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A Trial Investigating the Efficacy and Safety of Insulin Degludec/Insulin Aspart Once Daily Plus Insulin Aspart for the Remaining Meals Versus Insulin Detemir Once or Twice Daily Plus Meal Time Insulin Aspart in Children and Adolescents With Type 1 Diabetes Mellitus

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ClinicalTrials.gov Identifier: NCT01835431
Recruitment Status : Completed
First Posted : April 19, 2013
Results First Posted : November 17, 2015
Last Update Posted : September 10, 2018
Sponsor:
Information provided by (Responsible Party):
Novo Nordisk A/S

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Diabetes
Diabetes Mellitus, Type 1
Interventions Drug: insulin degludec/insulin aspart
Drug: insulin aspart
Drug: insulin detemir
Enrollment 362
Recruitment Details

The trial was conducted at 63 sites in 14 countries as follows: Belgium: 3 sites; Brazil: 1 sites; Canada:

3 sites; Czech Republic 3 sites; Croatia: 2 sites; Israel: 6 sites; Macedonia: 2 sites; Poland: 3 sites; Russia: 5 sites; Serbia: 4 sites; Slovenia: 1 sites; South Africa: 2 sites; Spain: 5 sites; and United States: 23 sites.

Pre-assignment Details  
Arm/Group Title IDegAsp OD IDet OD/BID
Hide Arm/Group Description Insulin degludec/insulin aspart (IDegAsp) once daily (OD) 2-4U was administered subcutaneously in the thigh, upper arm (deltoid area) or abdomen with the main meal and IAsp was given with the remaining meals 1-3 times daily for 16 weeks. Insulin detemir (IDet) OD/BID (once daily /twice daily) 2-4U was administered subcutaneously in the thigh, upper arm (deltoid area) or abdomen with the main meal and IAsp was given with the remaining meals 2-4 times daily for 16 weeks
Period Title: Overall Study
Started 182 180
Exposed 181 [1] 179 [2]
Completed 174 168
Not Completed 8 12
Reason Not Completed
Adverse Event             1             0
other             0             2
Withdrawal by Subject             6             10
Protocol Violation             1             0
[1]
One subject was withdrawn before exposure.
[2]
One subject was withdrawn before exposure
Arm/Group Title IDegAsp OD IDet OD/BID Total
Hide Arm/Group Description Insulin degludec/insulin aspart (IDegAsp) once daily (OD) 2-4U was administered subcutaneously in the thigh, upper arm (deltoid area) or abdomen with the main meal and IAsp was given with the remaining meals 1-3 times daily for 16 weeks. Insulin detemir (IDet) OD/BID (once daily /twice daily) 2-4U was administered subcutaneously in the thigh, upper arm (deltoid area) or abdomen with the main meal and IAsp was given with the remaining meals 2-4 times daily for 16 weeks Total of all reporting groups
Overall Number of Baseline Participants 182 180 362
Hide Baseline Analysis Population Description
The Full Analysis set (FAS) included all randomised subjects.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 182 participants 180 participants 362 participants
10.5  (4.3) 10.8  (4.6) 10.6  (4.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 182 participants 180 participants 362 participants
Female
93
  51.1%
94
  52.2%
187
  51.7%
Male
89
  48.9%
86
  47.8%
175
  48.3%
HbA1c  
Mean (Standard Deviation)
Unit of measure:  Percentage (%)
Number Analyzed 182 participants 180 participants 362 participants
8.1  (1.2) 8.1  (1.2) 8.1  (1.2)
Fasting plasma Glucose (FPG)   [1] 
Mean (Standard Deviation)
Unit of measure:  mmol/L
Number Analyzed 182 participants 180 participants 362 participants
8.6  (4.4) 8.1  (4.2) 8.4  (4.3)
[1]
Measure Description: Capillary blood samples for fasting plasma glucose (FPG) were taken either at home or at the clinic in the morning on the day of visits 2, 14 and 18 by use of a home blood sampling kit. At baseline FPG assessment: IDegAsp OD: 172 subjects, IDet: 166 subjects. In total: 338 subjects
