Safety of Insulin Detemir Produced by a New Process as Measured by Antibody Formation in Subjects With Type 1 Diabetes

Study Overview
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Brief Summary
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The trial was conducted in Germany, The Republic of Macedonia, Russian Federation, Serbia and South Africa. The aim of this trial was to make a safety comparison of insulin detemir produced by a new production method (NN729) with insulin detemir made by the previous production method (NN304). Subjects were treated with NN729 or NN304 for a period of 52 weeks at the same total daily dose and frequency of administration as their own pre-trial basal insulin . During the trial doses were individualised based on subject's plasma glucose measurements.

Official Title
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A 12-months Multi-national, Multi-centre, Double Blind, Randomised, Parallel Safety and Efficacy Comparison of Insulin Detemir Produced by the Current Process and Insulin Detemir Produced by the NN729 Process in Subjects With Type 1 Diabetes on a Basal-bolus Regimen With Insulin Aspart as the Bolus Insulin

Conditions
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Diabetes, Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: insulin detemir
* Drug: insulin aspart
* Drug: insulin detemir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 diabetes for at least 12 months Basal-bolus treatment for at least 3 months Body Mass Index (BMI) less than or equal to 35.0 kg/m^2 HbA1c (glycosylated haemoglobin) less than or equal to 12.0% Exclusion Criteria: Known or suspected allergy to trial products or related products Pregnancy, breast-feeding or the intention to become pregnant or not using adequate contraceptive measures Receipt of any trial drug within 1 month prior to this trial Mental incapacity, unwillingness or language barriers precluding adequate understanding or cooperation Conditions that may interfere with trial participation as judged by Investigator: proliferative retinopathy or maculopathy requiring acute treatment within the last six months, recurrent major hypoglycaemia, impaired hepatic or renal function, cardiac problems, uncontrolled hypertension (treated and untreated)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: NN304<br>Individually adjusted dosage of insulin detemir produced by the NN304 process, administered sub-cutaneously (s.c.) 1-2 times daily + Individually adjusted dosage of insulin aspart, administered sub-cutaneously (s.c.) at meals for 52 weeks | Drug: insulin detemir<br>* NN304 injected s.c. (under the skin). Given as basal insulin.<br>Drug: insulin aspart<br>* Injected s.c. (under the skin). Given as bolus insulin.<br>|
| Experimental: NN729<br>Individually adjusted dosage of insulin detemir produced by the NN729 process, administered sub-cutaneously (s.c.) 1-2 times daily + Individually adjusted dosage of insulin aspart, administered sub-cutaneously (s.c.) at meals for 52 weeks | Drug: insulin aspart<br>* Injected s.c. (under the skin). Given as bolus insulin.<br>Drug: insulin detemir<br>* NN729 injected s.c. (under the skin). Given as basal insulin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Insulin Detemir - Human Insulin Cross-reacting Antibodies | Measured change in concentrations of insulin detemir cross-reacting antibodies and the change ratio from baseline to end of trial was calculated. The unit for measuring antibody levels is %B/T (amount of tracer bound to the antibodies in the precipitate (B) expressed in percentage of the total amount of tracer (T) added to the mixture). The change ratio does not have any unit as it is a ratio. | week 0, week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hypoglycaemic Episodes | Number of hypoglycaemic episodes from Week 0 to Week 52, defined as major, minor, or symptoms only. Major if unable to treat her/himself. Minor if able to treat her/himself and plasma glucose below 3.1 mmol/L. Symptoms only if able to treat her/himself and no plasma glucose measurement or plasma glucose higher than or equal to 3.1 mmol/L. Hypoglycaemic episodes occurring in the time frame between 23:00 hours (included) and 06:00 hours (excluded) were defined as nocturnal. | Weeks 0-52 | 
| Glycaemic Control Parameters (Change in HbA1c) | HbA1c (Glycosylated haemoglobin). | week 0, week 52 | 
| Glycaemic Control Parameters (Change in Fasting Plasma Glucose [FPG]) |  | week 0, week 52 | 
| Glycaemic Control Parameters (9-point Self Measured Plasma Glucose [SMPG]) | point is Before Breakfast point is 120 minutes after Breakfast point is Before Lunch point is 120 minutes after Lunch point is Before Dinner point is 120 minutes after Dinner point is at Bedtime point is At 03:00 A.M. point is Before Breakfast the Following Day | week 0, 26 and 52 | 
| Change From Baseline in Detemir Specific Antibodies | Measured change in concentrations of antibody values for insulin detemir specific antibodies and the change ratio from the baseline to end of trial was calculated. The unit for measuring antibody levels is %B/T (amount of tracer bound to the antibodies in the precipitate (B) expressed in percentage of the total amount of tracer (T) added to the mixture). The change ratio does not have any unit as it is a ratio. | Week 0, week 52 | 
| Change From Baseline in Total Antibodies | Measured change in concentrations of total insulin antibodies values (the sum of insulin detemir specific and insulin detemir - human insulin cross-reacting antibodies) and the change ratio from baseline to end of trial was calculated. The unit for measuring antibody levels is %B/T (amount of tracer bound to the antibodies in the precipitate (B) expressed in percentage of the total amount of tracer (T) added to the mixture). The change ratio does not have any unit as it is a ratio. | Week 0, week 52 | 
