Diabetes, Diabetes Mellitus, Type 1
Conditions
Brief summary
This trial is conducted in Europe. The aim of this research is to assess the safety of continuous treatment with insulin detemir following participation in trial NN304-1689 (NCT00435019) on antibody development.
Interventions
DRUGinsulin detemir
Treat-to-target dose titration scheme (individually adjusted), injection s.c. (under the skin), once or twice daily.
DRUGinsulin aspart
Treat-to target dose titration scheme (individually adjusted), injection s.c. (under the skin), at larger meals.
Sponsors
Novo Nordisk A/S
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Informed Consent 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 subject must sign and date the Informed Consent Form. * Finalised 52 weeks of treatment with insulin detemir in trial NN304-1689. * Fertile females (girls who have had their first menstrual period) must use adequate contraception (barrier methods, contraceptive pills or intrauterine device (IUD)) if there is any risk of pregnancy in the opinion of the Investigator. For Denmark and France only contraceptive pills or intrauterine device are considered as adequate contraceptive methods.
Exclusion criteria
* Significant concomitant disease such as endocrine, hepatic, renal, cardiac, respiratory, neurological, gastrointestinal, malignant or pancreatic diseases as judged by the Investigator. * Pregnant or the intention of becoming pregnant. * Previous participation in this trial (defined as enrolment).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Detemir-insulin Aspart Cross-reacting Antibodies | week 0, 52 and 104 | Estimated amount of bound antibodies in percent of total antibodies. The primary analysis of cross-reacting antibodies included results from blood samples taken before insulin detemir and less than 3 hours after insulin aspart injection. In addition, an analysis was done including results from samples taken before insulin detemir and less than 2.5 hours after insulin aspart injection. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Glycosylated Haemoglobin A1c (HbA1c) | At 104 weeks | Glycosylated Haemoglobin A1c (HbA1c) measured after 104 weeks. |
| Fasting Plasma Glucose Values | At 104 weeks | FPG (Fasting Plasma Glucose) values after 104 weeks. |
| Hypoglycaemic Episodes | Weeks 0-104 | Mild: signs/symptoms but able to treat him/herself. Moderate: signs/symptoms not able to treat him/herself. Responds to oral treatment. Severe: signs/symptoms and unable to treat him/herself. semiconscious/unconscious/in coma +/- convulsion and may require parenteral treatment. |
| BMI (Body Mass Index) | At 104 weeks | BMI (Body Mass Index) after 104 weeks. |
| SD-score (Z-score) for Body Weight | At 104 weeks | Standard deviation-score (SD-score) after 104 weeks. The SD-score for weight was calculated based on a British reference population from 1990. To estimate the growth of children, standardised mean weight values were calculated for each month of age and for each sex. Thus, a child with a weight equal to the mean value for its age and sex has an SD score of 0, while a child with a weight 2 SDs above the mean value for its age and sex has an SD score of +2. |
| Diabetic Ketoacidosis | At 104 weeks | Diabetic ketoacidosis requiring hospitalisation |
| Insulin Dose | At 104 weeks | Daily insulin doses (basal (Insulin Detemir) and bolus (Insulin Aspart)) at week 104. |
| Development of Insulin Detemir Specific Antibodies and Insulin Aspart Specific Antibodies | At 0, 52 and 104 weeks | Amount of Insulin Detemir and Insulin Aspart specific antibodies in percent of total antibodies after 0, 52 and 104 weeks. |
