Comparison of Insulin Detemir and Insulin Aspart in 2 Separate Injections Twice Daily to Extemporaneous Mixing Injection Regimen Twice Daily - The Paediatric Mixing Trial

Study Overview
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Brief Summary
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This trial is conducted in Europe. The aim of the trial is to compare two methods of injection in basal-bolus insulin regimen in children with type 1 diabetes with insulin detemir associated with insulin aspart given twice daily in either separate or mixed injections and to investigate if there is any clinical impact in choosing one regimen over another.

Official Title
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A Randomised, Multicentric, Open Labelled, Parallel Group Trial With Insulin Aspart and Insulin Detemir, Investigating the Glycaemic Effect and Profile in Children With Type 1 Diabetes, of Two Separate Levemir® + NovoRapid® Injections and Extemporaneous Mixing - The Paediatric MIXING Trial

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
* Drug: insulin aspart


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Parents' Informed Consent (IC) obtained before any trial-related activities Obtained child's assent (when possible) Type 1 diabetes Treatment with insulin detemir and insulin aspart either in extemporaneous mixed or separate injections HbA1c (glycosylated haemoglobin A1c) lesser than or equal to 8.6% Exclusion Criteria: History of alcoholism, drug abuse, or psychiatric disease or personality disorders likely to invalidate voluntary consent or to prevent good compliance with the trial protocol Mental incapacity, unwillingness or language barrier precluding adequate understanding or co-operation Anticipated change or new use in concomitant medication known to interfere with glucose metabolism, such as systemic corticotherapy more than 5 mg/day (prednisone) Any other condition that the Investigator (trial physician) feels would interfere with trial participation or evaluation of results

