Diabetes, Diabetes Mellitus, Type 1
Conditions
Brief summary
This trial is conducted in Africa, Asia, Europe and the United States of America (USA). The aim of this trial is to investigate the efficacy and safety of insulin degludec in children and adolescents with type 1 diabetes mellitus.
Interventions
DRUGinsulin degludec
Injected subcutaneously (under the skin) once daily. Dose individually adjusted.
DRUGinsulin detemir
Injected subcutaneously (under the skin) once or twice daily. Dose individually adjusted.
DRUGinsulin aspart
Injected subcutaneously (under the skin) as mealtime bolus insulin. 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
1 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Informed consent, and child assent as age-appropriate, obtained before any trial-related activities (Trial-related activities are any procedure that would not have been performed during normal management of the subject). The parents or legal representative of the child must sign and date the Informed Consent Form according to local requirements. The child, if possible, parents or legal representative of the child must sign and date the Child Assent Form according to local requirements * Male or female diagnosed with type 1 diabetes mellitus (T1DM) (based on clinical judgement and supported by laboratory analysis as per local guidelines) * Ongoing daily treatment with insulin (any regimen) for at least 3 months prior to Visit 1 (screening). No OADs (oral anti-diabetic drugs) are allowed * HbA1c (glycosylated haemoglobin) maximum 11%
Exclusion criteria
* Known or suspected hypersensitivity to trial product(s) or related products * Previous participation in this trial. Participation is defined as randomisation * Girls who are pregnant, breastfeeding or intend to become pregnant * Girls who have had menarche and are not using adequate contraceptive measures according to local requirements * Known hypoglycaemic unawareness or recurrent severe hypoglycaemic events as judged by the Investigator (trial physician) * More than 1 diabetic ketoacidosis requiring hospitalisation within the last 3 months prior to Visit 1 * Significant concomitant disease, except for conditions associated with type 1 diabetes mellitus, which in the Investigator's opinion could interfere with the trial * The receipt of any investigational drug within 1 month prior to Visit 1
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c (Glycosylated Haemoglobin) (%) at 26 Weeks (Analysed by Central Laboratory) | Week 0, week 26 | Change from baseline in HbA1c (%) after 26 weeks of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Blood Glucose (FPG) at 26 Weeks (Analysed by Central Laboratory) | Week 0, week 26 | Change from baseline in FPG after 26 weeks of treatment. |
| Change From Baseline in Fasting Blood Glucose (FPG) at 52 Weeks (Analysed by Central Laboratory) | Week 0, week 52 | Change from baseline in FPG after 52 weeks of treatment. |
| Number of Treatment Emergent Adverse Events (TEAEs) | After 26 weeks and 52 weeks of treatment | TEAE is defined as an event that has onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment. |
| Number of Hypoglycaemic Episodes | After 26 weeks and 52 weeks of treatment | Number of hypoglycaemic episodes (severe episodes or episodes with plasma glucose (PG) below or equal to 3.9 mmol/L (70 mg/dL) with or without symptoms of hypoglycaemia) during the trial; nocturnal \[11 p.m. - 7 a.m./23:00 - 07:00\] and over the entire day (24 hours) |
| Change From Baseline in HbA1c (%) at 52 Weeks (Analysed by Central Laboratory) | Week 0, week 52 | Change from baseline in HbA1c (%) after 52 weeks of treatments. |
| Number of Episodes With Self Monitored Blood Ketones Above 1.5 mmol (Capillary Blood Ketone Measurement to be Performed if Self-measured Plasma Glucose (SMPG) Exceeds 14.0 mmol/l (250 mg/dL)) | After 26 weeks and 52 weeks of treatment | Blood ketones \> 1.5mmol/L (Capillary blood ketone measurement to be performed if SMPG exceeds 14.0mmol/L (250mg/dL) )after 26 and 52 weeks of treatment |