1.Primary Outcome
Title Change From Baseline in HbA1c (Glycosylated Haemoglobin) (%)
Hide Description Percentage point change in glycosylated haemoglobin A1c (HbA1c) from baseline (week 0) to 16 Weeks. Change from baseline summary statistics at week 16 contains only those who had both baseline and week 16 assesment.
Time Frame Week 0 to week 16
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS included all randomised subjects. 20 subjects were withdrawn and only 4 subjects though completed the study did not have assesments.
Arm/Group Title IDegAsp OD IDet OD/BID
Hide Arm/Group Description:
Insulin degludec/insulin aspart (IDegAsp) once daily (OD) 2-4U was administered subcutaneously in the thigh, upper arm (deltoid area) or abdomen with the main meal and IAsp was given with the remaining meals 1-3 times daily for 16 weeks.
Insulin detemir (IDet) OD/BID (once daily /twice daily) 2-4U was administered subcutaneously in the thigh, upper arm (deltoid area) or abdomen with the main meal and IAsp was given with the remaining meals 2-4 times daily for 16 weeks
Overall Number of Participants Analyzed 173 165
Mean (Standard Deviation)
Unit of Measure: percentage (%)
-0.3  (1.0) -0.3  (0.9)
2.Secondary Outcome
Title Change From Baseline in Fasting Plasma Glucose
Hide Description Change from baseline in FPG after 16 weeks of treatment. Change from baseline summary statistics at week 16 contains only those who had both baseline and week 16 assesment.
Time Frame week 0, week 16
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS included all randomised subjects. 338 subjects had assessment at baseline, 326 had assessment at week 16, 2 subjects were withdrawn before exposure and 22 subjects week 16 assessment was not done.
Arm/Group Title IDegAsp OD IDet OD/BID
Hide Arm/Group Description:
Insulin degludec/insulin aspart (IDegAsp) once daily (OD) 2-4U was administered subcutaneously in the thigh, upper arm (deltoid area) or abdomen with the main meal and IAsp was given with the remaining meals 1-3 times daily for 16 weeks.
Insulin detemir (IDet) OD/BID (once daily /twice daily) 2-4U was administered subcutaneously in the thigh, upper arm (deltoid area) or abdomen with the main meal and IAsp was given with the remaining meals 2-4 times daily for 16 weeks
Overall Number of Participants Analyzed 162 148
Mean (Standard Deviation)
Unit of Measure: mmol/L
-0.3  (6.4) -0.1  (4.8)
3.Secondary Outcome
Title Incidence of Treatment Emergent Adverse Events (TEAEs)
Hide Description A Treatment Emergent Adverse Event (TEAE) was defined as an event with onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day on randomised treatment.
Time Frame After 16 weeks of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
The Safety analysis set (SAS) included all subjects receiving at least one dose of the trial product or its comparator
Arm/Group Title IDegAsp OD IDet OD/BID
Hide Arm/Group Description:
Insulin degludec/insulin aspart (IDegAsp) once daily (OD) 2-4U was administered subcutaneously in the thigh, upper arm (deltoid area) or abdomen with the main meal and IAsp was given with the remaining meals 1-3 times daily for 16 weeks.
Insulin detemir (IDet) OD/BID (once daily /twice daily) 2-4U was administered subcutaneously in the thigh, upper arm (deltoid area) or abdomen with the main meal and IAsp was given with the remaining meals 2-4 times daily for 16 weeks
Overall Number of Participants Analyzed 181 179
Measure Type: Number
Unit of Measure: number of events
501 460
4.Secondary Outcome
Title Number of Treatment Emergent Confirmed Hypoglycaemic Episodes (Plasma Glucose (PG) Below 3.1mmol/L (56mg/dL) or Severe Hypoglycaemia)
Hide Description

Treatment emergent hypoglycaemic episodes (PG < 3.1 mmol/L (56 mg/dL) or severe hypoglycaemia).

Confirmed hypoglycaemic episodes were defined as episodes that were either:

