Clinical Trial Results:
A 52-Week, Multinational, Multi-Centre, Open-Labelled Extension Trial of Insulin Detemir in Children and Adolescents 3-17 years with Type 1 Diabetes on a Basal-Bolus Regimen with Insulin Aspart as Bolus Insulin Trial Phase: 3
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Summary
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EudraCT number |
2006-002478-23 |
Trial protocol |
GB FI DK HU CZ FR BG |
Global end of trial date |
07 Sep 2009
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Results information
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Results version number |
v1(current) |
This version publication date |
15 Mar 2016
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First version publication date |
31 Jul 2015
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
NN304-1690
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00623194 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Novo Nordisk A/S
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Sponsor organisation address |
Novo Allé, Bagsvaerd, Denmark, 2880
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Public contact |
Global Clinical Registry (GCR, 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
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Scientific contact |
Global Clinical Registry (GCR, 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000412-PIP01-08 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
17 Feb 2010
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
07 Sep 2009
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Global end of trial reached? |
Yes
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Global end of trial date |
07 Sep 2009
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To study the development of insulin detemir-insulin aspart cross-reacting antibodies following a 104 week-period (52 weeks in NN304-1689 and 52 weeks in NN304-1690) of insulin detemir treatment in children and adolescents.
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Protection of trial subjects |
The trial was conducted in accordance with the Declaration of Helsinki (October 2000, amended 2002 and 2004) and ICH Good Clinical Practice (01-May-1996).
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Background therapy |
The subjects were treated with insulin detemir and completed 52 weeks of treatment in the NN304-1689 trial. | ||
Evidence for comparator |
Not applicable | ||
Actual start date of recruitment |
19 Feb 2008
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 20
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Country: Number of subjects enrolled |
United Kingdom: 2
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Country: Number of subjects enrolled |
Bulgaria: 19
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Country: Number of subjects enrolled |
Czech Republic: 18
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Country: Number of subjects enrolled |
Denmark: 6
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Country: Number of subjects enrolled |
Finland: 7
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Country: Number of subjects enrolled |
France: 2
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Country: Number of subjects enrolled |
Hungary: 10
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Country: Number of subjects enrolled |
Macedonia, the former Yugoslav Republic of: 11
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Country: Number of subjects enrolled |
Russian Federation: 40
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Country: Number of subjects enrolled |
Turkey: 11
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Worldwide total number of subjects |
146
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EEA total number of subjects |
84
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
88
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Adolescents (12-17 years) |
58
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
The trial sites included 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). | ||||||||||||||
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Pre-assignment
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Screening details |
At entry subjects had finalised 52-weeks treatment with insulin detemir (Trial NN304-1689, NCT00435019).The subjects continued treatment with insulin detemir and insulin aspart doses used in Trial NN304-1689. | ||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||
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Arms
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Arm title
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Insulin Detemir | ||||||||||||||
Arm description |
Subjects received insulin detemir up to twice daily plus insulin aspart at larger meals. Doses were adjusted individually (treatment up to 104 weeks). | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
Levemir
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Investigational medicinal product code |
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Other name |
Insulin detemir
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Insulin detemir was administered subcutaneously once or twice daily at the same time of the day as in Trial NN304-1689. All subjects also received insulin aspart as bolus insulin immediately before or after main meals. The dose of insulin was continuously and individually adjusted based on plasmaglucose (PG) measurements according to the NN304-1689 Titration Guideline.
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Investigational medicinal product name |
NovoRapid
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Investigational medicinal product code |
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Other name |
Insulin aspart
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
All subjects received insulin aspart as bolus insulin immediately before or after main meals. The dose of insulin was continuously and individually adjusted based on plasmaglucose (PG) measurements according to the NN304-1689 Titration Guideline.
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Baseline characteristics reporting groups
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Reporting group title |
Overall Study
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Reporting group description |
Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Insulin Detemir
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Reporting group description |
Subjects received insulin detemir up to twice daily plus insulin aspart at larger meals. Doses were adjusted individually (treatment up to 104 weeks). | ||
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End point title |
Insulin detemir-insulin aspart cross-reacting antibodies. [1] | ||||||||||||||||||||
End point description |
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. For all subjects the difference between the individual subject’s antibody measurements at Visit 10 and Visit 1 exension were calculated. This individual difference was used to adjust the antibody measurements. These corrected values were used for all analyses
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End point type |
Primary
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End point timeframe |
week 0, 52 and 104.
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: In order to clarify if the antibody measurements stabilised or decreased the parameter of interest was the estimated slope of the model. No other statistical analysis was provided for Insulin Detemir-insulin Aspart Cross-reacting Antibodies. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Development of insulin detemir specific antibodies and insulin aspart specific antibodies | ||||||||||||||||||||
End point description |
Amount of insulin detemir and insulin aspart specific antibodies in percent of total antibodies after 0, 52 and 104 weeks. The blood samples analysed were taken before insulin detemir and less than 3 hours after insulin aspart injection.
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End point type |
Secondary
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End point timeframe |
At 0, 52 and 104 weeks
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
BMI (Body Mass Index) | ||||||||
End point description |
BMI (Body Mass Index) after 104 weeks.
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End point type |
Secondary
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End point timeframe |
At 104 weeks
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| No statistical analyses for this end point | |||||||||
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End point title |
SD-score (Z-score) for Body Weight | ||||||||
End point description |
Standard deviation-score (SD-score or z-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.
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End point type |
Secondary
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End point timeframe |
At 104 weeks
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| No statistical analyses for this end point | |||||||||
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End point title |
Occurrence of ketoacidosis requiring hospitalisation during treatment | ||||||
End point description |
Number of diabetic ketoacidosis events requiring hospitalisation.