| Steady-state Plasma Concentrations of Insulin Degludec and Insulin Detemir on Three Different Visits (Three Different Weeks) During the First 26 Weeks of Treatment | Between week 1 and week 26 | Steady state plasma concentrations of insulin degludec and insulin detemir on three different visits (three different weeks) during the trial. |
| Insulin Antibodies (Insulin Degludec Specific, Insulin Detemir Specific, Insulin Aspart Specific and Antibodies Cross-reacting to Human Insulin) | After 52 weeks of treatment | Antibody measurements : the values presented are week 52 (LOCF). The measurement of insulin antibodies after 26 and 52 weeks of treatment was done to fulfil the requirement of monitoring the long term immunogenicity. The unit of measure is percentage bound/total (%B/T) for these antibodies. The Antibodies cross reacting to Human Insulin is abbreviated as X-reacting AB Hu Insulin below) |
| Number of Self-measured Hyperglycaemia (Episodes of PG Above 11.1 mmol/L (200 mg/dL)) | After 26 weeks and 52 weeks of treatment | Episodes of PG \>11.1mmol/L (200mg/dL) |
Countries
Bulgaria, Finland, France, Germany, Italy, Japan, Netherlands, North Macedonia, Russia, South Africa, United Kingdom, United States
Participant flow
Recruitment details
The trial was conducted at 72 sites in 12 countries as follows: Bulgaria (2), Finland (5), France (4), Germany (3), Italy (2), Japan (15), Netherlands (5), Republic of Macedonia (2), Russian Federation (6), South Africa (2), United Kingdom (4), United States (22)
Participants by arm
| Arm | Count |
|---|---|
| IDeg + IAsp Subjects from 1 to 18 years of age were randomised into treatment arms, IDeg OD as basal insulin and IAsp as mealtime bolus insulin for a period of 26 weeks followed by extension trial for a period of 26 weeks. IDeg was given once a day at approximately the same time of the day. Basal and bolus insulin titration was done according to the lowest pre-breakfast SMPG value measured on the three days prior to the visit/ phone contact for IDeg. | 174 |
| IDet + IAsp Subjects from 1 to 18 years of age were randomised into treatment arms, IDet OD as basal insulin and IAsp as mealtime bolus insulin for a period of 26 weeks followed by extension trial for a period of 26 weeks. IDet was given once a day at approximately the same time of the day. Basal and bolus insulin titration was done according to the lowest pre-breakfast SMPG value measured on the three days prior to the visit/ phone contact for IDet. | 176 |
| Total | 350 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Extension Trial (26 Weeks) | Adverse Event | 0 | 1 |
| Extension Trial (26 Weeks) | Withdrawal by Subject | 1 | 5 |
| Main Trial (26 Weeks) | Adverse Event | 0 | 2 |
| Main Trial (26 Weeks) | Unclassified | 0 | 2 |
| Main Trial (26 Weeks) | Withdrawal by Subject | 4 | 7 |
Baseline characteristics
| Characteristic | IDeg + IAsp | IDet + IAsp | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 174 Participants | 176 Participants | 350 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 78 Participants | 78 Participants | 156 Participants |
| Sex: Female, Male Male | 96 Participants | 98 Participants | 194 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 146 / 174 | 143 / 175 |
| serious Total, serious adverse events | 18 / 174 | 16 / 175 |
Outcome results
Primary
Change From Baseline in HbA1c (Glycosylated Haemoglobin) (%) at 26 Weeks (Analysed by Central Laboratory)
Change from baseline in HbA1c (%) after 26 weeks of treatment.
Time frame: Week 0, week 26
Population: Full Analysis Set (FAS) Included all randomised subjects. LOCF values are presented for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg + IAsp | Change From Baseline in HbA1c (Glycosylated Haemoglobin) (%) at 26 Weeks (Analysed by Central Laboratory) | -0.20 percentage of glycosylated haemoglobin | Standard Deviation 0.95 |
| IDet + IAsp | Change From Baseline in HbA1c (Glycosylated Haemoglobin) (%) at 26 Weeks (Analysed by Central Laboratory) | -0.31 percentage of glycosylated haemoglobin | Standard Deviation 0.89 |
Secondary
Change From Baseline in Fasting Blood Glucose (FPG) at 26 Weeks (Analysed by Central Laboratory)
Change from baseline in FPG after 26 weeks of treatment.