  1. Severe (i.e. the child is having altered mental status and cannot assist in their care, is semiconscious or unconscious or in coma with or without convulsions and may require parenteral therapy (glucagon or i.v. glucose), or
  2. An episode biochemically confirmed by PG value of <3.1 mmol/L (56 mg/dL), with or without symptoms consistent with hypoglycaemia.
Time Frame After 16 weeks of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
The SAS included all subjects receiving at least one dose of the trial product or its comparator
Arm/Group Title IDegAsp OD IDet OD/BID
Hide Arm/Group Description:
Insulin degludec/insulin aspart (IDegAsp) once daily (OD) 2-4U was administered subcutaneously in the thigh, upper arm (deltoid area) or abdomen with the main meal and IAsp was given with the remaining meals 1-3 times daily for 16 weeks.
Insulin detemir (IDet) OD/BID (once daily /twice daily) 2-4U was administered subcutaneously in the thigh, upper arm (deltoid area) or abdomen with the main meal and IAsp was given with the remaining meals 2-4 times daily for 16 weeks
Overall Number of Participants Analyzed 181 179
Measure Type: Number
Unit of Measure: episodes
2532 2672
5.Secondary Outcome
Title Number of Treatment Emergent Nocturnal Confirmed Hypoglycaemic Episodes
Hide Description The confirmed hypoglycaemic episodes occurring between 23:00 and 07:00 were considered for this endpoint
Time Frame After 16 weeks of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
The SAS included all subjects receiving at least one dose of the trial product or its comparator
Arm/Group Title IDegAsp OD IDet OD/BID
Hide Arm/Group Description:
Insulin degludec/insulin aspart (IDegAsp) once daily (OD) 2-4U was administered subcutaneously in the thigh, upper arm (deltoid area) or abdomen with the main meal and IAsp was given with the remaining meals 1-3 times daily for 16 weeks.
Insulin detemir (IDet) OD/BID (once daily /twice daily) 2-4U was administered subcutaneously in the thigh, upper arm (deltoid area) or abdomen with the main meal and IAsp was given with the remaining meals 2-4 times daily for 16 weeks
Overall Number of Participants Analyzed 181 179
Measure Type: Number
Unit of Measure: episodes
316 291
6.Secondary Outcome
Title Number of Hyperglycaemic Episodes (PG Above 14.0 mmol/L (250 mg/dL) Where Subject Looks/Feels Ill
Hide Description The episode of hyperglycaemia was noted when the glucose measurement was 14.0mmol/L or above and the subject looked /felt ill.
Time Frame After 16 weeks of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
The SAS included all subjects receiving at least one dose of the trial product or its comparator
Arm/Group Title IDegAsp OD IDet OD/BID
Hide Arm/Group Description:
Insulin degludec/insulin aspart (IDegAsp) once daily (OD) 2-4U was administered subcutaneously in the thigh, upper arm (deltoid area) or abdomen with the main meal and IAsp was given with the remaining meals 1-3 times daily for 16 weeks.
Insulin detemir (IDet) OD/BID (once daily /twice daily) 2-4U was administered subcutaneously in the thigh, upper arm (deltoid area) or abdomen with the main meal and IAsp was given with the remaining meals 2-4 times daily for 16 weeks
Overall Number of Participants Analyzed 181 179
Measure Type: Number
Unit of Measure: episodes
599 449
7.Secondary Outcome
Title Number of Hyperglycaemic Episodes (PG Above 14.0 mmol/L (250 mg/dL) Where Subject Looks/Feels Ill With Ketosis (Blood Ketones Above 1.5 mmol/L)
Hide Description The episode of hyperglycaemia was noted when the glucose measurement was 14.0mmol/L or above and the subject looked /felt ill. The ketone meaurement involved an additional finger prick and ketosis was considered present if blood ketones were higher than 1.5mmol/L
Time Frame After 16 weeks of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
The SAS included all subjects receiving at least one dose of the trial product or its comparator
Arm/Group Title IDegAsp OD IDet OD/BID
Hide Arm/Group Description:
Insulin degludec/insulin aspart (IDegAsp) once daily (OD) 2-4U was administered subcutaneously in the thigh, upper arm (deltoid area) or abdomen with the main meal and IAsp was given with the remaining meals 1-3 times daily for 16 weeks.
Insulin detemir (IDet) OD/BID (once daily /twice daily) 2-4U was administered subcutaneously in the thigh, upper arm (deltoid area) or abdomen with the main meal and IAsp was given with the remaining meals 2-4 times daily for 16 weeks
Overall Number of Participants Analyzed 181 179
Measure Type: Number
Unit of Measure: episodes
6 12
Time Frame Onset date on or after the first day of esxposure to randomised treatment and no later than 7 days after the last day on randomised treatment
Adverse Event Reporting Description The SAS included all subjects receiving at least one dose of the trial product or its comparator
 
