Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted globally. The aim of this trial is to compare cardiovascular safety of insulin degludec versus insulin glargine in subjects with type 2 diabetes at high risk of cardiovascular events.
Interventions
DRUGinsulin degludec
Injected once daily subcutaneously (s.c., under the skin)
DRUGinsulin glargine
Injected once daily subcutaneously (s.c., under the skin)
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
- Type 2 diabetes - Age above or equal to 50 years with predefined previous cardiovascular disease(s) or renal disease or age above or equal to 60 years with predefined cardiovascular risk factors - HbA1c (glycosylated haemoglobin) above or equal to 7.0% or HbA1c below 7.0% and current insulin treatment corresponding to above or equal to 20 U of basal insulin per day - One or more oral or injectable antidiabetic agent(s)
Exclusion criteria
- An acute coronary or cerebrovascular event in the previous 60 days - Planned coronary, carotid or peripheral artery revascularisation - Chronic heart failure NYHA (New York Heart Association) class IV - Current or past (within the last 5 years) malignant neoplasms (except basal cell and squamous cell skin carcinoma)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time From Randomisation to First Occurrence of a Major Adverse Cardiovascular Event (MACE): Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke | From randomisation to individual end of trial date (maximum patient year observation: 2.75 years) | Time from randomisation to first occurrence of an event adjudication committee (EAC)-confirmed 3-component major adverse cardiovascular event (MACE): cardiovascular death, non-fatal myocardial infarction, or nonfatal stroke. Events with EAC-confirmed onset date between randomisation and individual end of trial were included in the analyses. The number of subjects experiencing first EAC-confirmed MACEs, date between randomisation to the end of trial, both days included were presented. The trial was event driven and planned to last up to a maximum of 60.5 months. The actual trial duration (time from first subject first visit to last subject last visit) was 35.6 months. The maximum trial duration for a single subject was 33.1 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of EAC-confirmed Severe Hypoglycaemic Episodes | From randomisation to individual end of trial (maximum patient year observation: 2.75 years) | Number of severe hypoglycaemic episodes from week 0 to the last assessment (up to 35.6 months). The episode of severe hypoglycaemia is an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. The trial was event driven and planned to last up to a maximum of 60.5 months. The actual trial duration (time from first subject first visit to last subject last visit) was 35.6 months. The maximum trial duration for a single subject was 33.1 months. |
| Occurrence of at Least One EAC Confirmed Severe Hypoglycaemic Episode Within a Subject (Yes/no) | From randomisation to individual end of trial date (maximum patient year observation: 2.75 years) | Occurrence of at least one EAC-confirmed severe hypoglycaemic episode within a subject from week 0 to the last assessment (up to 35.6 months). The episode of severe hypoglycaemia is an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. |
| Change in Glycosylated Haemoglobin (HbA1c) | Randomisation to 24 months | Mean change in HbA1c from week 0 to month 24. |
Countries
Algeria, Argentina, Brazil, Canada, Croatia, Greece, India, Italy, Japan, Malaysia, Mexico, Poland, Romania, Russia, South Africa, South Korea, Spain, Thailand, United Kingdom, United States
Participant flow
Recruitment details
The trial was conducted at 438 sites in 20 countries as follows: Algeria: 6; Argentina: 4; Brazil: 10; Canada: 6; Croatia: 5; Greece: 6; India: 26; Italy: 10; Japan: 8; Republic of Korea: 4; Malaysia: 8; Mexico: 7; Poland: 8; Romania: 4; Russian Federation: 20; South Africa: 15; Spain: 6; Thailand: 6; United Kingdom: 8; United States: 271.