Time frame: Week 0, week 26
Population: Full Analysis Set (FAS) Included all randomised subjects. LOCF values are presented for this endpoint. 338 subjects were considered, as 12 excluded from PP analysis set, 1 withdrawn, 11 subjects did not have a valid HbA1c measurements after 12 weeks. FPG samples were missing for 9 subjects.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg + IAsp | Change From Baseline in Fasting Blood Glucose (FPG) at 26 Weeks (Analysed by Central Laboratory) | -0.67 mmol/L | Standard Deviation 5.99 |
| IDet + IAsp | Change From Baseline in Fasting Blood Glucose (FPG) at 26 Weeks (Analysed by Central Laboratory) | 0.50 mmol/L | Standard Deviation 8.37 |
Secondary
Change From Baseline in Fasting Blood Glucose (FPG) at 52 Weeks (Analysed by Central Laboratory)
Change from baseline in FPG after 52 weeks of treatment.
Time frame: Week 0, week 52
Population: Full Analysis Set (FAS) Included all randomised subjects. LOCF values are presented for this endpoint. 338 subjects were considered, as 12 excluded from PP analysis set, 1 withdrawn, 11 subjects did not have a valid HbA1c measurements after 12 weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg + IAsp | Change From Baseline in Fasting Blood Glucose (FPG) at 52 Weeks (Analysed by Central Laboratory) | -1.29 mmol/L | Standard Deviation 6.53 |
| IDet + IAsp | Change From Baseline in Fasting Blood Glucose (FPG) at 52 Weeks (Analysed by Central Laboratory) | 1.10 mmol/L | Standard Deviation 8.24 |
Secondary
Change From Baseline in HbA1c (%) at 52 Weeks (Analysed by Central Laboratory)
Change from baseline in HbA1c (%) after 52 weeks of treatments.
Time frame: Week 0, week 52
Population: Full Analysis Set (FAS) Included all randomised subjects. LOCF values are presented for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDeg + IAsp | Change From Baseline in HbA1c (%) at 52 Weeks (Analysed by Central Laboratory) | -0.27 percentage of glycosylated haemoglobin | Standard Deviation 1.07 |
| IDet + IAsp | Change From Baseline in HbA1c (%) at 52 Weeks (Analysed by Central Laboratory) | -0.22 percentage of glycosylated haemoglobin | Standard Deviation 1.03 |
Secondary
Insulin Antibodies (Insulin Degludec Specific, Insulin Detemir Specific, Insulin Aspart Specific and Antibodies Cross-reacting to Human Insulin)
Antibody measurements : the values presented are week 52 (LOCF). The measurement of insulin antibodies after 26 and 52 weeks of treatment was done to fulfil the requirement of monitoring the long term immunogenicity. The unit of measure is percentage bound/total (%B/T) for these antibodies. The Antibodies cross reacting to Human Insulin is abbreviated as X-reacting AB Hu Insulin below)
Time frame: After 52 weeks of treatment
Population: Full Analysis Set (FAS) Included all randomised subjects. LOCF values are presented for this endpoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IDeg + IAsp | Insulin Antibodies (Insulin Degludec Specific, Insulin Detemir Specific, Insulin Aspart Specific and Antibodies Cross-reacting to Human Insulin) | Insulin aspart specific antibodies | 1.1 %B/T | Standard Deviation 2.6 |
| IDeg + IAsp | Insulin Antibodies (Insulin Degludec Specific, Insulin Detemir Specific, Insulin Aspart Specific and Antibodies Cross-reacting to Human Insulin) | Insulin Detemir specific antibodies | NA %B/T | — |
| IDeg + IAsp | Insulin Antibodies (Insulin Degludec Specific, Insulin Detemir Specific, Insulin Aspart Specific and Antibodies Cross-reacting to Human Insulin) | Insulin Degludec specific antibodies | 0 %B/T | Standard Deviation 0.3 |