| Laboratory Values: Creatine Serum Umol/L | At 104 weeks | Creatine serum after 104 weeks. |
| Laboratory Values: Sodium Serum, Potassium Serum and Haemoglobin (mmol/L) | At 104 weeks | Sodium Serum, Potassium Serum and Haemoglobin after 104 weeks. |
| Laboratory Values: Alkaline Phosphatase Serum, Alanine Aminotransferase Serum and Lactate Dehydrogenase Serum (U/L) | At 104 weeks | Alkaline phosphatase serum, Alanine Aminotransferase serum and Lactate Dehydrogenase serum after 104 weeks. |
| Laboratory Values: Leukocytes and Thrombocytes | At 104 weeks | Leukocytes and Thrombocytes after 104 weeks. |
| Fundoscopy/Fundus Photography | at 52 weeks and at 104 weeks | Fundoscopy after 104 weeks. Abn. CS = Abnormal, clinically significant Abn. NCS = Abnormal, Not clinically significant Abn. CS = Abnormal, clinically significant Abn. NCS = Abnormal, Not clinically significant |
| Vital Signs: Blood Pressure | At 104 weeks | Blood pressure (Systolic and Diastolic) after 104 weeks. |
| Vital Signs: Pulse | At 104 weeks | Pulse at week 104 |
| Laboratory Values: Albumin Serum and Total Protein Serum (g/dL) | At 104 weeks | Albumin Serum and Total Protein Serum after 104 weeks. |
Countries
Bulgaria, Czechia, Denmark, Finland, France, Hungary, North Macedonia, Poland, Russia, Turkey (Türkiye), United Kingdom
Participant flow
Recruitment details
29 sites in 11 countries: (Bulgaria (3 sites), Czech Republic (3 sites), Denmark (2 sites), Finland (4 sites), France (1 site), Hungary (2 sites), Macedonia (1 site), Poland (4 sites), Russian Federation (4 sites), Turkey (4 sites) and United Kingdom (1 site)
Pre-assignment details
At entry subjects had finalised 52-weeks treatment with insulin detemir plus insulin aspart (Trial NN304-1689, NCT00435019). Subjects treated with NPH insulin plus insulin aspart in trial NN304-1689 were not offered to continue in this extension trial. Subjects continued treatment with insulin detemir and insulin aspart doses from trial NN304-1689.
Participants by arm
| Arm | Count |
|---|---|
| Insulin Detemir Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks) | 146 |
| Total | 146 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lack of Efficacy | 1 |
| Overall Study | Protocol Violation | 3 |
| Overall Study | Unclassified | 1 |
Baseline characteristics
| Characteristic | Insulin Detemir |
|---|---|
| Age 13-16 years | 50 participants |
| Age 2-5 years | 37 participants |
| Age 6-12 years | 59 participants |
| Age, Continuous | 10.1 years STANDARD_DEVIATION 4.2 |
| BMI | 18.14 kg/m^2 STANDARD_DEVIATION 2.81 |
| Height | 1.39 meters STANDARD_DEVIATION 0.26 |
| Pubertal Status Tanner grade 1 | 83 participants |
| Pubertal Status Tanner grade 2+ | 63 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 144 Participants |
| Sex: Female, Male Female | 77 Participants |
| Sex: Female, Male Male | 69 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 108 / 146 |
| serious Total, serious adverse events | 12 / 146 |
Outcome results
Primary
Insulin Detemir-insulin Aspart Cross-reacting Antibodies
Estimated amount of bound antibodies in percent of total antibodies. The primary analysis of cross-reacting antibodies included results from blood samples taken before insulin detemir and less than 3 hours after insulin aspart injection. In addition, an analysis was done including results from samples taken before insulin detemir and less than 2.5 hours after insulin aspart injection.
