Trial Outcomes & Findings for Safety Follow-up on Children and Adolescents With Type 1 Diabetes Treated With Insulin Detemir. An Extension to Trial NN304-1689 (NCT NCT00623194)

NCT ID: NCT00623194

Last Updated: 2016-11-28

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 146 participants
• Primary outcome timeframe: week 0, 52 and 104
• Results posted on: 2016-11-28

Participant Flow

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)

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.

Participant milestones

Measure	Insulin Detemir Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks)
Overall Study STARTED	146
Overall Study COMPLETED	141
Overall Study NOT COMPLETED	5

Reasons for withdrawal

Measure	Insulin Detemir Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks)
Overall Study Lack of Efficacy	1
Overall Study Protocol Violation	3
Overall Study Unclassified	1

Baseline Characteristics

Safety Follow-up on Children and Adolescents With Type 1 Diabetes Treated With Insulin Detemir. An Extension to Trial NN304-1689

Baseline characteristics by cohort

Measure	Insulin Detemir n=146 Participants Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks)
Age, Continuous	10.1 years STANDARD_DEVIATION 4.2 • n=5 Participants
Sex: Female, Male Female	77 Participants n=5 Participants
Sex: Female, Male Male	69 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	144 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants
Age 2-5 years	37 participants n=5 Participants
Age 6-12 years	59 participants n=5 Participants
Age 13-16 years	50 participants n=5 Participants
Height	1.39 meters STANDARD_DEVIATION 0.26 • n=5 Participants
BMI	18.14 kg/m^2 STANDARD_DEVIATION 2.81 • n=5 Participants
Pubertal Status Tanner grade 1	83 participants n=5 Participants
Pubertal Status Tanner grade 2+	63 participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Insulin Detemir n=146 Participants Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks)
Insulin Detemir-insulin Aspart Cross-reacting Antibodies Week 0 (3 hours)	31.11 Percent bound of total Standard Error 1.25
Insulin Detemir-insulin Aspart Cross-reacting Antibodies Week 52 (3 hours)	43.99 Percent bound of total Standard Error 1.02
Insulin Detemir-insulin Aspart Cross-reacting Antibodies Week 104 (3 hours)	35.96 Percent bound of total Standard Error 1.14
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 Aspart Cross-reacting Antibodies Week 52 (2.5 hours)	44.09 Percent bound of total Standard Error 1.01
Insulin Detemir-insulin Aspart Cross-reacting Antibodies Week 104 (2.5 hours)	35.92 Percent bound of total Standard Error 1.13

SECONDARY outcome

Timeframe: 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.

Amount of Insulin Detemir and Insulin Aspart specific antibodies in percent of total antibodies after 0, 52 and 104 weeks.

Outcome measures

Measure	Insulin Detemir n=146 Participants Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks)
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
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
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
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
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
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 outcome

Timeframe: 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.

Glycosylated Haemoglobin A1c (HbA1c) measured after 104 weeks.

Outcome measures

Measure	Insulin Detemir n=146 Participants Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks)
Glycosylated Haemoglobin A1c (HbA1c)	8.74 Percent (%) glycosylated haemoglobin Standard Deviation 1.52

SECONDARY outcome

Timeframe: 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.

FPG (Fasting Plasma Glucose) values after 104 weeks.

Outcome measures

Measure	Insulin Detemir n=146 Participants Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks)
Fasting Plasma Glucose Values	7.71 mmol/L Standard Deviation 3.55

SECONDARY outcome

Timeframe: Weeks 0-104

Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.

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.

Outcome measures

Measure	Insulin Detemir n=146 Participants Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks)
Hypoglycaemic Episodes Total hypoglycaemic episodes, night-time	2469 events
Hypoglycaemic Episodes Overall, Mild	10530 events
Hypoglycaemic Episodes Overall, Moderate	450 events
Hypoglycaemic Episodes Overall, Severe	7 events
Hypoglycaemic Episodes Overall, Biochemical	5080 events
Hypoglycaemic Episodes Overall, Unclassified	7 events
Hypoglycaemic Episodes Daytime, Mild	9080 events
Hypoglycaemic Episodes Daytime, Moderate	396 events
Hypoglycaemic Episodes Daytime, Severe	3 events
Hypoglycaemic Episodes Daytime, Biochemical	4122 events
Hypoglycaemic Episodes Daytime, Unclassified	4 events
Hypoglycaemic Episodes Night-time, Mild	1450 events
Hypoglycaemic Episodes Night-time, Moderate	54 events
Hypoglycaemic Episodes Night-time, Severe	4 events
Hypoglycaemic Episodes Night-time, Biochemical	958 events
Hypoglycaemic Episodes Night-time, Unclassified	3 events
Hypoglycaemic Episodes Total hypoglycaemic episodes	16074 events
Hypoglycaemic Episodes Total hypoglycaemic episodes, daytime	13605 events

SECONDARY outcome

Timeframe: At 104 weeks

Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.

