Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial was conducted in Africa, Asia, Europe, North and South America. The aim of the trial was to compare efficacy and safety of insulin degludec and insulin glargine in insulin naïve subjects with type 2 diabetes.
Interventions
DRUGInsulin Degludec
Administered subcutaneously (under the skin), dose individually adjusted, once daily in combination with metformin at the unchanged, stable, pre-randomisation dose level and dosing frequency.
DRUGInsulin Glargine
Administered subcutaneously (under the skin), dose individually adjusted, once daily in combination with metformin at the unchanged, stable, pre-randomisation dose level and dosing frequency.
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
* Type 2 diabetes mellitus (diagnosed clinically) for at least 6 months * Insulin naïve subjects (Allowed are: previous short term insulin treatment up to 14 days; treatment during hospitalisation or during gestational diabetes is allowed for periods longer than 14 days) * Current treatment: metformin monotherapy or metformin in any combination with an insulin secretagogue (sulfonylurea or glinide), dipeptidyl peptidase IV (DPP-IV) inhibitor, alfa-glucosidase-inhibitors (acarbose) with unchanged dosing for at least 3 months prior to randomisation (Visit 2) with the minimum doses stated: metformin: alone or in combination (including fixed combination) 1500 mg daily, or maximum tolerated dose (at least 1000 mg daily), insulin secretagogue (sulfonylurea or glinide): minimum half of the daily maximal dose according to local labelling, DPP-IV inhibitor: minimum 100 mg daily or according to local labelling, alfa-glucosidase-inhibitors (acarbose): minimum half of the daily maximal dose or maximum tolerated dose * HbA1c (glycosylated haemoglobin) 7.0-10.0% (both inclusive) by central laboratory analysis * BMI (Body Mass Index) below or equal to 40.0 kg/m\^2
Exclusion criteria
* Treatment with TZDs (thiazoledinedione), or GLP-1 (glucagon-like peptide 1) receptor agonists within the last 3 months prior to Visit 1 (screening) * Anticipated change in concomitant medication known to interfere significantly with glucose metabolism, such as systemic corticosteroids, beta-blockers, MAO (monoamine oxidase) inhibitors * Cardiovascular disease within the last 6 months prior to Visit 1 (screening) defined as stroke; decompensated heart failure NYHA (New York Heart Association) class III or IV; myocardial infarction; unstable angina pectoris; or coronary arterial bypass graft or angioplasty * Any clinically significant disease or disorder, except for conditions associated with type 2 diabetes mellitus, which in the Investigator's opinion could interfere with the results of the trial * Previous participation in this trial. Participation is defined as randomised. Re-screening of screening failures is allowed only once within the limits of the recruitment period * Known or suspected hypersensitivity to trial product(s) or related products
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c (%) (Analysed by Central Laboratory) | Week 0, week 26 | Change from baseline in HbA1c (%) after 26 weeks of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Severe and Minor Treatment Emergent Hypoglycaemic Episodes | On or after the first day of exposure to randomised trial drug (week 0) and no later than 7 days after last exposure to randomised trial drug (week 27) | Confirmed hypoglycaemic episodes consisted of episodes of severe hypoglycaemia as well as minor hypoglycaemic episodes with a confirmed PG value of less than 3.1 mmol/L (56 mg/dL).Minor hypoglycaemic episode is defined as an episode with symptoms consistent with hypoglycaemia with confirmation by full blood glucose \< 2.8 mmol/L (50 mg/dL), or PG \< 3.1 mmol/L (56 mg/dL) and which is handled by the subject himself/herself or any asymptomatic full blood glucose value \< 2.8 mmol/L (50 mg/dL) or PG value \< 3.1 mmol/L (56 mg/dL). |
| Change From Baseline in FPG (Fasting Plasma Glucose) (Analysed by Central Laboratory) | Week 0, week 26 | Change from baseline in FPG after 26 weeks of treatment. |
| Within-subject Variability as Measured by Coefficient of Variation (CV%) in Pre-breakfast SMPG (Self-measured Plasma Glucose) | Week 26 | Within subject Coefficient of variation(CV\[%\]) in pre-breakfast self measured plasma glucose for dose adjustment after 26 treatment weeks are displayed below. |
| Responder for HbA1c (Below 7.0%) at End of Trial Without Severe and Minor Hypoglycaemic Episodes | Week 26 | A responder for HbA1c without severe or confirmed hypoglycaemia is defined as a subject, who meets the HbA1c target at end of trial without treatment emergent severe or confirmed hypoglycaemia during the last 12 weeks of treatment or within 7 days from last treatment. |
| Number of Treatment Emergent AEs (Adverse Events) | On or after the first day of exposure to randomised trial drug (week 0) and no later than seven days after last exposure to randomised trial drug (week 27) | Treatment emergent events (after first trial product administration and no later than 7 days after last trial product administration) |
Countries
Brazil, Canada, China, Romania, South Africa, Ukraine, United States
Participant flow
Recruitment details
The trial was conducted at 68 sites in six countries as follows: Brazil: 3 sites; Canada: 7 sites; China: 37 sites; South Africa: 4 sites; Ukraine: 6 sites; United States: 11 sites.
