Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Asia and North America. The aim of this trial is to compare the efficacy and safety of insulin degludec/insulin aspart (IDegAsp) once daily in insulin-naïve subjects with type 2 diabetes mellitus when using two different titration algorithms (dose individually adjusted) as add-on to subject's ongoing treatment with metformin.
Interventions
DRUGinsulin degludec/insulin aspart
Insulin degludec/insulin aspart injected subcutaneously (under the skin) once daily. Dose individually adjusted.
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 (diagnosed clinically) for 24 weeks or longer prior to randomisation (visit 2) * Insulin naïve subjects (Allowed are: Previous short term insulin treatment no longer than or equal to 14 days in total; Treatment during hospitalisation or during gestational diabetes is allowed for periods longer than 14 days in total) * Current treatment: Metformin alone or metformin in any combination of 1 or 2 additional OADs (oral anti-diabetic drug) including an insulin secretagogue (sulfonylurea or glinide), dipeptidyl peptidase IV (DPP-IV) inhibitors, alpha-glucosidase inhibitors or thiazolidinediones (TZDs) - all with unchanged dosing for at least 12 weeks prior to randomisation (visit 2). Metformin dose, alone or in combination (including fixed combination), must be at least 1000 mg daily * HbA1c (glycosylated haemoglobin) 7.0-10.0% (both inclusive) * BMI (Body Mass Index) below or equal to 45 kg/m\^2 * Ability and willingness to adhere to the protocol including self measurement of plasma glucose
Exclusion criteria
* Treatment with GLP-1 (glucagon like peptide) receptor agonists within the last 12 weeks prior to randomisation (visit 2) * Recurrent severe hypoglycaemia (more than one severe hypoglycaemic event during the last 12 months) or hypoglycaemic unawareness as judged by the Investigator (trial physician) * Previous participation in this trial. Participation is defined as randomised. Re-screening is allowed once during the recruitment period * Known or suspected hypersensitivity to trial products or related products * The receipt of any investigational drug within 4 weeks prior to randomisation (visit 2) * Anticipated significant lifestyle changes during the study, e.g. shift work (including permanent night/evening shift workers) as well as highly variable eating habits
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glycosylated Haemoglobin (HbA1c) | Week 0, week 26 | Change from baseline in HbA1c after 26 weeks of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fasting Plasma Glucose (FPG) | Week 0, week 26 | Change from baseline in FPG after 26 weeks of treatment. |
| Rate of Treatment Emergent Adverse Events (AEs) | Week 0 to Week 26 + 7 days follow up | Corresponds to rate of AEs per 100 patient years of exposure. Severity assessed by investigator. Mild: no or transient symptoms, no interference with subject's daily activities. Moderate: marked symptoms, moderate interference with subject's daily activities. Severe: considerable interference with subject's daily activities, unacceptable. Serious AE: AE that at any dose results in any of the following: death, a life-threatening experience, in-subject hospitalization/prolongation of existing hospitalisation, persistent/significant disability/incapacity/congenital anomaly/birth defect. |
| Rate of Confirmed Hypoglycaemic Episodes | Week 0 to Week 26 + 7 days follow up | Rate of confirmed hypoglycaemic episodes per 100 patient years of exposure (PYE). Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia as well as minor hypoglycaemic episodes. Severe hypoglycaemic episodes were defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes were defined as able to treat her/himself and plasma glucose below 3.1 mmol/L. |
| Rate of Nocturnal Confirmed Hypoglycaemic Episodes | Week 0 to Week 26 + 7 days follow up | Rate of nocturnal confirmed hypoglycaemic episodes per 100 patient years of exposure (PYE). Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia as well as minor hypoglycaemic episodes. Severe hypoglycaemic episodes were defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes were defined as able to treat her/himself and plasma glucose below 3.1 mmol/L. Nocturnal hypoglycaemic episodes were defined as occurring between 00:01 and 05:59 a.m. |
Countries
Malaysia, Mexico, Puerto Rico, South Korea, Thailand, Turkey (Türkiye), United States
Participant flow
Recruitment details
This trial was conducted at 38 sites in 6 countries: Malaysia, Mexico, South Korea, Thailand, Turkey and the United States (U.S.).