Participants by arm
| Arm | Count |
|---|---|
| Insulin Degludec Subjects received IDeg 100 units/mL OD S.C. (under the skin) in the thigh, upper arm, or the abdominal wall between dinner and bedtime. Subjects continued their pre-trial medication except for the basal insulin, which was replaced by investigational medicinal product (IMP; IDeg). The pre-trial bolus insulin was allowed and could be replaced with IAsp at the discretion of the investigator. For subjects previously receiving premixed/biphasic insulin the basal component was calculated and switched to IDeg OD, and the bolus insulin component to bolus insulin. For subjects previously receiving premixed/biphasic insulin BID, the total basal component was calculated, reduced by 20- 30% and switched to IDeg OD, and the bolus component was calculated and switched to IAsp. The trial was event driven for with a realised observation period up to 33 months. | 3,818 |
| Insulin Glargine Subjects received IGlar 100 units/mL OD subcutaneously (S.C.; under the skin) in the thigh, upper arm, or the abdominal wall between dinner and bedtime. Subjects continued their pretrial medication except for the basal insulin, which was replaced by investigational medicinal product (IMP; IGlar). The pre-trial bolus insulin was allowed and could be replaced with IAsp at the discretion of the investigator. For subjects previously receiving premixed/biphasic insulin the basal component was calculated and switched to IGlar OD, and the bolus insulin component to bolus insulin. For subjects previously receiving premixed/biphasic insulin BID, the total basal component was calculated, reduced by 20- 30% and switched to IGlar OD, and the bolus component was calculated and switched to IAsp. The trial was event driven with a realised observation period up to 33 months. | 3,819 |
| Total | 7,637 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse event (not hypoglycaemia) | 0 | 1 |
| Overall Study | Hypoglycaemia | 1 | 1 |
| Overall Study | Lack of glycaemic control | 1 | 1 |
| Overall Study | Lost to Follow-up | 4 | 1 |
| Overall Study | Other | 70 | 68 |
Baseline characteristics
| Characteristic | Insulin Degludec | Insulin Glargine | Total |
|---|---|---|---|
| Age, Continuous | 64.9 years STANDARD_DEVIATION 7.3 | 65.0 years STANDARD_DEVIATION 7.5 | 65.0 years STANDARD_DEVIATION 7.4 |
| HbA1c | 8.44 percentage of HbA1c STANDARD_DEVIATION 1.63 | 8.41 percentage of HbA1c STANDARD_DEVIATION 1.67 | 8.43 percentage of HbA1c STANDARD_DEVIATION 1.65 |
| Sex: Female, Male Female | 1422 Participants | 1437 Participants | 2859 Participants |
| Sex: Female, Male Male | 2396 Participants | 2382 Participants | 4778 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 3,818 | 0 / 3,819 |
| serious Total, serious adverse events | 1,473 / 3,818 | 1,517 / 3,819 |
Outcome results
Primary
Time From Randomisation to First Occurrence of a Major Adverse Cardiovascular Event (MACE): Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke
Time from randomisation to first occurrence of an event adjudication committee (EAC)-confirmed 3-component major adverse cardiovascular event (MACE): cardiovascular death, non-fatal myocardial infarction, or nonfatal stroke. Events with EAC-confirmed onset date between randomisation and individual end of trial were included in the analyses. The number of subjects experiencing first EAC-confirmed MACEs, date between randomisation to the end of trial, both days included were presented. The trial was event driven and planned to last up to a maximum of 60.5 months. The actual trial duration (time from first subject first visit to last subject last visit) was 35.6 months. The maximum trial duration for a single subject was 33.1 months.
