Diabetes, Diabetes Mellitus, Type 1
Conditions
Brief summary
This trial is conducted in Europe and in the United States of America (USA). The aim of this trial is to investigate the efficacy and safety of NN1250 (insulin degludec) in subjects with type 1 diabetes.
Interventions
DRUGinsulin degludec
Injected subcutaneously (under the skin) once daily
DRUGinsulin glargine
Insulin glargine injected subcutaneously (under the skin) once daily
DRUGinsulin aspart
At least three daily doses at meal-time
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 1 diabetes for 12 months or longer, hereof the last 3 months with injection based therapies * Current treatment with any basal insulin (e.g. insulin glargine, insulin detemir, NPH insulin) using one or two daily injections and with three or more daily meal-time insulin injections (e.g. insulin aspart, insulin lispro, insulin glulisine, human insulin) used as bolus insulin therapy * HbA1c maximum 10.0 % by central laboratory analysis * Body Mass Index (BMI) below or equal to 35.0 kg/m\^2 * Ability to self-manage insulin therapy as assessed by confirmation (verbal confirmation at screening visit) of a changed insulin dose in the preceding two months prior to screening * Ability and willingness to adhere to the protocol including performance of self measured plasma glucose (SMPG) profiles and self adjustment of insulin doses
Exclusion criteria
* Use within the last 3 months prior to Visit 1 of any antidiabetic glucose lowering drug other than insulin * Cardiovascular disease, within the last 6 months prior to visit 1, defined as: stroke; decompensated heart failure New York Heart Association (NYHA) class III or IV; myocardial infarction; unstable angina pectoris; or coronary arterial bypass graft or angioplasty * Uncontrolled treated/ untreated severe hypertension (systolic blood pressure above or equal to 180 millimetre (mm) mercury (Hg) and/or diastolic blood pressure above or equal to 100 mmHg) * Pregnancy, breast-feeding, the intention of becoming pregnant or not using adequate contraceptive measures according to local requirements * Cancer and medical history of cancer (except basal cell skin cancer or squamous cell skin cancer)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Main Trial (Primary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 26 Weeks of Treatment | Week 0, Week 26 | Change from baseline in HbA1c after 26 weeks of treatment |
| Extension Trial (Primary Endpoint): Rate of Confirmed Hypoglycaemic Episodes | Week 0 to Week 52 + 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 are defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes are defined as able to treat her/himself and plasma glucose below 3.1 mmol/L. |
| Extension Trial (Primary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes | Week 0 to Week 52 + 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 are defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes are defined as able to treat her/himself and plasma glucose below 3.1 mmol/L. Nocturnal hypoglycaemic episodes are defined as occurring between 00:01 and 05:59 a.m. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Extension Trial (Secondary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 52 Weeks of Treatment | Week 0, Week 52 | Change from baseline in HbA1c after 52 weeks of treatment. |
| Main Trial (Secondary Endpoint): Change in Fasting Plasma Glucose (FPG) After 26 Weeks of Treatment | Week 0, Week 26 | Change from baseline in FPG after 26 weeks of treatment |
| Extension Trial (Secondary Endpoint): Change in Fasting Plasma Glucose (FPG) After 52 Weeks of Treatment | Week 0, Week 52 | Change from baseline in FPG after 52 weeks of treatment. |
Countries
Belgium, Germany, Greece, Norway, Poland, United Kingdom, United States
Participant flow
Recruitment details
The main/extension trial periods were conducted at 71/68 sites in 6 countries: Belgium (5/5 sites), Germany (7/7 sites), Norway (5/5 sites), Poland (5/5 sites), United Kingdom (UK) (12/11 sites), and United States of America (U.S.) (37/35 sites). 57 patients did not participate in the extension trial.
Pre-assignment details
All subjects who completed the 26-week main trial and were found to be eligible for the extension trial were offered to participate in the 26-week extension trial (NCT01079234). Total duration of trial was up to 52 weeks (26 weeks+ 26 weeks) with two times 7-12 day follow-up periods.