BMI (Body Mass Index) after 104 weeks.

Outcome measures

Measure	Insulin Detemir n=144 Participants Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks)
BMI (Body Mass Index)	18.88 kg/m^2 Standard Deviation 3.19

SECONDARY outcome

Timeframe: At 104 weeks

Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.

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.

Outcome measures

Measure	Insulin Detemir n=144 Participants Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks)
SD-score (Z-score) for Body Weight	0.13 SD-scores Standard Deviation 0.97

SECONDARY outcome

Timeframe: At 104 weeks

Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.

Diabetic ketoacidosis requiring hospitalisation

Outcome measures

Measure	Insulin Detemir n=146 Participants Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks)
Diabetic Ketoacidosis	3 events

SECONDARY outcome

Timeframe: At 104 weeks

Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.

Daily insulin doses (basal (Insulin Detemir) and bolus (Insulin Aspart)) at week 104.

Outcome measures

Measure	Insulin Detemir n=144 Participants Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks)
Insulin Dose Insulin Detemir dose (Basal)	0.66 U/kg Standard Deviation 0.29
Insulin Dose Insulin Aspart dose (Bolus)	0.51 U/kg Standard Deviation 0.19

SECONDARY outcome

Timeframe: At 104 weeks

Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.

Albumin Serum and Total Protein Serum after 104 weeks.

Outcome measures

Measure	Insulin Detemir n=144 Participants Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks)
Laboratory Values: Albumin Serum and Total Protein Serum (g/dL) Albumin serum (n=144)	4.32 g/dL Standard Deviation 0.25
Laboratory Values: Albumin Serum and Total Protein Serum (g/dL) Total Protein serum (n=144)	7.09 g/dL Standard Deviation 0.45

SECONDARY outcome

Timeframe: At 104 weeks

Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.

Creatine serum after 104 weeks.

Outcome measures

Measure	Insulin Detemir n=144 Participants Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks)
Laboratory Values: Creatine Serum Umol/L	51.08 Umol/L Standard Deviation 13.55

SECONDARY outcome

Timeframe: At 104 weeks

Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.

Sodium Serum, Potassium Serum and Haemoglobin after 104 weeks.

Outcome measures

Measure	Insulin Detemir n=144 Participants Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks)
Laboratory Values: Sodium Serum, Potassium Serum and Haemoglobin (mmol/L) Sodium Serum (n=144)	141.6 mmol/L Standard Deviation 3.11
Laboratory Values: Sodium Serum, Potassium Serum and Haemoglobin (mmol/L) Potassium serum (n=137)	4.38 mmol/L Standard Deviation 0.50
Laboratory Values: Sodium Serum, Potassium Serum and Haemoglobin (mmol/L) Haemoglobin (n=144)	8.28 mmol/L Standard Deviation 0.65

SECONDARY outcome

Timeframe: At 104 weeks

Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.

Alkaline phosphatase serum, Alanine Aminotransferase serum and Lactate Dehydrogenase serum after 104 weeks.

Outcome measures

Measure	Insulin Detemir n=144 Participants Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks)
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 197.10
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
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 outcome

Timeframe: At 104 weeks

Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.

Leukocytes and Thrombocytes after 104 weeks.

Outcome measures

Measure	Insulin Detemir n=144 Participants Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks)
Laboratory Values: Leukocytes and Thrombocytes Leukocytes (n=144)	6.72 10^9/L Standard Deviation 1.85
Laboratory Values: Leukocytes and Thrombocytes Thrombocytes (n=144)	301.90 10^9/L Standard Deviation 76.55

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Measure	Insulin Detemir n=146 Participants Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks)
Fundoscopy/Fundus Photography Abnormal, clinically significant	1 participants
Fundoscopy/Fundus Photography Abnormal, not clinically significant	8 participants
Fundoscopy/Fundus Photography Normal	131 participants
Fundoscopy/Fundus Photography Missing	6 participants
Fundoscopy/Fundus Photography Abn CS baseline and 104 weeks	1 participants

SECONDARY outcome

Timeframe: At 104 weeks

Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.

