Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted globally. The aim of the trial is to investigate the efficacy and safety of insulin detemir versus insulin Neutral Protamine Hagedorn (NPH) in combination with the maximum tolerated dose of metformin and diet/exercise on glycaemic control in children and adolescents with type 2 diabetes insufficiently controlled on the maximum tolerated dose of metformin with or without other oral antidiabetic drug(s) with or without basal insulin.
Interventions
DRUGInsulin detemir
Administered subcutaneously (s.c., under the skin) once or twice daily. The subjects' pre-trial OAD's i.e. metformin treatment should continue unchanged during the treatment period.
DRUGInsulin NPH
Administered subcutaneously (s.c., under the skin) once or twice daily. The subjects' pre-trial OADs i.e. metformin treatment should continue unchanged during the treatment period.
BEHAVIORALDiet/exercise
Intervention will be performed through family based changes in eating and activity behaviours.
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
10 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Informed consent from the subject or a legally acceptable representative (LAR) and child assent from the subject obtained before any trial-related activities.Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial * Male or female, above or equal to 10 years and below or equal to 17 years at the time of signing informed consent/assent * Diagnosis of type 2 diabetes mellitus at least 3 months prior to screening * Treated with the maximum tolerated stable dose of metformin for at least 3 months prior to screening or have documented complete metformin intolerance * HbA1c (glycosylated haemoglobin) above or equal to 7.0% and below or equal to 10.5% (above or equal to 53 mmol/mol and below or equal to 91 mmol/mol) at screening
Exclusion criteria
* Maturity onset diabetes of the young (MODY) * Fasting C-peptide at screening below 0.6 ng/mL * Impaired liver function defined as alanine aminotransferase (ALT) above or equal to 2.5 times upper normal limit * Known proliferative retinopathy or maculopathy requiring acute treatment as judged by the investigator * Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria in a period of 3 months before the day of screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c (Glycosylated Haemoglobin) | week 0, week 26 | Estimated mean change in HbA1c (glycosylated haemoglobin) from baseline to week 26. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects Achieving HbA1c Below 7.0%, Who Have Not Experienced Any Treatment Emergent Severe Hypoglycaemic Episodes Within the Last 14 Weeks of Treatment. | At week 26 | Proportion of subjects achieving HbA1c \<7.0% is presented as percentage of subjects achieving HbA1c \<7.0%, who have not experienced any treatment emergent severe hypoglycaemic episodes (an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) within the last 14 weeks of treatment. |
| Proportion of Subjects Achieving HbA1c Below 7.5%, Who Have Not Experienced Any Treatment Emergent Severe Hypoglycaemic Episodes Within the Last 14 Weeks of Treatment | At week 26 | Proportion of subjects achieving HbA1c below 7.5% is presented as percentage of subjects achieving HbA1c \<7.5%, who have not experienced any treatment emergent severe hypoglycaemic episodes (an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) within the last 14 weeks of treatment. |
| Change in Body Weight Standard Deviation Score (SDS) | week 0, week 26 | Change in body weight standard deviation score (SDS) from baseline to week 26. In order to reduce the variability in body weight measurements, SDS were calculated. SDS for weight was derived by comparing the actual measurements with standard growth charts for the United States. Standard values provided by the standard growth charts according to the subject's sex and age at the time of the measurement were used to calculate the SDS. |
| Total Number of Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes | Weeks 0 - 26 | Total number of treatment emergent severe (an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or blood glucose confirmed symptomatic hypoglycaemic episodes (plasma glucose value \<3.1 mmol/L \[56 mg/dL\] with symptoms consistent with hypoglycaemia) experienced by the subjects during the trial. |
| Incidence of Adverse Events (AEs) | weeks 0 - 26 | The total number of treatment emergent adverse events (the onset of the adverse event is on or after the first day of trial product administration, and no later than 7 days after the last day of trial product administration) reported during the 26 weeks of treatment. |
| Total Number of Treatment Emergent Nocturnal (23:00-06:59) Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes | Weeks 0 - 26 | The total number of blood glucose confirmed symptomatic nocturnal (time of onset between 23:00 and 06.59 both inclusive) severe (an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or blood glucose confirmed symptomatic hypoglycaemic episodes (plasma glucose value \<3.1 mmol/L \[56 mg/dL\] with symptoms consistent with hypoglycaemia) experienced by the subjects during the trial. |
Countries
Argentina, Brazil, Croatia, Egypt, Germany, Greece, Hungary, India, Israel, Italy, Lebanon, Malaysia, Mexico, Morocco, Poland, Portugal, Russia, Serbia, South Africa, South Korea, Spain, Taiwan, Turkey (Türkiye), United States
Participant flow
Recruitment details
The following 12 countries screened subjects (no. of sites that randomised subjects within parentheses): Brazil (1), Germany (1), India (3), Israel (1), South Korea (1), Malaysia (3), Mexico (1), Russian Federation (1) Taiwan (3), Turkey (3), United States (6), Hungary (0). A total of 24 sites in 11 countries randomised subjects to treatment.