Pre-assignment details
Subjects continued their metformin monotherapy or metformin in any combination with 1 or 2 additional oral antidiabetic drugs including an insulin secretagogue (sulfonylurea or glinide), dipeptidyl peptidase IV inhibitors, α-glucosidase inhibitors, thiazolidinediones, all with unchanged dosing for at least 12 weeks prior to randomisation.
Participants by arm
| Arm | Count |
|---|---|
| IDegAsp Simple Insulin degludec/insulin aspart (IDegAsp) was given once daily (OD) subcutaneously (3-4 days intervals between doses) with pre-trial metformin according to simple titration algorithm: self-titration was performed twice weekly based on pre-breakfast self-measured plasma glucose (SMPG) value measured on the day of insulin titration. | 136 |
| IDegAsp Step Wise Insulin degludec/insulin aspart (IDegAsp) was given once daily (OD) subcutaneously (at least 5 days intervals between doses) with pre-trial metformin according to step wise titration algorithm: self-titration was performed once weekly based on the lowest value of three pre-breakfast SMPG values measured on three consecutive days, the two days prior to and on the day of insulin titration. | 140 |
| Total | 276 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Unclassified | 1 | 4 |
| Overall Study | Withdrawal Criteria | 8 | 5 |
Baseline characteristics
| Characteristic | Total | IDegAsp Simple | IDegAsp Step Wise |
|---|---|---|---|
| Age, Continuous | 56.4 years STANDARD_DEVIATION 9.5 | 57.0 years STANDARD_DEVIATION 9.4 | 55.8 years STANDARD_DEVIATION 9.7 |
| Fasting plasma glucose (FPG) | 8.9 mmol/L STANDARD_DEVIATION 2.4 | 8.9 mmol/L STANDARD_DEVIATION 2.4 | 9.0 mmol/L STANDARD_DEVIATION 2.3 |
| Glycosylated haemoglobin (HbA1c) | 8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 | 8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 | 8.2 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.8 |
| Sex: Female, Male Female | 143 Participants | 59 Participants | 84 Participants |
| Sex: Female, Male Male | 133 Participants | 77 Participants | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 20 / 134 | 26 / 140 |
| serious Total, serious adverse events | 1 / 134 | 6 / 140 |
Outcome results
Primary
Change in Glycosylated Haemoglobin (HbA1c)
Change from baseline in HbA1c after 26 weeks of treatment.
Time frame: Week 0, week 26
Population: The full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDegAsp Simple | Change in Glycosylated Haemoglobin (HbA1c) | -1.33 percentage of glycosylated haemoglobin | Standard Deviation 1.03 |
| IDegAsp Step Wise | Change in Glycosylated Haemoglobin (HbA1c) | -1.09 percentage of glycosylated haemoglobin | Standard Deviation 0.82 |
Secondary
Change in Fasting Plasma Glucose (FPG)
Change from baseline in FPG after 26 weeks of treatment.
Time frame: Week 0, week 26
Population: The full analysis set (FAS) included all randomised subjects and missing data were imputed using last observation carried forward (LOCF). For 2 subjects baseline values were missing, hence not included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDegAsp Simple | Change in Fasting Plasma Glucose (FPG) | -2.99 mmol/L | Standard Deviation 3.03 |
| IDegAsp Step Wise | Change in Fasting Plasma Glucose (FPG) | -2.73 mmol/L | Standard Deviation 2.91 |
Secondary
Rate of Confirmed Hypoglycaemic Episodes
Rate of confirmed hypoglycaemic episodes per 100 patient years of exposure (PYE). Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia as well as minor hypoglycaemic episodes. Severe hypoglycaemic episodes were defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes were defined as able to treat her/himself and plasma glucose below 3.1 mmol/L.