Blood pressure (Systolic and Diastolic) after 104 weeks.

Outcome measures

Measure	Insulin Detemir n=143 Participants Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks)
Vital Signs: Blood Pressure Systolic Blood Pressure	109.5 mmHg Standard Deviation 13.6
Vital Signs: Blood Pressure Diastolic Blood Pressure	66.6 mmHg Standard Deviation 8.9

SECONDARY outcome

Timeframe: At 104 weeks

Population: The safety analysis set included all subjects with a signed informed consent who were exposed in the extension.

Pulse at week 104

Outcome measures

Measure	Insulin Detemir n=141 Participants Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks)
Vital Signs: Pulse	82.6 beats/minute Standard Deviation 9.0

Adverse Events

Insulin Detemir

Serious events: 12 serious events

Other events: 108 other events

Deaths: 0 deaths

Serious adverse events

Measure	Insulin Detemir n=146 participants at risk Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks)
Infections and infestations Gastroenteritis	1.4% 2/146 • Number of events 2 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.
Infections and infestations Abscess limb	0.68% 1/146 • Number of events 1 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.
Infections and infestations Gastroenteritis shigella	0.68% 1/146 • Number of events 1 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.
Infections and infestations Influenza	0.68% 1/146 • Number of events 1 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.
Infections and infestations Otitis media acute	0.68% 1/146 • Number of events 1 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.
Infections and infestations Soft tissue infection	0.68% 1/146 • Number of events 1 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.
Infections and infestations Viral infection	0.68% 1/146 • Number of events 1 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.
Metabolism and nutrition disorders Diabetic ketoacidosis	2.1% 3/146 • Number of events 3 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.
Metabolism and nutrition disorders Hypoglycaemia	1.4% 2/146 • Number of events 3 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.
Metabolism and nutrition disorders Diabetes mellitus inadequate control	0.68% 1/146 • Number of events 1 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.
Metabolism and nutrition disorders Hypoglycaemia unconsciousness	0.68% 1/146 • Number of events 1 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.
Injury, poisoning and procedural complications Burns second degrees	0.68% 1/146 • Number of events 1 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.

Other adverse events

Measure	Insulin Detemir n=146 participants at risk Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks)
Infections and infestations Nasopharyngitis	48.6% 71/146 • Number of events 164 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.
Infections and infestations Upper Respiratory Tract Infection	14.4% 21/146 • Number of events 44 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.
Infections and infestations Pharyngitis	13.7% 20/146 • Number of events 41 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.
Infections and infestations Influenza	11.6% 17/146 • Number of events 38 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.
Infections and infestations Gastroenteritis	10.3% 15/146 • Number of events 21 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.
Infections and infestations Bronchitis	6.2% 9/146 • Number of events 16 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.
Infections and infestations Viral infection	6.8% 10/146 • Number of events 12 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.
Infections and infestations Rhinitis	6.2% 9/146 • Number of events 11 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.
Infections and infestations Acute Tonsilliitis	5.5% 8/146 • Number of events 8 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.
Nervous system disorders Headache	17.1% 25/146 • Number of events 84 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.
Gastrointestinal disorders Abdominal pain upper	5.5% 8/146 • Number of events 13 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.
Gastrointestinal disorders Abdominal pain	6.2% 9/146 • Number of events 10 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.
Gastrointestinal disorders Vomiting	6.8% 10/146 • Number of events 10 • The adverse events were collected over a period of 104 weeks. The safety analysis set is all subjects exposed to at least one dose of trial drug.

Additional Information

Public Access to Clinical Trials

Novo Nordisk A/S

Email: clinicaltrials@novonordisk.com

Results disclosure agreements

• Principal investigator is a sponsor employee Novo Nordisk reserves the right not to release data until specified milestones, e.g., a Clinical Trial Report is available. At the end of the trial, one or more manuscripts for publication will be prepared in collaboration between authors and Novo Nordisk. Novo Nordisk will not suppress or veto publications; however Novo Nordisk reserves the right to postpone publication and/or communication for a short time to protect intellectual property.
• Publication restrictions are in place

Restriction type: OTHER