Time frame: week 0, 52 and 104
Population: Full analysis set 146 (100%), safety analysis set 146 (100%)~The full analysis set was used for efficacy analyses and included subjects with signed informed consent who had been exposed to trial drug in extension.~The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Detemir | Insulin Detemir-insulin Aspart Cross-reacting Antibodies | Week 0 (3 hours) | 31.11 Percent bound of total | Standard Error 1.25 |
| Insulin Detemir | Insulin Detemir-insulin Aspart Cross-reacting Antibodies | Week 52 (3 hours) | 43.99 Percent bound of total | Standard Error 1.02 |
| Insulin Detemir | Insulin Detemir-insulin Aspart Cross-reacting Antibodies | Week 104 (3 hours) | 35.96 Percent bound of total | Standard Error 1.14 |
| Insulin Detemir | Insulin Detemir-insulin Aspart Cross-reacting Antibodies | Week 0 (2.5 hours) | 31.22 Percent bound of total | Standard Error 1.23 |
| Insulin Detemir | Insulin Detemir-insulin Aspart Cross-reacting Antibodies | Week 52 (2.5 hours) | 44.09 Percent bound of total | Standard Error 1.01 |
| Insulin Detemir | Insulin Detemir-insulin Aspart Cross-reacting Antibodies | Week 104 (2.5 hours) | 35.92 Percent bound of total | Standard Error 1.13 |
Secondary
BMI (Body Mass Index)
BMI (Body Mass Index) after 104 weeks.
Time frame: At 104 weeks
Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Detemir | BMI (Body Mass Index) | 18.88 kg/m^2 | Standard Deviation 3.19 |
Secondary
Development of Insulin Detemir Specific Antibodies and Insulin Aspart Specific Antibodies
Amount of Insulin Detemir and Insulin Aspart specific antibodies in percent of total antibodies after 0, 52 and 104 weeks.
Time frame: At 0, 52 and 104 weeks
Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Detemir | Development of Insulin Detemir Specific Antibodies and Insulin Aspart Specific Antibodies | Insulin Detemir specific, week 0 | 2.81 Percent bound of total | Standard Error 1.28 |
| Insulin Detemir | Development of Insulin Detemir Specific Antibodies and Insulin Aspart Specific Antibodies | Insulin Detemir specific, week 52 | 4.40 Percent bound of total | Standard Error 1.27 |
| Insulin Detemir | Development of Insulin Detemir Specific Antibodies and Insulin Aspart Specific Antibodies | Insulin Detemir specific, week 104 | 3.05 Percent bound of total | Standard Error 1.27 |
| Insulin Detemir | Development of Insulin Detemir Specific Antibodies and Insulin Aspart Specific Antibodies | Insulin Aspart specific, week 0 | 1.32 Percent bound of total | Standard Error 0.67 |
| Insulin Detemir | Development of Insulin Detemir Specific Antibodies and Insulin Aspart Specific Antibodies | Insulin Aspart specific, week 52 | 2.79 Percent bound of total | Standard Error 0.64 |
| Insulin Detemir | Development of Insulin Detemir Specific Antibodies and Insulin Aspart Specific Antibodies | Insulin Aspart specific, week 104 | 1.99 Percent bound of total | Standard Error 0.65 |
Secondary
Diabetic Ketoacidosis
Diabetic ketoacidosis requiring hospitalisation
Time frame: At 104 weeks
Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Detemir | Diabetic Ketoacidosis | 3 events |
Secondary
Fasting Plasma Glucose Values
FPG (Fasting Plasma Glucose) values after 104 weeks.
Time frame: At 104 weeks
Population: Full analysis set 146 (100%) The full analysis set was used for efficacy analyses and included subjects with signed informed consent who had been exposed to trial drug in extension.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Detemir | Fasting Plasma Glucose Values | 7.71 mmol/L | Standard Deviation 3.55 |
Secondary
Fundoscopy/Fundus Photography
Fundoscopy after 104 weeks. Abn. CS = Abnormal, clinically significant Abn. NCS = Abnormal, Not clinically significant Abn. CS = Abnormal, clinically significant Abn. NCS = Abnormal, Not clinically significant
Time frame: at 52 weeks and at 104 weeks
Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Insulin Detemir | Fundoscopy/Fundus Photography | Abnormal, clinically significant | 1 participants |
| Insulin Detemir | Fundoscopy/Fundus Photography | Abnormal, not clinically significant | 8 participants |
| Insulin Detemir | Fundoscopy/Fundus Photography | Normal | 131 participants |
| Insulin Detemir | Fundoscopy/Fundus Photography | Missing | 6 participants |
| Insulin Detemir | Fundoscopy/Fundus Photography | Abn CS baseline and 104 weeks | 1 participants |
Secondary
Glycosylated Haemoglobin A1c (HbA1c)
Glycosylated Haemoglobin A1c (HbA1c) measured after 104 weeks.
