Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Asia, Europe and the United States of America (USA). The aim of this trial is to investigate the efficacy and safety of insulin degludec/liraglutide in insulin naïve subjects inadequately controlled with SU (sulphonylurea) alone or in combination with metformin. All subjects will continue their pre-trial SU treatment with or without metformin treatment without changing the frequency or dose throughout the trial.
Interventions
DRUGinsulin degludec/liraglutide
Injected subcutaneously (under the skin) once daily. Dose individually adjusted.
DRUGplacebo
Injected subcutaneously (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 No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects with type 2 diabetes mellitus * HbA1c 7.0-9.0% (53-75 mmol/mol) (both inclusive) * Subjects on stable daily dose of sulphonylurea (above or equal to half of the max approved dose according to local label) with or without metformin (above or equal to 1500 mg or max tolerated dose) for at least 90 days prior to screening visit (Visit 1) * Body Mass Index (BMI) below or equal to 40 kg/m\^2
Exclusion criteria
* Any use of oral anti-diabetic drugs (OADs) (other than SU in monotherapy or in combinationwith metformin) below or equal to 90 days prior to screening visit (Visit 1) * Use of any drug (other than SU in monotherapy or in combination with metformin), which in the Investigators opinion could interfere with the blood glucose level (e.g. systemic corticosteroids) * Previous treatment with glucagon-like peptide-1 (GLP-1) receptor agonist (e.g. exenatide, liraglutide) * 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 above or equal to 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 clinical 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 product * History of chronic pancreatitis or idiopathic acute pancreatitis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glycosylated Haemoglobin (HbA1c) | Week 0, Week 26 | Change in HbA1c from baseline to 26 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Adverse Events (AEs) | After 26 weeks of treatment | An AE was any unfavourable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a product, whether or not considered related to the product. Reported values are hypoglycemia event rate per 100 PYE. |
| Responders Achieving Pre-defined Target: HbA1c Below 7.0% (53 mmol/Mol) | Week 26 | Percentage of subjects having HbA1c below 7% at week 26. |
| Number of Treatment Emergent (Confirmed) Hypoglycaemic Episodes | After 26 weeks of treatment | An event was treatment emergent if the onset of the episode occurs after the first administration of trial product and no later than 7 days after last trial product administration. Confirmed hypoglycaemic episodes were defined as hypoglycaemic episodes that were either severe or minor. Minor hypoglycaemic episodes were defined as: 1. An episode with symptoms consistent with hypoglycaemia and confirmed by blood glucose value \<2.8 mmol/L (50 mg/dL) or plasma glucose \<3.1 mmol/L (56 mg/dL) and which was handled by the subject himself/herself. 2. Any asymptomatic PG value \<3.1 mmol/L (56 mg/dL) or blood glucose value \<2.8 mmol/L (50 mg/dL). Severe hypoglycemia was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Reported values are hypoglycemia event rate per 100 patient-years of exposure (PYE). |
| Change From Baseline in Fasting Plasma Glucose (FPG) | Week 0, week 26 | Change from baseline in FPG at week 26. |
| Change From Baseline in Body Weight | Week 0, week 26 | Change from baseline in body weight at week 26. |
| Responders Achieving Pre-defined Target: HbA1c Below or Equal to 6.5% (48 mmol/Mol) | Week 26 | Percentage of subjects having HbA1c below 6.5% at week 26 |
Countries
Bulgaria, Canada, Germany, India, Israel, Puerto Rico, Turkey (Türkiye), United States
Participant flow
Recruitment details
The trial was conducted at 77 sites in 7 countries: Bulgaria (7), Canada (9), Germany (6), India (6), Israel (7), Turkey (3), United States (39).
Pre-assignment details
The trial included a 2 week screening period to assess subject eligibility.
Participants by arm
| Arm | Count |
|---|---|
| IDegLira In this arm, Subjects suboptimally controlled on SU +/- metformin, were given s.c. injection of IDegLira. SU and metformin were maintained at the stable pre-trial dose throughout the duration of the trial. IDegLira was injected in the thigh, upper arm (deltoid region) or abdomen once daily preferably at the same time every day. The injection area chosen remained unchanged throughout the trial, but rotation within the area was recommended. Treatment with IDegLira was initiated at 10 dose steps containing 10 units insulin degludec and 0.36 mg liraglutide. Adjustment of the IDegLira dose was performed twice weekly based on the mean of 3 preceding daily fasting SMPG values on 3 consecutive days (fasting glycaemic target of 4.0-6.0 mmol/L). | 289 |
| Placebo In this arm, subjects suboptimally controlled on SU +/- metformin, were given s.c. injection of placebo solution (matched to IDegLira) and was initiated and titrated as described for IDegLira. SU and metformin were maintained at the stable pre-trial dose throughout the duration of the trial. Placebo solution was injected in the thigh, upper arm (deltoid region) or abdomen once daily preferably at the same time every day. The injection area chosen remained unchanged throughout the trial, but rotation within the area was recommended. Adjustment of placebo was performed twice weekly based on the mean of 3 preceding daily fasting SMPG values on 3 consecutive days (fasting glycaemic target of 4.0-6.0 mmol/L). | 146 |
| Total | 435 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 2 |
| Overall Study | Protocol Violation | 13 | 10 |
| Overall Study | Unclassified | 14 | 13 |
| Overall Study | Withdrawal Criteria | 2 | 10 |
Baseline characteristics
| Characteristic | IDegLira | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 60 years STANDARD_DEVIATION 9.6 | 59.4 years STANDARD_DEVIATION 10.8 | 59.8 years STANDARD_DEVIATION 10 |
| Body weight | 87.2 kilograms STANDARD_DEVIATION 18.6 | 89.3 kilograms STANDARD_DEVIATION 17.5 | 87.9 kilograms STANDARD_DEVIATION 18.2 |
| Fasting plasma glucose | 9.1 mmol/L STANDARD_DEVIATION 2.2 | 9.1 mmol/L STANDARD_DEVIATION 2.1 | 9.1 mmol/L STANDARD_DEVIATION 2.1 |
| Glycosylated haemoglobin | 7.9 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.6 | 7.9 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.6 | 7.9 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.6 |
| Sex: Female, Male Female | 135 Participants | 73 Participants | 208 Participants |
| Sex: Female, Male Male | 154 Participants | 73 Participants | 227 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 83 / 288 | 38 / 146 |
| serious Total, serious adverse events | 14 / 288 | 5 / 146 |
Outcome results
Primary
Change in Glycosylated Haemoglobin (HbA1c)
Change in HbA1c from baseline to 26 weeks.