Participants by arm
| Arm | Count |
|---|---|
| IDeg OD FF Insulin degludec (IDeg) was given once daily (OD) subcutaneously (s.c.) with alternating morning and evening dosing according to a fixed flexible (FF) schedule (approximately 8-40 hours intervals) in combination with insulin aspart (IAsp) for 26 weeks in main period. Insulin doses were individually adjusted by the subjects. | 164 |
| IDeg OD Insulin degludec (IDeg) was given once daily (OD) subcutaneously (s.c.) with the evening meal in combination with insulin aspart (IAsp) for 26 weeks in main period. Insulin doses were individually adjusted by the subjects. | 165 |
| IGlar OD Insulin glargine (IGlar) was given once daily (OD) subcutaneously (s.c.) according to local labelling in combination with insulin aspart (IAsp) for 52 weeks (26 weeks in main period + 26 weeks in extension period). Insulin doses were individually adjusted by the subjects. | 164 |
| Total | 493 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Extension: Week 27 to 52 | Adverse Event | 0 | 0 | 1 | 0 |
| Extension: Week 27 to 52 | Lack of Efficacy | 0 | 0 | 0 | 2 |
| Extension: Week 27 to 52 | Protocol Violation | 0 | 0 | 2 | 5 |
| Extension: Week 27 to 52 | Unclassified | 0 | 0 | 4 | 7 |
| Extension: Week 27 to 52 | Withdrawal criteria | 0 | 0 | 4 | 2 |
| Main: Week 0 to 26 | Adverse Event | 5 | 4 | 1 | 0 |
| Main: Week 0 to 26 | Lack of Efficacy | 2 | 1 | 1 | 0 |
| Main: Week 0 to 26 | Protocol Violation | 6 | 2 | 4 | 0 |
| Main: Week 0 to 26 | Unclassified | 7 | 13 | 4 | 0 |
| Main: Week 0 to 26 | Withdrawal criteria | 6 | 6 | 2 | 0 |
Baseline characteristics
| Characteristic | IDeg OD FF | IDeg OD | IGlar OD | Total |
|---|---|---|---|---|
| Age, Continuous | 42.6 years STANDARD_DEVIATION 13.4 | 44.5 years STANDARD_DEVIATION 13.1 | 44.1 years STANDARD_DEVIATION 12.6 | 43.7 years STANDARD_DEVIATION 13.1 |
| Fasting plasma glucose (FPG) | 9.6 mmol/L STANDARD_DEVIATION 4.1 | 10.0 mmol/L STANDARD_DEVIATION 4 | 9.7 mmol/L STANDARD_DEVIATION 4.2 | 9.8 mmol/L STANDARD_DEVIATION 4.1 |
| Gender Female | 62 Participants | 71 Participants | 76 Participants | 209 Participants |
| Gender Male | 102 Participants | 94 Participants | 88 Participants | 284 Participants |
| HbA1c (glycosylated haemoglobin) | 7.7 percentage of glycosylated haemoglobin STANDARD_DEVIATION 1 | 7.7 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.9 | 7.7 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.9 | 7.7 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.9 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 187 / 329 | 105 / 161 |
| serious Total, serious adverse events | 25 / 329 | 12 / 161 |
Outcome results
Primary
Extension Trial (Primary Endpoint): 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 are defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes are defined as able to treat her/himself and plasma glucose below 3.1 mmol/L.
Time frame: Week 0 to Week 52 + 7 days follow up
Population: Safety analysis set includes all subjects who received at least one dose of the investigational product or its comparator. The subjects randomised to 2 IDeg arms during the main trial were pooled into the IDeg OD F in extension trial.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDeg OD FF | Extension Trial (Primary Endpoint): Rate of Confirmed Hypoglycaemic Episodes | 6341 Episodes/100 years of patient exposure |
| IDeg OD | Extension Trial (Primary Endpoint): Rate of Confirmed Hypoglycaemic Episodes | 6811 Episodes/100 years of patient exposure |
Primary
Extension Trial (Primary Endpoint): Rate of Nocturnal 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 are defined as requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes are defined as able to treat her/himself and plasma glucose below 3.1 mmol/L. Nocturnal hypoglycaemic episodes are defined as occurring between 00:01 and 05:59 a.m.