Pre-assignment details
Subjects continued treatment with metformin on their pre-study dose(s) throughout the trial.
Participants by arm
| Arm | Count |
|---|---|
| Insulin Detemir + Metformin + Diet/Exercise Subjects were treated with insulin detemir 100 U/mL administered subcutaneously in the thigh region once or twice daily for a period of 26 weeks. For insulin naïve subjects, insulin detemir was initiated at a dose of 0.1-0.2 U/kg with a maximum dose of 10 U at the investigators discretion. Subjects who were already on basal insulin were switched to insulin detemir unit-to-unit once or twice daily, depending on previous injection frequency. Subjects were dosed according to individual requirements during the trial period. All subjects continued treatment with metformin on their pre-study dose(s) throughout the trial. The diet/exercise intervention was performed through changes in eating and activity behaviours. | 20 |
| Insulin NPH + Metformin + Diet/Exercise Subjects were treated with NPH 100 IU/mL administered subcutaneously in the thigh region once or twice daily for a period of 26 weeks. For insulin naïve subjects, insulin NPH was initiated at a dose of 0.1-0.2 U/kg with a maximum dose of 10 U at the investigators discretion. Subjects who were already on basal insulin were switched to insulin NPH unit-to-unit once or twice daily, depending on previous injection frequency. Subjects were dosed according to individual requirements during the trial period. All subjects continued treatment with metformin on their pre-study dose(s) throughout the trial. The diet/exercise intervention was performed through changes in eating and activity behaviours. | 22 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by parent | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
| Overall Study | Withdrawal Criteria | 1 | 0 |
Baseline characteristics
| Characteristic | Insulin Detemir + Metformin + Diet/Exercise | Insulin NPH + Metformin + Diet/Exercise | Total |
|---|---|---|---|
| Age, Continuous | 15.0 Years STANDARD_DEVIATION 2.1 | 15.0 Years STANDARD_DEVIATION 2.2 | 15.0 Years STANDARD_DEVIATION 2.1 |
| Body weight standard deviation score | 1.532 standard deviation score STANDARD_DEVIATION 0.685 | 1.260 standard deviation score STANDARD_DEVIATION 0.835 | 1.390 standard deviation score STANDARD_DEVIATION 0.771 |
| Glycosylated haemoglobin (HbA1c) | 8.72 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.86 | 8.95 percentage of glycosylated haemoglobin STANDARD_DEVIATION 1.05 | 8.84 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.96 |
| Sex: Female, Male Female | 12 Participants | 15 Participants | 27 Participants |
| Sex: Female, Male Male | 8 Participants | 7 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 20 | 9 / 22 |
| serious Total, serious adverse events | 0 / 20 | 1 / 22 |
Outcome results
Primary
Change in HbA1c (Glycosylated Haemoglobin)
Estimated mean change in HbA1c (glycosylated haemoglobin) from baseline to week 26.
Time frame: week 0, week 26
Population: Full analysis set included all the randomised subjects.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Detemir + Metformin + Diet/Exercise | Change in HbA1c (Glycosylated Haemoglobin) | -0.64 Percentage of glycosylated haemoglobin | Standard Error 0.32 |
| Insulin NPH + Metformin + Diet/Exercise | Change in HbA1c (Glycosylated Haemoglobin) | -0.81 Percentage of glycosylated haemoglobin | Standard Error 0.31 |
Comparison: HbA1c measurements were analysed with a mixed model for repeated measurements with an unstructured covariance matrix. The model included treatment, visit, age group, prior antidiabetic therapy and interaction between prior antidiabetic therapy and age group as fixed factors and the HbA1c baseline value as covariate. Interactions between visit and all factors and covariates were also included in the model.p-value: 0.307595% CI: [-0.74, 1.09]Mixed Models Analysis
Secondary
Change in Body Weight Standard Deviation Score (SDS)
Change in body weight standard deviation score (SDS) from baseline to week 26. In order to reduce the variability in body weight measurements, SDS were calculated. SDS for weight was derived by comparing the actual measurements with standard growth charts for the United States. Standard values provided by the standard growth charts according to the subject's sex and age at the time of the measurement were used to calculate the SDS.
Time frame: week 0, week 26
Population: Full analysis set included all the randomised subjects.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Detemir + Metformin + Diet/Exercise | Change in Body Weight Standard Deviation Score (SDS) | 0.006 standard deviation score | Standard Deviation 0.192 |
| Insulin NPH + Metformin + Diet/Exercise | Change in Body Weight Standard Deviation Score (SDS) | 0.098 standard deviation score | Standard Deviation 0.139 |
Secondary
Incidence of Adverse Events (AEs)
The total number of treatment emergent adverse events (the onset of the adverse event is on or after the first day of trial product administration, and no later than 7 days after the last day of trial product administration) reported during the 26 weeks of treatment.