Time frame: Week 0, Week 26
Population: Full analysis set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDegLira | Change in Glycosylated Haemoglobin (HbA1c) | -1.45 percentage of glycosylated haemoglobin | Standard Deviation 0.84 |
| Placebo | Change in Glycosylated Haemoglobin (HbA1c) | -0.46 percentage of glycosylated haemoglobin | Standard Deviation 0.83 |
Comparison: Superiority of IDegLira versus placebo therapy would be concluded if the 95% CI for the treatment differences for change in HbA1c lied entirely below 0%; implying that the two-sided p-value calculated by the ANCOVA model for testing the hypothesis of no difference between treatments was less than 5%.p-value: <0.00195% CI: [-1.18, -0.87]ANCOVA
Secondary
Change From Baseline in Body Weight
Change from baseline in body weight at week 26.
Time frame: Week 0, week 26
Population: Full analysis set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDegLira | Change From Baseline in Body Weight | 0.5 kilogram | Standard Deviation 3.1 |
| Placebo | Change From Baseline in Body Weight | -1 kilogram | Standard Deviation 2.6 |
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG)
Change from baseline in FPG at week 26.
Time frame: Week 0, week 26
Population: Full analysis set. Number of subjects analyzed=subjects with data available for FPG.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDegLira | Change From Baseline in Fasting Plasma Glucose (FPG) | -2.6 mmol/L | Standard Deviation 2.61 |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) | -0.31 mmol/L | Standard Deviation 2.43 |
Secondary
Number of Adverse Events (AEs)
An AE was any unfavourable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a product, whether or not considered related to the product. Reported values are hypoglycemia event rate per 100 PYE.
Time frame: After 26 weeks of treatment
Population: Safety analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDegLira | Number of Adverse Events (AEs) | 401.4 event rate per 100 PYE |
| Placebo | Number of Adverse Events (AEs) | 367 event rate per 100 PYE |
Secondary
Number of Treatment Emergent (Confirmed) Hypoglycaemic Episodes
An event was treatment emergent if the onset of the episode occurs after the first administration of trial product and no later than 7 days after last trial product administration. Confirmed hypoglycaemic episodes were defined as hypoglycaemic episodes that were either severe or minor. Minor hypoglycaemic episodes were defined as: 1. An episode with symptoms consistent with hypoglycaemia and confirmed by blood glucose value \<2.8 mmol/L (50 mg/dL) or plasma glucose \<3.1 mmol/L (56 mg/dL) and which was handled by the subject himself/herself. 2. Any asymptomatic PG value \<3.1 mmol/L (56 mg/dL) or blood glucose value \<2.8 mmol/L (50 mg/dL). Severe hypoglycemia was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Reported values are hypoglycemia event rate per 100 patient-years of exposure (PYE).
Time frame: After 26 weeks of treatment
Population: Safety analysis set included all subjects receiving at least one dose of the trial product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDegLira | Number of Treatment Emergent (Confirmed) Hypoglycaemic Episodes | 351.7 event rate per 100 PYE |
| Placebo | Number of Treatment Emergent (Confirmed) Hypoglycaemic Episodes | 135.2 event rate per 100 PYE |
Secondary
Responders Achieving Pre-defined Target: HbA1c Below 7.0% (53 mmol/Mol)
Percentage of subjects having HbA1c below 7% at week 26.
Time frame: Week 26
Population: Full analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDegLira | Responders Achieving Pre-defined Target: HbA1c Below 7.0% (53 mmol/Mol) | 79.2 percentage of subjects |
| Placebo | Responders Achieving Pre-defined Target: HbA1c Below 7.0% (53 mmol/Mol) | 28.8 percentage of subjects |
Secondary
Responders Achieving Pre-defined Target: HbA1c Below or Equal to 6.5% (48 mmol/Mol)
Percentage of subjects having HbA1c below 6.5% at week 26
Time frame: Week 26
Population: Full analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDegLira | Responders Achieving Pre-defined Target: HbA1c Below or Equal to 6.5% (48 mmol/Mol) | 64 percentage of subjects |
| Placebo | Responders Achieving Pre-defined Target: HbA1c Below or Equal to 6.5% (48 mmol/Mol) | 12.3 percentage of subjects |