Time frame: Week 0 to Week 26 + 7 days follow up
Population: The safety analysis set included all subjects who received at least one dose of the investigational product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDegAsp Simple | Rate of Confirmed Hypoglycaemic Episodes | 326 Episodes/100 years of patient exposure |
| IDegAsp Step Wise | Rate of Confirmed Hypoglycaemic Episodes | 207 Episodes/100 years of patient exposure |
Secondary
Rate of Nocturnal Confirmed Hypoglycaemic Episodes
Rate of nocturnal confirmed hypoglycaemic episodes per 100 patient years of exposure (PYE). Confirmed hypoglycaemic episodes consisted of severe hypoglycaemia as well as minor hypoglycaemic episodes. Severe hypoglycaemic episodes were defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes were defined as able to treat her/himself and plasma glucose below 3.1 mmol/L. Nocturnal hypoglycaemic episodes were defined as occurring between 00:01 and 05:59 a.m.
Time frame: Week 0 to Week 26 + 7 days follow up
Population: The safety analysis set included all subjects who received at least one dose of the investigational product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDegAsp Simple | Rate of Nocturnal Confirmed Hypoglycaemic Episodes | 52 Episodes/100 years of patient exposure |
| IDegAsp Step Wise | Rate of Nocturnal Confirmed Hypoglycaemic Episodes | 41 Episodes/100 years of patient exposure |
Secondary
Rate of Treatment Emergent Adverse Events (AEs)
Corresponds to rate of AEs per 100 patient years of exposure. Severity assessed by investigator. Mild: no or transient symptoms, no interference with subject's daily activities. Moderate: marked symptoms, moderate interference with subject's daily activities. Severe: considerable interference with subject's daily activities, unacceptable. Serious AE: AE that at any dose results in any of the following: death, a life-threatening experience, in-subject hospitalization/prolongation of existing hospitalisation, persistent/significant disability/incapacity/congenital anomaly/birth defect.
Time frame: Week 0 to Week 26 + 7 days follow up
Population: The safety analysis set included all subjects who received at least one dose of the investigational product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IDegAsp Simple | Rate of Treatment Emergent Adverse Events (AEs) | Adverse events (AEs) | 226 Events/100 years of patient exposure |
| IDegAsp Simple | Rate of Treatment Emergent Adverse Events (AEs) | Serious AEs | 2 Events/100 years of patient exposure |
| IDegAsp Simple | Rate of Treatment Emergent Adverse Events (AEs) | Severe AEs | 3 Events/100 years of patient exposure |
| IDegAsp Simple | Rate of Treatment Emergent Adverse Events (AEs) | Moderate AEs | 68 Events/100 years of patient exposure |
| IDegAsp Simple | Rate of Treatment Emergent Adverse Events (AEs) | Mild AEs | 155 Events/100 years of patient exposure |
| IDegAsp Simple | Rate of Treatment Emergent Adverse Events (AEs) | Fatal AEs | 0 Events/100 years of patient exposure |
| IDegAsp Step Wise | Rate of Treatment Emergent Adverse Events (AEs) | Mild AEs | 228 Events/100 years of patient exposure |
| IDegAsp Step Wise | Rate of Treatment Emergent Adverse Events (AEs) | Adverse events (AEs) | 342 Events/100 years of patient exposure |
| IDegAsp Step Wise | Rate of Treatment Emergent Adverse Events (AEs) | Moderate AEs | 112 Events/100 years of patient exposure |
| IDegAsp Step Wise | Rate of Treatment Emergent Adverse Events (AEs) | Serious AEs | 13 Events/100 years of patient exposure |
| IDegAsp Step Wise | Rate of Treatment Emergent Adverse Events (AEs) | Fatal AEs | 0 Events/100 years of patient exposure |
| IDegAsp Step Wise | Rate of Treatment Emergent Adverse Events (AEs) | Severe AEs | 3 Events/100 years of patient exposure |