| IDeg + IAsp | Insulin Antibodies (Insulin Degludec Specific, Insulin Detemir Specific, Insulin Aspart Specific and Antibodies Cross-reacting to Human Insulin) | X-reacting AB Hu Insulin | 17.2 %B/T | Standard Deviation 7.7 |
| IDet + IAsp | Insulin Antibodies (Insulin Degludec Specific, Insulin Detemir Specific, Insulin Aspart Specific and Antibodies Cross-reacting to Human Insulin) | X-reacting AB Hu Insulin | 26.0 %B/T | Standard Deviation 19.3 |
| IDet + IAsp | Insulin Antibodies (Insulin Degludec Specific, Insulin Detemir Specific, Insulin Aspart Specific and Antibodies Cross-reacting to Human Insulin) | Insulin aspart specific antibodies | 1.5 %B/T | Standard Deviation 2.3 |
| IDet + IAsp | Insulin Antibodies (Insulin Degludec Specific, Insulin Detemir Specific, Insulin Aspart Specific and Antibodies Cross-reacting to Human Insulin) | Insulin Degludec specific antibodies | NA %B/T | — |
| IDet + IAsp | Insulin Antibodies (Insulin Degludec Specific, Insulin Detemir Specific, Insulin Aspart Specific and Antibodies Cross-reacting to Human Insulin) | Insulin Detemir specific antibodies | 6.1 %B/T | Standard Deviation 6.5 |
Secondary
Number of Episodes With Self Monitored Blood Ketones Above 1.5 mmol (Capillary Blood Ketone Measurement to be Performed if Self-measured Plasma Glucose (SMPG) Exceeds 14.0 mmol/l (250 mg/dL))
Blood ketones \> 1.5mmol/L (Capillary blood ketone measurement to be performed if SMPG exceeds 14.0mmol/L (250mg/dL) )after 26 and 52 weeks of treatment
Time frame: After 26 weeks and 52 weeks of treatment
Population: Full Analysis Set (FAS) Included all randomised subjects
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IDeg + IAsp | Number of Episodes With Self Monitored Blood Ketones Above 1.5 mmol (Capillary Blood Ketone Measurement to be Performed if Self-measured Plasma Glucose (SMPG) Exceeds 14.0 mmol/l (250 mg/dL)) | 52 weeks | 109 episodes |
| IDeg + IAsp | Number of Episodes With Self Monitored Blood Ketones Above 1.5 mmol (Capillary Blood Ketone Measurement to be Performed if Self-measured Plasma Glucose (SMPG) Exceeds 14.0 mmol/l (250 mg/dL)) | 26 weeks | 44 episodes |
| IDet + IAsp | Number of Episodes With Self Monitored Blood Ketones Above 1.5 mmol (Capillary Blood Ketone Measurement to be Performed if Self-measured Plasma Glucose (SMPG) Exceeds 14.0 mmol/l (250 mg/dL)) | 52 weeks | 161 episodes |
| IDet + IAsp | Number of Episodes With Self Monitored Blood Ketones Above 1.5 mmol (Capillary Blood Ketone Measurement to be Performed if Self-measured Plasma Glucose (SMPG) Exceeds 14.0 mmol/l (250 mg/dL)) | 26 weeks | 86 episodes |
Secondary
Number of Hypoglycaemic Episodes
Number of hypoglycaemic episodes (severe episodes or episodes with plasma glucose (PG) below or equal to 3.9 mmol/L (70 mg/dL) with or without symptoms of hypoglycaemia) during the trial; nocturnal \[11 p.m. - 7 a.m./23:00 - 07:00\] and over the entire day (24 hours)
Time frame: After 26 weeks and 52 weeks of treatment
Population: Safety analysis set included all subjects receiving at least one dose of investigational product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IDeg + IAsp | Number of Hypoglycaemic Episodes | 52 weeks (entire day) | 21560 episodes |
| IDeg + IAsp | Number of Hypoglycaemic Episodes | 26 weeks (nocturnal) | 1261 episodes |
| IDeg + IAsp | Number of Hypoglycaemic Episodes | 52 weeks (nocturnal) | 2336 episodes |
| IDeg + IAsp | Number of Hypoglycaemic Episodes | 26 weeks (entire day) | 11712 episodes |
| IDet + IAsp | Number of Hypoglycaemic Episodes | 52 weeks (nocturnal) | 2586 episodes |
| IDet + IAsp | Number of Hypoglycaemic Episodes | 26 weeks (nocturnal) | 1458 episodes |
| IDet + IAsp | Number of Hypoglycaemic Episodes | 52 weeks (entire day) | 18373 episodes |