Time frame: Week 0 to Week 52 + 7 days follow up
Population: Safety analysis set includes all subjects who received at least one dose of the investigational product or its comparator.The subjects randomised to 2 IDeg arms during the main trial were pooled into the IDeg OD F in extension trial.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDeg OD FF | Extension Trial (Primary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes | 848 Episodes/100 years of patient exposure |
| IDeg OD | Extension Trial (Primary Endpoint): Rate of Nocturnal Confirmed Hypoglycaemic Episodes | 640 Episodes/100 years of patient exposure |
Primary
Main Trial (Primary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 26 Weeks of Treatment
Change from baseline in HbA1c after 26 weeks of treatment
Time frame: Week 0, Week 26
Population: Full analysis set (FAS) includes all randomised subjects and missing data is imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg OD FF | Main Trial (Primary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 26 Weeks of Treatment | -0.40 percentage of glycosylated haemoglobin | Standard Deviation 0.59 |
| IDeg OD | Main Trial (Primary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 26 Weeks of Treatment | -0.41 percentage of glycosylated haemoglobin | Standard Deviation 0.71 |
| IGlar OD | Main Trial (Primary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 26 Weeks of Treatment | -0.58 percentage of glycosylated haemoglobin | Standard Deviation 0.72 |
Secondary
Extension Trial (Secondary Endpoint): Change in Fasting Plasma Glucose (FPG) After 52 Weeks of Treatment
Change from baseline in FPG after 52 weeks of treatment.
Time frame: Week 0, Week 52
Population: Full analysis set (FAS) includes all randomised subjects and missing data is imputed using last observation carried forward (LOCF). FPG baseline values were missing for 6 subjects. The subjects randomised to 2 IDeg arms during the main trial were pooled into the IDeg OD F in extension trial.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg OD FF | Extension Trial (Secondary Endpoint): Change in Fasting Plasma Glucose (FPG) After 52 Weeks of Treatment | -0.61 mmol/L | Standard Deviation 5.23 |
| IDeg OD | Extension Trial (Secondary Endpoint): Change in Fasting Plasma Glucose (FPG) After 52 Weeks of Treatment | -1.73 mmol/L | Standard Deviation 5.32 |
Secondary
Extension Trial (Secondary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 52 Weeks of Treatment
Change from baseline in HbA1c after 52 weeks of treatment.
Time frame: Week 0, Week 52
Population: Full analysis set (FAS) includes all randomised subjects and missing data is imputed using last observation carried forward (LOCF). The subjects randomised to 2 IDeg arms during the main trial were pooled into the IDeg OD F in extension trial.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg OD FF | Extension Trial (Secondary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 52 Weeks of Treatment | -0.21 percentage of glycosylated haemoglobin | Standard Deviation 0.73 |
| IDeg OD | Extension Trial (Secondary Endpoint): Change in Glycosylated Haemoglobin (HbA1c) After 52 Weeks of Treatment | -0.13 percentage of glycosylated haemoglobin | Standard Deviation 0.67 |
Secondary
Main Trial (Secondary Endpoint): Change in Fasting Plasma Glucose (FPG) After 26 Weeks of Treatment
Change from baseline in FPG after 26 weeks of treatment
Time frame: Week 0, Week 26
Population: Full analysis set (FAS) includes all randomised subjects and missing data is imputed using last observation carried forward (LOCF). For 6 subjects baseline values were missing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg OD FF | Main Trial (Secondary Endpoint): Change in Fasting Plasma Glucose (FPG) After 26 Weeks of Treatment | -1.28 mmol/L | Standard Deviation 5.03 |
| IDeg OD | Main Trial (Secondary Endpoint): Change in Fasting Plasma Glucose (FPG) After 26 Weeks of Treatment | -2.54 mmol/L | Standard Deviation 5.11 |
| IGlar OD | Main Trial (Secondary Endpoint): Change in Fasting Plasma Glucose (FPG) After 26 Weeks of Treatment | -1.33 mmol/L | Standard Deviation 5.21 |