Time frame: From randomisation to individual end of trial date (maximum patient year observation: 2.75 years)
Population: The analysis was based on the FAS, which included all randomised subjects.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Insulin Degludec | Time From Randomisation to First Occurrence of a Major Adverse Cardiovascular Event (MACE): Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke | First EAC-confirmed MACE | 325 Participants |
| Insulin Degludec | Time From Randomisation to First Occurrence of a Major Adverse Cardiovascular Event (MACE): Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke | Myocardial infarction (non-fatal) | 143 Participants |
| Insulin Degludec | Time From Randomisation to First Occurrence of a Major Adverse Cardiovascular Event (MACE): Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke | Stroke (non-fatal) | 68 Participants |
| Insulin Degludec | Time From Randomisation to First Occurrence of a Major Adverse Cardiovascular Event (MACE): Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke | Cardiovascular death | 114 Participants |
| Insulin Glargine | Time From Randomisation to First Occurrence of a Major Adverse Cardiovascular Event (MACE): Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke | Cardiovascular death | 119 Participants |
| Insulin Glargine | Time From Randomisation to First Occurrence of a Major Adverse Cardiovascular Event (MACE): Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke | First EAC-confirmed MACE | 356 Participants |
| Insulin Glargine | Time From Randomisation to First Occurrence of a Major Adverse Cardiovascular Event (MACE): Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke | Stroke (non-fatal) | 74 Participants |
| Insulin Glargine | Time From Randomisation to First Occurrence of a Major Adverse Cardiovascular Event (MACE): Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke | Myocardial infarction (non-fatal) | 163 Participants |
Comparison: The hazard ratio (HR) (IDeg vs IGlar) was based on Cox regression with investigational medicinal product as only factor for primary analysis.p-value: <0.00195% CI: [0.781, 1.055]Regression, Cox
Secondary
Change in Glycosylated Haemoglobin (HbA1c)
Mean change in HbA1c from week 0 to month 24.
Time frame: Randomisation to 24 months
Population: The analysis was based on the FAS. The number of subjects analysed are the number of subjects with the available data after 24 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec | Change in Glycosylated Haemoglobin (HbA1c) | -0.86 percentage of HbA1c | Standard Deviation 1.51 |
| Insulin Glargine | Change in Glycosylated Haemoglobin (HbA1c) | -0.84 percentage of HbA1c | Standard Deviation 1.57 |
Secondary
Number of EAC-confirmed Severe Hypoglycaemic Episodes
Number of severe hypoglycaemic episodes from week 0 to the last assessment (up to 35.6 months). The episode of severe hypoglycaemia is an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. The trial was event driven and planned to last up to a maximum of 60.5 months. The actual trial duration (time from first subject first visit to last subject last visit) was 35.6 months. The maximum trial duration for a single subject was 33.1 months.
Time frame: From randomisation to individual end of trial (maximum patient year observation: 2.75 years)
Population: The analysis was based on the FAS, which included all randomised subjects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Degludec | Number of EAC-confirmed Severe Hypoglycaemic Episodes | 280 Number of severe episodes |
| Insulin Glargine | Number of EAC-confirmed Severe Hypoglycaemic Episodes | 472 Number of severe episodes |
Comparison: Superiority was considered confirmed if the upper limit of the two-sided 95% confidence interval for the rate ratio (RR) was below 1.0 or equivalent if the p-value for the one-sided test of H0: RR ≥1.0 against Ha: RR \<1.0, was less than 2.5%p-value: <0.00195% CI: [0.476, 0.759]Negative binomial regression
Secondary
Occurrence of at Least One EAC Confirmed Severe Hypoglycaemic Episode Within a Subject (Yes/no)
Occurrence of at least one EAC-confirmed severe hypoglycaemic episode within a subject from week 0 to the last assessment (up to 35.6 months). The episode of severe hypoglycaemia is an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions.
Time frame: From randomisation to individual end of trial date (maximum patient year observation: 2.75 years)
Population: The analysis was based on the FAS, which included all randomised subjects.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Insulin Degludec | Occurrence of at Least One EAC Confirmed Severe Hypoglycaemic Episode Within a Subject (Yes/no) | 187 Participants |
| Insulin Glargine | Occurrence of at Least One EAC Confirmed Severe Hypoglycaemic Episode Within a Subject (Yes/no) | 252 Participants |
Comparison: Superiority of IDeg to IGlar was considered confirmed if the upper limit of the two-sided 95% confidence interval for the odds ratio (OR) was below 1.0 or equivalent if the p-value for the one-sided test of H0: OR ≥1.0 against Ha: OR\<1.0, was less than 2.5%.p-value: <0.00195% CI: [0.6, 0.866]Regression, Logistic