Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted globally. The aim of the trial is to compare efficacy of insulin degludec/insulin aspart (IDegAsp) twice daily (BID) + insulin aspart (IAsp) once daily (OD) versus basal bolus with insulin degludec (IDeg) OD + IAsp three times a day (TID) in controlling glycaemia by evaluating glycosylated haemoglobin (HbA1c). The trial is an extension to trial NN5401-3941 (NCT01680341).
Interventions
DRUGinsulin degludec/insulin aspart
For subcutaneous (s.c., under the skin) administration twice daily in combination with up to 2 oral antidiabetic drugs (OADs- dose and dosing frequency of OAD should remain unchanged).
DRUGinsulin degludec
For subcutaneous (s.c., under the skin) administration once daily in combination with up to 2 oral antidiabetic drugs (OADs- dose and dosing frequency of OAD should remain unchanged).
DRUGinsulin aspart
For subcutaneous (s.c., under the skin) administration once daily. Dose of IDegAsp and IAsp are 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
* HbA1c equal to or above 7.0% measured after 26 weeks of treatment in NN5401-3941 (NCT01680341), by central laboratory
Exclusion criteria
* Uncontrolled or untreated severe hypertension defined as systolic blood pressure equal to or above 180 mmHg and/or diastolic blood pressure equal to or above 100 mmHg * Impaired liver function, defined as alanine aminotransferase (ALAT) or aspartate aminotransferase (ASAT) equal to or above 2.5 times upper limit of normal * Impaired renal function defined as serum-creatinine equal to or above 125 micromol/L (equal to or above 1.4 mg/dL) for males and equal to or above 110 micromol/L (equal to or above 1.3 mg/dL) for females
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c (Glycosylated Haemoglobin) | Week 0, week 26 | Change from baseline in HbA1c after 26 weeks of treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment Emergent Adverse Events (TEAEs) | During 26 weeks of treatment | A treatment emergent adverse event was defined as an event that had onset date on or after the first day of trial product administration, and no later than 7 days after the last dose of the trial product. |
| Number of Treatment Emergent Hypoglycaemic Episodes | During 26 weeks of treatment | Confirmed hypoglycaemic episodes were defined as episodes that are either: * severe (i.e., an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions) or * biochemically confirmed by a PG value of \<3.1 mmol/L (56 mg/dL), with or without symptoms consistent with hypoglycaemia. |
| Number of Treatment Emergent Nocturnal (00:01-05:59) Confirmed Hypoglycaemic Episodes | During 26 weeks of treatment | Hypoglycaemic episodes were defined as nocturnal if the time of onset was between 00:01 and 05:59 hours inclusive. Confirmed hypoglycaemic episodes were defined as severe hypoglycaemic episodes and/or a measured PG below 3.1 mmol/L (below 56 mg/dL). |
| Change From Baseline in Fasting Plasma Glucose (FPG) | Week 0, week 26 | Change from baseline in FPG after 26 weeks of treatment. FPG was analysed on blood samples from fasting subjects which were analysed centrally. |
Countries
Algeria, Germany, Malaysia, Turkey (Türkiye), United States
Participant flow
Recruitment details
The trial was conducted at 20 sites in 4 countries as follows: Germany: 1 site; Malaysia: 2 sites; Turkey: 1 site; United States: 16 sites. The subjects in this trial were to continue from trial NN5401-3941 (NCT01680341).
Pre-assignment details
Subjects who did not reach the HbA1c target \< 7.0% on IDegAsp BID after 26 weeks of treatment in trial NN5401-3941 were enrolled in this trial.