Pre-assignment details
The subjects discontinued their current Oral Antidiabetic drug (OAD) treatment at Visit 2 (randomisation visit) except for metformin, before starting the treatment with trial drugs.
Participants by arm
| Arm | Count |
|---|---|
| IDeg OD Insulin degludec (IDeg) 10U was injected subcutaneously (under the skin) once daily (OD) in the evening (start of main evening meal to bedtime) either in the thigh, upper arm (deltoid area) or abdomen along with metformin given orally for 26 weeks. At last treatment visit (Visit 28) subjects were instructed to switch basal insulin treatment to the intermediate acting insulin NPH until the follow-up visit (Visit 29). | 555 |
| IGlar OD Insulin glargine (IGlar) 10U was injected subcutaneously (under the skin) once daily (OD) in the evening (start of main evening meal to bedtime) either in the thigh, upper arm (deltoid area) or abdomen along with metformin given orally for 26 weeks. At last treatment visit (Visit 28) subjects were instructed to switch basal insulin treatment to the intermediate acting insulin NPH until the follow-up visit (Visit 29). | 278 |
| Total | 833 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 3 |
| Overall Study | Protocol Violation | 3 | 3 |
| Overall Study | Unclassified | 25 | 18 |
| Overall Study | Withdrawal criteria | 1 | 0 |
Baseline characteristics
| Characteristic | IDeg OD | IGlar OD | Total |
|---|---|---|---|
| Age, Continuous | 55.9 years STANDARD_DEVIATION 9.7 | 56.6 years STANDARD_DEVIATION 9.2 | 56.2 years STANDARD_DEVIATION 9.6 |
| Fasting Plasma Glucose (FPG) | 9.4 mmol/L STANDARD_DEVIATION 2.4 | 9.4 mmol/L STANDARD_DEVIATION 2.5 | 9.4 mmol/L STANDARD_DEVIATION 2.5 |
| HbA1c | 8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.9 | 8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 | 8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 |
| Sex: Female, Male Female | 256 Participants | 146 Participants | 402 Participants |
| Sex: Female, Male Male | 299 Participants | 132 Participants | 431 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 100 / 553 | 58 / 278 |
| serious Total, serious adverse events | 16 / 553 | 10 / 278 |
Outcome results
Primary
Change From Baseline in HbA1c (%) (Analysed by Central Laboratory)
Change from baseline in HbA1c (%) after 26 weeks of treatment.
Time frame: Week 0, week 26
Population: The FAS included all randomised subjects. Last Observation Carried Forward (LOCF) values were presented for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg OD | Change From Baseline in HbA1c (%) (Analysed by Central Laboratory) | -1.3 percentage of glycosylated haemoglobin | Standard Deviation 1.1 |
| IGlar OD | Change From Baseline in HbA1c (%) (Analysed by Central Laboratory) | -1.2 percentage of glycosylated haemoglobin | Standard Deviation 1 |
Secondary
Change From Baseline in FPG (Fasting Plasma Glucose) (Analysed by Central Laboratory)
Change from baseline in FPG after 26 weeks of treatment.