Time frame: At 104 weeks
Population: Full analysis set 146 (100%) The full analysis set was used for efficacy analyses and included subjects with signed informed consent who had been exposed to trial drug in extension.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Detemir | Glycosylated Haemoglobin A1c (HbA1c) | 8.74 Percent (%) glycosylated haemoglobin | Standard Deviation 1.52 |
Secondary
Hypoglycaemic Episodes
Mild: signs/symptoms but able to treat him/herself. Moderate: signs/symptoms not able to treat him/herself. Responds to oral treatment. Severe: signs/symptoms and unable to treat him/herself. semiconscious/unconscious/in coma +/- convulsion and may require parenteral treatment.
Time frame: Weeks 0-104
Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Insulin Detemir | Hypoglycaemic Episodes | Overall, Mild | 10530 events |
| Insulin Detemir | Hypoglycaemic Episodes | Overall, Moderate | 450 events |
| Insulin Detemir | Hypoglycaemic Episodes | Overall, Severe | 7 events |
| Insulin Detemir | Hypoglycaemic Episodes | Overall, Biochemical | 5080 events |
| Insulin Detemir | Hypoglycaemic Episodes | Overall, Unclassified | 7 events |
| Insulin Detemir | Hypoglycaemic Episodes | Daytime, Mild | 9080 events |
| Insulin Detemir | Hypoglycaemic Episodes | Daytime, Moderate | 396 events |
| Insulin Detemir | Hypoglycaemic Episodes | Daytime, Severe | 3 events |
| Insulin Detemir | Hypoglycaemic Episodes | Daytime, Biochemical | 4122 events |
| Insulin Detemir | Hypoglycaemic Episodes | Daytime, Unclassified | 4 events |
| Insulin Detemir | Hypoglycaemic Episodes | Night-time, Mild | 1450 events |
| Insulin Detemir | Hypoglycaemic Episodes | Night-time, Moderate | 54 events |
| Insulin Detemir | Hypoglycaemic Episodes | Night-time, Severe | 4 events |
| Insulin Detemir | Hypoglycaemic Episodes | Night-time, Biochemical | 958 events |
| Insulin Detemir | Hypoglycaemic Episodes | Night-time, Unclassified | 3 events |
| Insulin Detemir | Hypoglycaemic Episodes | Total hypoglycaemic episodes | 16074 events |
| Insulin Detemir | Hypoglycaemic Episodes | Total hypoglycaemic episodes, daytime | 13605 events |
| Insulin Detemir | Hypoglycaemic Episodes | Total hypoglycaemic episodes, night-time | 2469 events |
Secondary
Insulin Dose
Daily insulin doses (basal (Insulin Detemir) and bolus (Insulin Aspart)) at week 104.
Time frame: At 104 weeks
Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Detemir | Insulin Dose | Insulin Aspart dose (Bolus) | 0.51 U/kg | Standard Deviation 0.19 |
| Insulin Detemir | Insulin Dose | Insulin Detemir dose (Basal) | 0.66 U/kg | Standard Deviation 0.29 |
Secondary
Laboratory Values: Albumin Serum and Total Protein Serum (g/dL)
Albumin Serum and Total Protein Serum after 104 weeks.
Time frame: At 104 weeks
Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Detemir | Laboratory Values: Albumin Serum and Total Protein Serum (g/dL) | Albumin serum (n=144) | 4.32 g/dL | Standard Deviation 0.25 |
| Insulin Detemir | Laboratory Values: Albumin Serum and Total Protein Serum (g/dL) | Total Protein serum (n=144) | 7.09 g/dL | Standard Deviation 0.45 |
Secondary
Laboratory Values: Alkaline Phosphatase Serum, Alanine Aminotransferase Serum and Lactate Dehydrogenase Serum (U/L)
Alkaline phosphatase serum, Alanine Aminotransferase serum and Lactate Dehydrogenase serum after 104 weeks.