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End point type |
Secondary
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End point timeframe |
At 104 weeks
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| No statistical analyses for this end point | |||||||
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End point title |
Insulin Dose | ||||||||||||
End point description |
Daily insulin doses (basal (Insulin Detemir) and bolus (Insulin Aspart)) at week 104.
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End point type |
Secondary
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End point timeframe |
At 104 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Laboratory safety parameters: Biochemistry - Albumin Serum (g/dL) | ||||||||
End point description |
Albumin Serum after 104 weeks.
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End point type |
Secondary
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End point timeframe |
At 104 weeks
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| No statistical analyses for this end point | |||||||||
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End point title |
Laboratory safety parameters: Biochemistry- Creatinine Serum umol/L | ||||||||
End point description |
Creatine serum after 104 weeks.
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End point type |
Secondary
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End point timeframe |
At 104 weeks
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| No statistical analyses for this end point | |||||||||
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End point title |
Laboratory safety parameters: Biochemistry - Sodium Serum (mmol/L) | ||||||||
End point description |
Sodium Serum, Potassium Serum and Haemoglobin after 104 weeks.
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End point type |
Secondary
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End point timeframe |
At 104 weeks
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| No statistical analyses for this end point | |||||||||
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End point title |
Laboratory safety parameters: Biochemistry- Alkaline Phosphatase Serum (U/L) | ||||||||
End point description |
Alkaline phosphatase serum after 104 weeks.
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End point type |
Secondary
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End point timeframe |
At 104 weeks
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| No statistical analyses for this end point | |||||||||
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End point title |
Laboratory safety parameters: Haematology - Leukocytes | ||||||||
End point description |
Leukocytes after 104 weeks.
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End point type |
Secondary
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End point timeframe |
At 104 weeks
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| No statistical analyses for this end point | |||||||||
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End point title |
Laboratory safety parameters: Fundoscopy/Fundus Photography | ||||||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
At 52 weeks and at 104 weeks
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Vital Signs: Blood Pressure | ||||||||||||
End point description |
Blood pressure (Systolic and Diastolic) after 104 weeks.
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End point type |
Secondary
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End point timeframe |
At 104 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Vital Signs: Pulse | ||||||||
End point description |
Pulse at week 104, measured after resting in a sitting position for 5 minutes.
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End point type |
Secondary
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End point timeframe |
At 104 weeks
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| No statistical analyses for this end point | |||||||||
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End point title |
Incidence of hypoglycaemia (mild, moderate, severe and biochemical) | ||||||||||||||||||||||||||||||||
End point description |
Incidence of hypoglycaemia (mild, moderate, severe and biochemical) – total, daytime and night time during treatment.
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. Biochemical: Plasma glucose < 3.6mmol/L with no signs or symptoms.
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End point type |
Secondary
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End point timeframe |
Weeks 0 - 104
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
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End point title |
Adverse events during treatment | ||||||||
End point description |
Adverse events during the treatment period expressed as number of events per 100 exposure years.
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End point type |
Secondary
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End point timeframe |
Adverse events from the first day on trial product (Visit 1 + 1 day) to one week after last day on trial product (Visit 5Ext + 7 days at most).
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| No statistical analyses for this end point | |||||||||
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End point title |
Laboratory safety parameters: Biochemistry - Total protein serum (g/dL) | ||||||||
End point description |
Total protein serum after 104 weeks.
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End point type |
Secondary
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End point timeframe |
At 104 weeks
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| No statistical analyses for this end point | |||||||||
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End point title |
Laboratory safety parameters: Biochemistry - Pottassium Serum (mmol/L) | ||||||||
End point description |
Potassium Serum after 104 weeks.
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End point type |
Secondary
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End point timeframe |
At 104 weeks
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| No statistical analyses for this end point | |||||||||
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End point title |
Laboratory safety parameters: Haematology - Haemoglobin (mmol/L) | ||||||||
End point description |
Haemoglobin after 104 weeks
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End point type |
Secondary
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End point timeframe |
At 104 weeks
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| No statistical analyses for this end point | |||||||||
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End point title |
Laboratory safety parameters: Biochemistry -Alanine Aminotransferase Serum (U/L) | ||||||||
End point description |
Alanine Aminotransferase serum after 104 weeks.
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End point type |
Secondary
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End point timeframe |
At 104 weeks
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| No statistical analyses for this end point | |||||||||
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End point title |
Laboratory safety parameters: Biochemistry - Lactate Dehydrogenase Serum (U/L) | ||||||||
End point description |
Lactate Dehydrogenase serum after 104 weeks.
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End point type |
Secondary
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End point timeframe |
At 104 weeks
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| No statistical analyses for this end point | |||||||||
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End point title |
Laboratory safety parameters: Haematology - Thrombocytes | ||||||||
End point description |
Thrombocytes after 104 weeks.
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End point type |
Secondary
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End point timeframe |
At 104 weeks
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
The adverse events were collected over a period of 104 weeks.
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Adverse event reporting additional description |
The safety analysis set is all subjects exposed to at least one dose of trial drug.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
11.1
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Reporting groups
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Reporting group title |
Insulin Detemir
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Reporting group description |
Insulin detemir up to twice daily plus insulin aspart at larger meals, doses are adjusted individually (treatment up to 104 weeks) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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29 Feb 2008 |
Substantial amendment no. 1, dated 28 January 2008, was prepared to implement the decision to use a paper-based diary in the trial. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| Not applicable | |||
