) Based on the Treatment Related Impact Measure - Diabetes (TRIM-D) | TRIM-D Treatment Burden Score | 10.8 Scores on a scale | Standard Deviation 18.8 |
| Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs) | Change From Baseline in Patient Reported Outcomes (PROs) Based on the Treatment Related Impact Measure - Diabetes (TRIM-D) | TRIM-D Daily Life Score | 6.3 Scores on a scale | Standard Deviation 18.4 |
| Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs) | Change From Baseline in Patient Reported Outcomes (PROs) Based on the Treatment Related Impact Measure - Diabetes (TRIM-D) | TRIM-D Diabetes Management Score | 10.9 Scores on a scale | Standard Deviation 21.3 |
| Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs) | Change From Baseline in Patient Reported Outcomes (PROs) Based on the Treatment Related Impact Measure - Diabetes (TRIM-D) | TRIM-D Compliance Score | 8.9 Scores on a scale | Standard Deviation 17.3 |
| Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs) | Change From Baseline in Patient Reported Outcomes (PROs) Based on the Treatment Related Impact Measure - Diabetes (TRIM-D) | TRIM-D Psychological Health Score | 7.3 Scores on a scale | Standard Deviation 14.7 |
| Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs) | Change From Baseline in Patient Reported Outcomes (PROs) Based on the Treatment Related Impact Measure - Diabetes (TRIM-D) | TRIM-D Total Score | 8.7 Scores on a scale | Standard Deviation 12 |
| Liraglutide or Exenatide + OADs | Change From Baseline in Patient Reported Outcomes (PROs) Based on the Treatment Related Impact Measure - Diabetes (TRIM-D) | TRIM-D Psychological Health Score | 1.4 Scores on a scale | Standard Deviation 16.5 |
| Liraglutide or Exenatide + OADs | Change From Baseline in Patient Reported Outcomes (PROs) Based on the Treatment Related Impact Measure - Diabetes (TRIM-D) | TRIM-D Treatment Burden Score | 5.7 Scores on a scale | Standard Deviation 19.3 |
| Liraglutide or Exenatide + OADs | Change From Baseline in Patient Reported Outcomes (PROs) Based on the Treatment Related Impact Measure - Diabetes (TRIM-D) | TRIM-D Compliance Score | 4.3 Scores on a scale | Standard Deviation 15.9 |
| Liraglutide or Exenatide + OADs | Change From Baseline in Patient Reported Outcomes (PROs) Based on the Treatment Related Impact Measure - Diabetes (TRIM-D) | TRIM-D Daily Life Score | 0.8 Scores on a scale | Standard Deviation 18.2 |
| Liraglutide or Exenatide + OADs | Change From Baseline in Patient Reported Outcomes (PROs) Based on the Treatment Related Impact Measure - Diabetes (TRIM-D) | TRIM-D Total Score | 3.1 Scores on a scale | Standard Deviation 12.2 |
| Liraglutide or Exenatide + OADs | Change From Baseline in Patient Reported Outcomes (PROs) Based on the Treatment Related Impact Measure - Diabetes (TRIM-D) | TRIM-D Diabetes Management Score | 4.1 Scores on a scale | Standard Deviation 19.8 |
Secondary
Number of Adverse Events (AEs)
Rate (events per 100 exposure years) of treatment-emergent adverse events (an event that had onset date (or an increase in severity) on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment) which occurred during the 26 weeks of treatment.
Time frame: After 26 weeks of treatment
Population: Full analysis set included all randomised subjects. A total of 436 subjects contributed to the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs) | Number of Adverse Events (AEs) | 410.1 events per 100 exposure years |
| Liraglutide or Exenatide + OADs | Number of Adverse Events (AEs) | 364.3 events per 100 exposure years |
Secondary
Number of Severe or Minor Hypoglycaemic Episodes
Rate (events per 100 patient years of exposure) of treatment-emergent confirmed hypoglycaemic episodes. The pool of severe and minor hypoglycaemic episodes was referred to as confirmed hypoglycaemic episodes. Severe hypoglycaemia was categorised as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes were defined as an episode with symptoms consistent with hypoglycaemia with confirmation by blood glucose \<2.8 mmol/L (50 mg/dL) or PG \<3.1 mmol/L (56 mg/dL), and which was handled by the subject himself/herself, or any asymptomatic blood glucose value \<2.8 mmol/L (50 mg/dL) or PG value \<3.1 mmol/L (56 mg/dL).
Time frame: After 26 weeks of treatment
Population: Full analysis set included all randomised subjects. A total of 436 subjects contributed to the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs) | Number of Severe or Minor Hypoglycaemic Episodes | 281.7 events per 100 patient years of exposure |
| Liraglutide or Exenatide + OADs | Number of Severe or Minor Hypoglycaemic Episodes | 12.1 events per 100 patient years of exposure |
Secondary
Responders Achieving Pre-defined Target: HbA1c Below 7.0% (53 mmol/Mol)
Percentage of subjects achieving HbA1c below 7.0% after 26 weeks of treatment.
Time frame: Week 26
Population: Full analysis set included all randomised subjects. Missing values (including intermittent missing values) were imputed using the last observation carried forward (LOCF) method.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs) | Responders Achieving Pre-defined Target: HbA1c Below 7.0% (53 mmol/Mol) | 75.3 Percentage |
| Liraglutide or Exenatide + OADs | Responders Achieving Pre-defined Target: HbA1c Below 7.0% (53 mmol/Mol) | 35.6 Percentage |
Secondary
Responders Achieving Pre-defined Target: HbA1c Below or Equal to 6.5% (48 mmol/Mol)
Percentage of responders achieving pre-defined target for HbA1c - HbA1c ≤ 6.5% (48 mmol/mol).
Time frame: Week 26
Population: Full analysis set included all randomised subjects. Missing values (including intermittent missing values) were imputed using the last observation carried forward (LOCF) method.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Degludec/Liraglutide + Oral Anti Diabetic Drugs (OADs) | Responders Achieving Pre-defined Target: HbA1c Below or Equal to 6.5% (48 mmol/Mol) | 63 Percentage |
| Liraglutide or Exenatide + OADs | Responders Achieving Pre-defined Target: HbA1c Below or Equal to 6.5% (48 mmol/Mol) | 22.6 Percentage |