Time frame: At 104 weeks
Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Detemir | Laboratory Values: Alkaline Phosphatase Serum, Alanine Aminotransferase Serum and Lactate Dehydrogenase Serum (U/L) | Alkaline phosphatase serum (n=144) | 226.7 U/L | Standard Deviation 197.1 |
| Insulin Detemir | Laboratory Values: Alkaline Phosphatase Serum, Alanine Aminotransferase Serum and Lactate Dehydrogenase Serum (U/L) | Alanine Aminotransferase serum (n=144) | 19.0 U/L | Standard Deviation 8.26 |
| Insulin Detemir | Laboratory Values: Alkaline Phosphatase Serum, Alanine Aminotransferase Serum and Lactate Dehydrogenase Serum (U/L) | Lactate Dehydrogenase serum (n=137) | 199.6 U/L | Standard Deviation 40.34 |
Secondary
Laboratory Values: Creatine Serum Umol/L
Creatine serum after 104 weeks.
Time frame: At 104 weeks
Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Detemir | Laboratory Values: Creatine Serum Umol/L | 51.08 Umol/L | Standard Deviation 13.55 |
Secondary
Laboratory Values: Leukocytes and Thrombocytes
Leukocytes and Thrombocytes after 104 weeks.
Time frame: At 104 weeks
Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Detemir | Laboratory Values: Leukocytes and Thrombocytes | Leukocytes (n=144) | 6.72 10^9/L | Standard Deviation 1.85 |
| Insulin Detemir | Laboratory Values: Leukocytes and Thrombocytes | Thrombocytes (n=144) | 301.90 10^9/L | Standard Deviation 76.55 |
Secondary
Laboratory Values: Sodium Serum, Potassium Serum and Haemoglobin (mmol/L)
Sodium Serum, Potassium Serum and Haemoglobin after 104 weeks.
Time frame: At 104 weeks
Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Detemir | Laboratory Values: Sodium Serum, Potassium Serum and Haemoglobin (mmol/L) | Sodium Serum (n=144) | 141.6 mmol/L | Standard Deviation 3.11 |
| Insulin Detemir | Laboratory Values: Sodium Serum, Potassium Serum and Haemoglobin (mmol/L) | Potassium serum (n=137) | 4.38 mmol/L | Standard Deviation 0.5 |
| Insulin Detemir | Laboratory Values: Sodium Serum, Potassium Serum and Haemoglobin (mmol/L) | Haemoglobin (n=144) | 8.28 mmol/L | Standard Deviation 0.65 |
Secondary
SD-score (Z-score) for Body Weight
Standard deviation-score (SD-score) after 104 weeks. The SD-score for weight was calculated based on a British reference population from 1990. To estimate the growth of children, standardised mean weight values were calculated for each month of age and for each sex. Thus, a child with a weight equal to the mean value for its age and sex has an SD score of 0, while a child with a weight 2 SDs above the mean value for its age and sex has an SD score of +2.
Time frame: At 104 weeks
Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Detemir | SD-score (Z-score) for Body Weight | 0.13 SD-scores | Standard Deviation 0.97 |
Secondary
Vital Signs: Blood Pressure
Blood pressure (Systolic and Diastolic) after 104 weeks.
Time frame: At 104 weeks
Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Detemir | Vital Signs: Blood Pressure | Diastolic Blood Pressure | 66.6 mmHg | Standard Deviation 8.9 |
| Insulin Detemir | Vital Signs: Blood Pressure | Systolic Blood Pressure | 109.5 mmHg | Standard Deviation 13.6 |
Secondary
Vital Signs: Pulse
Pulse at week 104
Time frame: At 104 weeks
Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Detemir | Vital Signs: Pulse | 82.6 beats/minute | Standard Deviation 9 |