| Clinical Laboratory Values (Change in Haematology - Basophilis) | Change from Baseline to Week 52 is calculated from the change in percentage ((Week 52 %) - (Baseline %)) per participant, averaged across all participants. Measured in serum at baseline and week 52. Serum samples were analysed at a central laboratory. | week 0, week 52 | 
| Clinical Laboratory Values (Change in Haematology - Eosinophils) | Change from Baseline to Week 52 is calculated from the change in percentage ((Week 52 %) - (Baseline %)) per participant, averaged across all participants. Measured in serum at baseline and week 52. Serum samples were analysed at a central laboratory. | Week 0, week 52 | 
| Clinical Laboratory Values (Change in Haematology - Haemoglobin) | Change from Baseline to Week 52 is calculated from the change in percentage ((Week 52 %) - (Baseline %)) per participant, averaged across all participants. Measured in serum at baseline and week 52. Serum samples were analysed at a central laboratory. | Week 0, week 52 | 
| Clinical Laboratory Values (Change in Haematology - Lymphocytes) | Change from Baseline to Week 52 is calculated from the change in percentage((Week 52 %) - (Baseline %)) per participant, averaged across all participants. Measured in serum at baseline and week 52. Serum samples were analysed at a central laboratory. | Week 0, week 52 | 
| Clinical Laboratory Values (Change in Haematology - Monocytes) | Change from Baseline to Week 52 is calculated from the change in percentage ((Week 52 %) - (Baseline %)) per participant, averaged across all participants. Measured in serum at baseline and week 52. Serum samples were analysed at a central laboratory. | Week 0, week 52 | 
| Clinical Laboratory Values (Change in Haematology - Neutrophils) | Change from Baseline to Week 52 is calculated from the change in percentage((Week 52 %) - (Baseline %)) per participant, averaged across all participants. Measured in serum at baseline and week 52. Serum samples were analysed at a central laboratory. | Week 0, week 52 | 
| Clinical Laboratory Values (Change in Haematology - Thrombocytes) | Change from Baseline to Week 52 is calculated from the change in percentage((Week 52 %) - (Baseline %)) per participant, averaged across all participants. Measured in serum at baseline and week 52. Serum samples were analysed at a central laboratory. | Week 0, week 52 | 
| Clinical Laboratory Values (Change in Haematology - Leucocytes) | Change from Baseline to Week 52 is calculated from the change in percentage((Week 52 %) - (Baseline %)) per participant, averaged across all participants. Measured in serum at baseline and week 52. Serum samples were analysed at a central laboratory. | Week 0, week 52 | 
| Clinical Laboratory Values (Change in Biochemistry - Albumin) | Change from Baseline to Week 52 is calculated from the change in percentage((Week 52 %) - (Baseline %)) per participant, averaged across all participants. Measured in serum at baseline and week 52. Serum samples were analysed at a central laboratory | Week 0, week 52 | 
| Clinical Laboratory Values (Change in Biochemistry - Alanine Aminotransferase [ALAT]) | Change from Baseline to Week 52 is calculated from the change in percentage((Week 52 %) - (Baseline %)) per participant, averaged across all participants. Measured in serum at baseline and week 52. Serum samples were analysed at a central laboratory. (ALAT = alanine aminotransferase) | Week 0, week 52 | 
| Clinical Laboratory Values (Change in Biochemistry - Alkaline Phosphatase [ALP]) | Change from Baseline to Week 52 is calculated from the change in percentage((Week 52 %) - (Baseline %)) per participant, averaged across all participants. Measured in serum at baseline and week 52. Serum samples were analysed at a central laboratory. (ALP = alkaline phosphatase) | Week 0, week 52 | 
| Clinical Laboratory Values (Change in Biochemistry - Creatinine) | Change from Baseline to Week 52 is calculated from the change in percentage((Week 52 %) - (Baseline %)) per participant, averaged across all participants. Measured in serum at baseline and week 52. Serum samples were analysed at a central laboratory | Week 0, week 52 | 
| Clinical Laboratory Values (Change in Biochemistry - Lactate Dehydrogenase [LDH]) | Change from Baseline to Week 52 is calculated from the change in percentage((Week 52 %) - (Baseline %)) per participant, averaged across all participants. Measured in serum at baseline and week 52. Serum samples were analysed at a central laboratory (LDH = lactate dehydrogenase) | Week 0, week 52 | 
| Clinical Laboratory Values (Change in Biochemistry - Potassium) | Change from Baseline to Week 52 is calculated from the change in percentage((Week 52 %) - (Baseline %)) per participant, averaged across all participants. Measured in serum at baseline and week 52. Serum samples were analysed at a central laboratory | Week 0, week 52 | 
| Clinical Laboratory Values (Change in Biochemistry - Sodium) | Change from Baseline to Week 52 is calculated from the change in percentage((Week 52 %) - (Baseline %)) per participant, averaged across all participants. Measured in serum at baseline and week 52. Serum samples were analysed at a central laboratory | Week 0, week 52 | 
| Clinical Laboratory Values (Change in Biochemistry - Total Protein) | Change from Baseline to Week 52 is calculated from the change in percentage((Week 52 %) - (Baseline %)) per participant, averaged across all participants. Measured in serum at baseline and week 52. Serum samples were analysed at a central laboratory | Week 0, week 52 | 
| Adverse Events |  | Weeks 0-52 |