Time frame: Week 0, week 26
Population: The FAS included all randomised subjects. LOCF values are presented for this endpoint. 7 subjects were not included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg OD | Change From Baseline in FPG (Fasting Plasma Glucose) (Analysed by Central Laboratory) | -3.35 mmol/L | Standard Deviation 2.91 |
| IGlar OD | Change From Baseline in FPG (Fasting Plasma Glucose) (Analysed by Central Laboratory) | -3.14 mmol/L | Standard Deviation 2.71 |
Secondary
Number of Severe and Minor Treatment Emergent Hypoglycaemic Episodes
Confirmed hypoglycaemic episodes consisted of episodes of severe hypoglycaemia as well as minor hypoglycaemic episodes with a confirmed PG value of less than 3.1 mmol/L (56 mg/dL).Minor hypoglycaemic episode is defined as an episode with symptoms consistent with hypoglycaemia with confirmation by full blood glucose \< 2.8 mmol/L (50 mg/dL), or PG \< 3.1 mmol/L (56 mg/dL) and which is handled by the subject himself/herself or any asymptomatic full blood glucose value \< 2.8 mmol/L (50 mg/dL) or PG value \< 3.1 mmol/L (56 mg/dL).
Time frame: On or after the first day of exposure to randomised trial drug (week 0) and no later than 7 days after last exposure to randomised trial drug (week 27)
Population: The Safety analysis set (SAS) included all subjects receiving at least one dose of the investigational product or its comparator.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDeg OD | Number of Severe and Minor Treatment Emergent Hypoglycaemic Episodes | 85 Episodes/100 years of patient exposure |
| IGlar OD | Number of Severe and Minor Treatment Emergent Hypoglycaemic Episodes | 97 Episodes/100 years of patient exposure |
Secondary
Number of Treatment Emergent AEs (Adverse Events)
Treatment emergent events (after first trial product administration and no later than 7 days after last trial product administration)
Time frame: On or after the first day of exposure to randomised trial drug (week 0) and no later than seven days after last exposure to randomised trial drug (week 27)
Population: The SAS included all subjects receiving at least one dose of investigational product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDeg OD | Number of Treatment Emergent AEs (Adverse Events) | 612 number of events |
| IGlar OD | Number of Treatment Emergent AEs (Adverse Events) | 387 number of events |
Secondary
Responder for HbA1c (Below 7.0%) at End of Trial Without Severe and Minor Hypoglycaemic Episodes
A responder for HbA1c without severe or confirmed hypoglycaemia is defined as a subject, who meets the HbA1c target at end of trial without treatment emergent severe or confirmed hypoglycaemia during the last 12 weeks of treatment or within 7 days from last treatment.
Time frame: Week 26
Population: The FAS included all randomised subjects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDeg OD | Responder for HbA1c (Below 7.0%) at End of Trial Without Severe and Minor Hypoglycaemic Episodes | 252 participants |
| IGlar OD | Responder for HbA1c (Below 7.0%) at End of Trial Without Severe and Minor Hypoglycaemic Episodes | 114 participants |
Secondary
Within-subject Variability as Measured by Coefficient of Variation (CV%) in Pre-breakfast SMPG (Self-measured Plasma Glucose)
Within subject Coefficient of variation(CV\[%\]) in pre-breakfast self measured plasma glucose for dose adjustment after 26 treatment weeks are displayed below.
Time frame: Week 26
Population: The FAS included all randomised subjects. Missing data were imputed using LOCF. For 2 subjects in the IDeg OD arm it was not possible to estimate CV(%) due to missing data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg OD | Within-subject Variability as Measured by Coefficient of Variation (CV%) in Pre-breakfast SMPG (Self-measured Plasma Glucose) | 10.65 percentage | Standard Deviation 9.15 |
| IGlar OD | Within-subject Variability as Measured by Coefficient of Variation (CV%) in Pre-breakfast SMPG (Self-measured Plasma Glucose) | 10.01 percentage | Standard Deviation 7.95 |