Participants by arm
| Arm | Count |
|---|---|
| IDegAsp BID + IAsp OD Subjects randomised to insulin degludec/insulin aspart (IDegAsp) twice daily (BID) + insulin aspart (IAsp) once daily (OD) , at the discretion of the investigator, started the doses of IDegAsp at week 26 in trial NN5401-3941 with breakfast and main evening meal and added 4 units of IAsp at lunch. IDegAsp was administered subcutaneously (s.c.) by injection in the thigh, the upper arm (deltoid area) or the abdominal wall. The chosen area of injection had to be the same throughout the trial, with rotation within a given region recommended. IAsp was injected s.c. with the main meal OD, preferably into the abdominal wall in accordance with local labelling. Additional doses of IAsp were only allowed, if needed due to intercurrent illness. Titration (self-titration) of both IDegAsp and IAsp was done once weekly. Titration of IAsp could also be done based on carbohydrate counting but at the investigator's discretion. IAsp dose reduction had to be done based on the investigator's discretion. | 20 |
| IDeg OD + IAsp TID Subjects randomised to insulin degludec (IDeg) OD + IAsp thrice daily (TID) were, at the discretion of the investigator, to start with 70% of the total daily dose of IDegAsp taken at Week 26 in trial NN5401-3941 as IDeg OD and 30% as IAsp divided into 3 doses. IDeg was administered s.c. by injection in the thigh, the upper arm (deltoid area) or the abdominal wall and the chosen area of injection had to be the same throughout the trial. Rotation of injection sites within a given region was recommended. The OD injection time could be changed from day to day. IAsp was injected s.c. with the main meals TID, preferably into the abdominal wall in accordance with local labelling. Additional doses of IAsp were only allowed, if needed. Titration (self-titration) of IDeg and IAsp was performed once weekly. Titration of IAsp could also be done based on carbohydrate counting but at the investigator's discretion. IAsp dose reduction had to be done based on the investigator's discretion. | 20 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Unclassified | 2 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | IDegAsp BID + IAsp OD | IDeg OD + IAsp TID | Total |
|---|---|---|---|
| Age, Continuous | 58.0 years STANDARD_DEVIATION 8 | 56.9 years STANDARD_DEVIATION 8.1 | 57.5 years STANDARD_DEVIATION 8 |
| Fasting plasma glucose (FPG) | 7.3 mmol/L STANDARD_DEVIATION 3.5 | 8.6 mmol/L STANDARD_DEVIATION 2.8 | 7.9 mmol/L STANDARD_DEVIATION 3.2 |
| Glycosylated haemoglobin (HbA1c) | 7.9 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.7 | 7.7 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.6 | 7.8 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.7 |
| Sex: Female, Male Female | 5 Participants | 9 Participants | 14 Participants |
| Sex: Female, Male Male | 15 Participants | 11 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 20 | 15 / 20 |
| serious Total, serious adverse events | 2 / 20 | 2 / 20 |
Outcome results
Primary
Change From Baseline in HbA1c (Glycosylated Haemoglobin)
Change from baseline in HbA1c after 26 weeks of treatment
Time frame: Week 0, week 26
Population: The FAS included all randomised subjects and missing data was imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| IDegAsp BID + IAsp OD | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | 0.05 percentage of glycosylated haemoglobin | Standard Error 0.2 |
| IDeg OD + IAsp TID | Change From Baseline in HbA1c (Glycosylated Haemoglobin) | -0.49 percentage of glycosylated haemoglobin | Standard Error 0.19 |
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG)
Change from baseline in FPG after 26 weeks of treatment. FPG was analysed on blood samples from fasting subjects which were analysed centrally.
Time frame: Week 0, week 26
Population: The FAS included all randomised subjects and missing data was imputed using LOCF. One subject in each arm did not have FPG values from week 0.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDegAsp BID + IAsp OD | Change From Baseline in Fasting Plasma Glucose (FPG) | -0.80 mmol/L | Standard Deviation 3.59 |
| IDeg OD + IAsp TID | Change From Baseline in Fasting Plasma Glucose (FPG) | -2.57 mmol/L | Standard Deviation 2.73 |
Secondary
Incidence of Treatment Emergent Adverse Events (TEAEs)
A treatment emergent adverse event was defined as an event that had onset date on or after the first day of trial product administration, and no later than 7 days after the last dose of the trial product.
Time frame: During 26 weeks of treatment
Population: Safety analysis set (SAS) included all subjects receiving at least one dose of the investigational product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDegAsp BID + IAsp OD | Incidence of Treatment Emergent Adverse Events (TEAEs) | 33 number of events |
| IDeg OD + IAsp TID | Incidence of Treatment Emergent Adverse Events (TEAEs) | 45 number of events |
Secondary
Number of Treatment Emergent Hypoglycaemic Episodes
Confirmed hypoglycaemic episodes were defined as episodes that are either: * severe (i.e., an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions) or * biochemically confirmed by a PG value of \<3.1 mmol/L (56 mg/dL), with or without symptoms consistent with hypoglycaemia.
Time frame: During 26 weeks of treatment
Population: The SAS included all subjects receiving at least one dose of the investigational product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDegAsp BID + IAsp OD | Number of Treatment Emergent Hypoglycaemic Episodes | 54 episodes |
| IDeg OD + IAsp TID | Number of Treatment Emergent Hypoglycaemic Episodes | 95 episodes |
Secondary
Number of Treatment Emergent Nocturnal (00:01-05:59) Confirmed Hypoglycaemic Episodes
Hypoglycaemic episodes were defined as nocturnal if the time of onset was between 00:01 and 05:59 hours inclusive. Confirmed hypoglycaemic episodes were defined as severe hypoglycaemic episodes and/or a measured PG below 3.1 mmol/L (below 56 mg/dL).
Time frame: During 26 weeks of treatment
Population: The SAS included all subjects receiving at least one dose of the investigational product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDegAsp BID + IAsp OD | Number of Treatment Emergent Nocturnal (00:01-05:59) Confirmed Hypoglycaemic Episodes | 13 episodes |
| IDeg OD + IAsp TID | Number of Treatment Emergent Nocturnal (00:01-05:59) Confirmed Hypoglycaemic Episodes | 12 episodes |