Arm/Group Title IDegAsp OD IDet OD/BID
Hide Arm/Group Description Insulin degludec/insulin aspart (IDegAsp) once daily (OD) 2-4U was administered subcutaneously in the thigh, upper arm (deltoid area) or abdomen with the main meal and IAsp was given with the remaining meals 1-3 times daily for 16 weeks. Insulin detemir (IDet) OD/BID (once daily /twice daily) 2-4U was administered subcutaneously in the thigh, upper arm (deltoid area) or abdomen with the main meal and IAsp was given with the remaining meals 2-4 times daily for 16 weeks
All-Cause Mortality
IDegAsp OD IDet OD/BID
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
IDegAsp OD IDet OD/BID
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   11/181 (6.08%)      7/179 (3.91%)    
Congenital, familial and genetic disorders     
Developmental glaucoma  1  1/181 (0.55%)  1 0/179 (0.00%)  0
Gastrointestinal disorders     
Constipation  1  1/181 (0.55%)  1 0/179 (0.00%)  0
Gastritis  1  1/181 (0.55%)  1 0/179 (0.00%)  0
Infections and infestations     
Laryngitis  1  0/181 (0.00%)  0 1/179 (0.56%)  1
Viral infection  1  1/181 (0.55%)  1 1/179 (0.56%)  1
Injury, poisoning and procedural complications     
Fall  1  0/181 (0.00%)  0 1/179 (0.56%)  1
Fibula Fracture  1  1/181 (0.55%)  1 0/179 (0.00%)  0
Tibia Fracture  1  1/181 (0.55%)  1 0/179 (0.00%)  0
Metabolism and nutrition disorders     
Diabetic Ketoacidosis  1  1/181 (0.55%)  1 1/179 (0.56%)  1
Hyperglycaemia  1  0/181 (0.00%)  0 1/179 (0.56%)  1
Hypoglycaemia  1  5/181 (2.76%)  5 1/179 (0.56%)  1
Musculoskeletal and connective tissue disorders     
Compartment syndrome  1  1/181 (0.55%)  1 0/179 (0.00%)  0
Nervous system disorders     
Hypoglycaemic seizure  1  1/181 (0.55%)  1 0/179 (0.00%)  0
Loss of consciousness  1  0/181 (0.00%)  0 1/179 (0.56%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 17.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
IDegAsp OD IDet OD/BID
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   96/181 (53.04%)      97/179 (54.19%)    
Gastrointestinal disorders     
Abdominal pain  1  10/181 (5.52%)  13 7/179 (3.91%)  13
Abdominal pain upper  1  14/181 (7.73%)  22 17/179 (9.50%)  26
Vomiting  1  22/181 (12.15%)  25 12/179 (6.70%)  13
General disorders     
Pyrexia  1  17/181 (9.39%)  26 10/179 (5.59%)  15
Infections and infestations     
Influenza  1  9/181 (4.97%)  10 10/179 (5.59%)  12
Nasopharyngitis  1  36/181 (19.89%)  43 32/179 (17.88%)  42
Pharyngitis  1  3/181 (1.66%)  3 10/179 (5.59%)  13
Upper respiratory tract infection  1  11/181 (6.08%)  12 17/179 (9.50%)  18
Nervous system disorders     
Headache  1  23/181 (12.71%)  47 32/179 (17.88%)  64
Respiratory, thoracic and mediastinal disorders     
cough  1  13/181 (7.18%)  16 9/179 (5.03%)  9
Oropharyngeal pain  1  9/181 (4.97%)  13 13/179 (7.26%)  14
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 17.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Novo Nordisk maintains the right to be informed of plans by any investigator to publish and to review any scientific paper, presentation, communication or other information concerning the investigation described in this protocol. Any such communication must be submitted in writing to Novo Nordisk before submission for comments. Comments will be given within four weeks from receipt of the planned communication
Results Point of Contact
Name/Title: Public Access to Clinical Trials
Organization: Novo Nordisk A/S
Responsible Party: Novo Nordisk A/S
ClinicalTrials.gov Identifier: NCT01835431     History of Changes
Other Study ID Numbers: NN5401-3816
2012-003566-41 ( EudraCT Number )
U1111-1133-0958 ( Other Identifier: WHO )
PIP no. be confirmed ( Other Identifier: EMA )
First Submitted: April 16, 2013
First Posted: April 19, 2013
Results First Submitted: October 13, 2015
Results First Posted: November 17, 2015
Last Update Posted: September 10, 2018