Time frame: weeks 0 - 26
Population: Safety analysis set included all subjects receiving at least one dose of randomised treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Detemir + Metformin + Diet/Exercise | Incidence of Adverse Events (AEs) | 30 Number of events |
| Insulin NPH + Metformin + Diet/Exercise | Incidence of Adverse Events (AEs) | 41 Number of events |
Secondary
Proportion of Subjects Achieving HbA1c Below 7.0%, Who Have Not Experienced Any Treatment Emergent Severe Hypoglycaemic Episodes Within the Last 14 Weeks of Treatment.
Proportion of subjects achieving HbA1c \<7.0% is presented as percentage of subjects achieving HbA1c \<7.0%, who have not experienced any treatment emergent severe hypoglycaemic episodes (an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) within the last 14 weeks of treatment.
Time frame: At week 26
Population: Full analysis set included all the randomised subjects. Only subjects who have been exposed for a minimum of 14 weeks contributed to the analysis (20 subjects in the Insulin detemir + metformin + diet/exercise arm and 21 subjects in the Insulin NPH + metformin + diet/exercise arm).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Detemir + Metformin + Diet/Exercise | Proportion of Subjects Achieving HbA1c Below 7.0%, Who Have Not Experienced Any Treatment Emergent Severe Hypoglycaemic Episodes Within the Last 14 Weeks of Treatment. | 25.0 Percentage of subjects |
| Insulin NPH + Metformin + Diet/Exercise | Proportion of Subjects Achieving HbA1c Below 7.0%, Who Have Not Experienced Any Treatment Emergent Severe Hypoglycaemic Episodes Within the Last 14 Weeks of Treatment. | 33.3 Percentage of subjects |
Secondary
Proportion of Subjects Achieving HbA1c Below 7.5%, Who Have Not Experienced Any Treatment Emergent Severe Hypoglycaemic Episodes Within the Last 14 Weeks of Treatment
Proportion of subjects achieving HbA1c below 7.5% is presented as percentage of subjects achieving HbA1c \<7.5%, who have not experienced any treatment emergent severe hypoglycaemic episodes (an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) within the last 14 weeks of treatment.
Time frame: At week 26
Population: Full analysis set included all the randomised subjects. Only subjects who have been exposed for a minimum of 14 weeks contributed to the analysis (20 subjects in the Insulin detemir + metformin + diet/exercise arm and 21 subjects in the Insulin NPH + metformin + diet/exercise arm).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Detemir + Metformin + Diet/Exercise | Proportion of Subjects Achieving HbA1c Below 7.5%, Who Have Not Experienced Any Treatment Emergent Severe Hypoglycaemic Episodes Within the Last 14 Weeks of Treatment | 30.0 Percentage of subjects |
| Insulin NPH + Metformin + Diet/Exercise | Proportion of Subjects Achieving HbA1c Below 7.5%, Who Have Not Experienced Any Treatment Emergent Severe Hypoglycaemic Episodes Within the Last 14 Weeks of Treatment | 38.1 Percentage of subjects |
Secondary
Total Number of Treatment Emergent Nocturnal (23:00-06:59) Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes
The total number of blood glucose confirmed symptomatic nocturnal (time of onset between 23:00 and 06.59 both inclusive) severe (an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or blood glucose confirmed symptomatic hypoglycaemic episodes (plasma glucose value \<3.1 mmol/L \[56 mg/dL\] with symptoms consistent with hypoglycaemia) experienced by the subjects during the trial.
Time frame: Weeks 0 - 26
Population: Safety analysis set included all subjects receiving at least one dose of randomised treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Insulin Detemir + Metformin + Diet/Exercise | Total Number of Treatment Emergent Nocturnal (23:00-06:59) Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes | Severe | 0 Number of episodes |
| Insulin Detemir + Metformin + Diet/Exercise | Total Number of Treatment Emergent Nocturnal (23:00-06:59) Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes | Blood glucose confirmed symptomatic | 0 Number of episodes |
| Insulin NPH + Metformin + Diet/Exercise | Total Number of Treatment Emergent Nocturnal (23:00-06:59) Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes | Severe | 0 Number of episodes |
| Insulin NPH + Metformin + Diet/Exercise | Total Number of Treatment Emergent Nocturnal (23:00-06:59) Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes | Blood glucose confirmed symptomatic | 1 Number of episodes |
Secondary
Total Number of Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes
Total number of treatment emergent severe (an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or blood glucose confirmed symptomatic hypoglycaemic episodes (plasma glucose value \<3.1 mmol/L \[56 mg/dL\] with symptoms consistent with hypoglycaemia) experienced by the subjects during the trial.
Time frame: Weeks 0 - 26
Population: Safety analysis set included all subjects receiving at least one dose of randomised treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Insulin Detemir + Metformin + Diet/Exercise | Total Number of Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes | Severe | 0 Number of episodes |
| Insulin Detemir + Metformin + Diet/Exercise | Total Number of Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes | Blood glucose confirmed symptomatic | 4 Number of episodes |
| Insulin NPH + Metformin + Diet/Exercise | Total Number of Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes | Severe | 0 Number of episodes |
| Insulin NPH + Metformin + Diet/Exercise | Total Number of Treatment Emergent Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes | Blood glucose confirmed symptomatic | 12 Number of episodes |