| IDet + IAsp | Number of Hypoglycaemic Episodes | 26 weeks (entire day) | 10991 episodes |
Secondary
Number of Self-measured Hyperglycaemia (Episodes of PG Above 11.1 mmol/L (200 mg/dL))
Episodes of PG \>11.1mmol/L (200mg/dL)
Time frame: After 26 weeks and 52 weeks of treatment
Population: Safety analysis set included all subjects receiving at least one dose of investigational product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IDeg + IAsp | Number of Self-measured Hyperglycaemia (Episodes of PG Above 11.1 mmol/L (200 mg/dL)) | 26 weeks | 31264 episodes |
| IDeg + IAsp | Number of Self-measured Hyperglycaemia (Episodes of PG Above 11.1 mmol/L (200 mg/dL)) | 52 weeks | 58679 episodes |
| IDet + IAsp | Number of Self-measured Hyperglycaemia (Episodes of PG Above 11.1 mmol/L (200 mg/dL)) | 26 weeks | 31173 episodes |
| IDet + IAsp | Number of Self-measured Hyperglycaemia (Episodes of PG Above 11.1 mmol/L (200 mg/dL)) | 52 weeks | 52831 episodes |
Secondary
Number of Treatment Emergent Adverse Events (TEAEs)
TEAE is defined as an event that has onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment.
Time frame: After 26 weeks and 52 weeks of treatment
Population: Safety analysis set included all subjects receiving at least one dose of investigational product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IDeg + IAsp | Number of Treatment Emergent Adverse Events (TEAEs) | TEAEs -26 weeks | 810 events |
| IDeg + IAsp | Number of Treatment Emergent Adverse Events (TEAEs) | TEAEs -52 weeks | 1462 events |
| IDet + IAsp | Number of Treatment Emergent Adverse Events (TEAEs) | TEAEs -26 weeks | 761 events |
| IDet + IAsp | Number of Treatment Emergent Adverse Events (TEAEs) | TEAEs -52 weeks | 1266 events |
Secondary
Steady-state Plasma Concentrations of Insulin Degludec and Insulin Detemir on Three Different Visits (Three Different Weeks) During the First 26 Weeks of Treatment
Steady state plasma concentrations of insulin degludec and insulin detemir on three different visits (three different weeks) during the trial.
Time frame: Between week 1 and week 26
Population: Full Analysis Set (FAS) Included all randomised subjects. 1 subject was excluded from the analysis in the IDet arm as he was withdrawn before exposure to trial drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IDeg + IAsp | Steady-state Plasma Concentrations of Insulin Degludec and Insulin Detemir on Three Different Visits (Three Different Weeks) During the First 26 Weeks of Treatment | week 2 | 4540.4 pmol/L | Standard Deviation 3999 |
| IDeg + IAsp | Steady-state Plasma Concentrations of Insulin Degludec and Insulin Detemir on Three Different Visits (Three Different Weeks) During the First 26 Weeks of Treatment | week 12 | 4148.1 pmol/L | Standard Deviation 3726.9 |
| IDeg + IAsp | Steady-state Plasma Concentrations of Insulin Degludec and Insulin Detemir on Three Different Visits (Three Different Weeks) During the First 26 Weeks of Treatment | week 26 | 4105.6 pmol/L | Standard Deviation 3456.5 |
| IDet + IAsp | Steady-state Plasma Concentrations of Insulin Degludec and Insulin Detemir on Three Different Visits (Three Different Weeks) During the First 26 Weeks of Treatment | week 26 | 6377.0 pmol/L | Standard Deviation 10930.6 |
| IDet + IAsp | Steady-state Plasma Concentrations of Insulin Degludec and Insulin Detemir on Three Different Visits (Three Different Weeks) During the First 26 Weeks of Treatment | week 2 | 3972.2 pmol/L | Standard Deviation 6721.8 |
| IDet + IAsp | Steady-state Plasma Concentrations of Insulin Degludec and Insulin Detemir on Three Different Visits (Three Different Weeks) During the First 26 Weeks of Treatment | week 12 | 5430.1 pmol/L | Standard Deviation 9067.7 |