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mixed injection<br> | Drug: insulin detemir<br>* Treat-to-target (individually adjusted) dose titration, s.c. (under the skin) injection, twice a day, mixed with insulin aspart<br>Drug: insulin aspart<br>* Treat-to-target (individually adjusted) dose titration, s.c. (under the skin) injection, twice a day, mixed with insulin detemir<br>|
| Active Comparator: Separate injection<br> | Drug: insulin detemir<br>* Treat-to-target (individually adjusted) dose titration, s.c. (under the skin) injection, twice a day, injected separately with insulin aspart<br>Drug: insulin aspart<br>* Treat-to-target (individually adjusted) dose titration, s.c. (under the skin) injection, twice a day, injected separately with insulin detemir<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glycosylated Haemoglobin A1c (HbA1c) | Measured for the Per Protocol (PP) set | Week 0 and Week 8 | 
| Glycosylated Haemoglobin A1c (HbA1c) | Measured for the ITT (Intention-to-Treat) set | Week 0 and Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fructosamine |  | Week 0 and Week 8 | 
| Self-measured Plasma Glucose Profile (Before Breakfast) |  | Week 0 and Week 8 | 
| Self-measured Plasma Glucose Profile (After Breakfast) |  | Week 0 and Week 8 | 
| Self-measured Plasma Glucose Profile (Before Dinner) |  | Week 0 and Week 8 | 
| Self-measured Plasma Glucose Profile (After Dinner) |  | Week 0 and Week 8 | 
| Pharmacokinetics: Cmax of Free Insulin | The observed peak drug concentration at time (T): T0, T0.5hour (hr), T1hr, T1.5hr, T2 hours (hrs), T2.5hrs, T3hrs, T3.5hrs, T4hrs | Week 0 and Week 8 | 
| Pharmacokinetics: Tmax of Free Insulin | The observed peak drug concentration at time (T): T0, T0.5hour (hr), T1hr, T1.5hr, T2hrs, T2.5hrs, T3hrs, T3.5hrs, T4hrs | Week 0 and Week 8 | 
| Pharmacokinetics: Area Under the Concentration vs. Time Curve From Time Zero to the Time of the Last Measured Level of Free Insulin | The observed peak drug concentration at time (T): T0, T0.5hour (hr), T1hr, T1.5hr, T2hrs, T2.5hrs, T3hrs, T3.5hrs, T4hrs | Week 0 and Week 8 | 
| Pharmacokinetics: Area Under the Concentration vs. Time Curve From Time Zero to Infinity of Free Insulin | The observed peak drug concentration at time (T): T0, T0.5hour (hr), T1hr, T1.5hr, T2hrs, T2.5hrs, T3hrs, T3.5hrs, T4hrs | Week 0 and Week 8 | 
| Pharmacokinetics: Terminal Phase Elimination Half-life (T½) - Parameter of Free Insulin | The observed peak drug concentration at time (T): T0, T0.5hour (hr), T1hr, T1.5hr, T2hrs, T2.5hrs, T3hrs, T3.5hrs, T4hrs | Week 0 and Week 8 | 
| Pharmacokinetics: Cmax of Insulin Detemir | The observed peak drug concentration at time (T): T0, T0.5hour (hr), T1hr, T1.5hr, T2hrs, T2.5hrs, T3hrs, T3.5hrs, T4hrs | Week 0 and Week 8 | 
| Pharmacokinetics: Tmax of Insulin Detemir | The observed peak drug concentration at time (T): T0, T0.5hour (hr), T1hr, T1.5hr, T2hrs, T2.5hrs, T3hrs, T3.5hrs, T4hrs | Week 0 and Week 8 | 
| Pharmacokinetics: Area Under the Concentration vs. Time Curve From Time Zero to the Time of the Last Measured Level of Insulin Detemir | The observed peak drug concentration at time (T): T0, T0.5hour (hr), T1hr, T1.5hr, T2hrs, T2.5hrs, T3hrs, T3.5hrs, T4hrs | Week 0 and Week 8 | 
| Pharmacokinetics: Area Under the Concentration vs. Time Curve From Time Zero to Infinity of Insulin Detemir | The observed peak drug concentration at time (T): T0, T0.5hour (hr), T1hr, T1.5hr, T2hrs, T2.5hrs, T3hrs, T3.5hrs, T4hrs | Week 0 and Week 8 | 
| Pharmacokinetics: Terminal Phase Elimination Half-life (T½) - Parameter of Insulin Detemir | The observed peak drug concentration at time (T): T0, T0.5hour (hr), T1hr, T1.5hr, T2hrs, T2.5hrs, T3hrs, T3.5hrs, T4hrs | Week 0 and Week 8 | 
| Pharmacokinetics: Cmax of Insulin Aspart | The observed peak drug concentration at time (T): T0, T0.5hour (hr), T1hr, T1.5hr, T2hrs, T2.5hrs, T3hrs, T3.5hrs, T4hrs | Week 0 and Week 8 | 
| Pharmacokinetics: Tmax of Insulin Aspart | The observed peak drug concentration at time (T): T0, T0.5hour (hr), T1hr, T1.5hr, T2hrs, T2.5hrs, T3hrs, T3.5hrs, T4hrs | Week 0 and Week 8 | 
| Pharmacokinetics: Area Under the Concentration vs. Time Curve From Time Zero to the Time of the Last Measured Level of Insulin Aspart | The observed peak drug concentration at time (T): T0, T0.5hour (hr), T1hr, T1.5hr, T2hrs, T2.5hrs, T3hrs, T3.5hrs, T4hrs | Week 0 and Week 8 | 
| Pharmacokinetics: Area Under the Concentration vs. Time Curve From Time Zero to Infinity of Insulin Aspart | The observed peak drug concentration at time (T): T0, T0.5hour (hr), T1hr, T1.5hr, T2hrs, T2.5hrs, T3hrs, T3.5hrs, T4hrs | Week 0 and Week 8 | 
| Pharmacokinetics: Terminal Phase Elimination Half-life (T½) - Parameter of Insulin Aspart | The observed peak drug concentration at time (T): T0, T0.5hour (hr), T1hr, T1.5hr, T2hrs, T2.5hrs, T3hrs, T3.5hrs, T4hrs | Week 0 and Week 8 | 
| Weight Z Score | Z score of weight. To estimate the growth of children, standardised mean weight values were calculated for each month of age and for each sex | Week 0 and Week 8 | 
| Body Mass Index (BMI) Z Score | Z score of BMI index. To estimate the growth of children, standardised mean BMI values were calculated for each month of age and for each sex | Week 0 and Week 8 | 
| Incidence of Hypoglycaemic Episodes - All Episodes | Number of hypoglycaemic episodes from Week 0 to Week 8, defined as self-measurement plasma glucose less than 56 mg/dL (3.1 mmol/L). Classified as major, minor or symptoms only. Major if unable to treat her/himself (given the age of the study population, the definition of major hypoglycemia was to be adapted through the investigator's judgment). Minor if able to treat her/himself and plasma glucose below 3.1 mmol/L (56 mg/dL). 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. | Weeks 0-8 | 
| Incidence of Hypoglycaemic Episodes - Glycaemia Below 0.56 g/L | Number of minor hypoglycaemic episodes from Week 0 to Week 8, defined as self-measurement plasma glucose below 3.1 mmol/L (56 mg/dL) and the child is able to treat her/himself. | Weeks 0-8 | 
| Incidence of Hypoglycaemic Episodes - Glycaemia Above or Equal to 0.56 g/L | Number of symptoms only hypoglycaemic episodes from Week 0 to Week 8, defined as self-measurement plasma glucose higher than or equal to 3.1 mmol/L (56 mg/dL) or no plasma glucose measurement and the child is able to treat her/himself. | Weeks 0-8 | 
| Percentage of Children Assessing Insulin Therapy Injection Pain as Sad Face | Via a paper diary, the children perceived insulin therapy injection pain by using a four-grade facial visual analogue scale (VAS): very sad face, sad face, happy face or very happy face. | Week 0 and Week 8 | 
| Percentage of Children Assessing Insulin Therapy Injection Pain as Happy Face | Via a paper diary, the children perceived insulin therapy injection pain by using a four-grade facial visual analogue scale (VAS): very sad face, sad face, happy face or very happy face. | Week 0 and week 8 | 
| Percentage of Children Assessing Insulin Therapy Injection Pain as Very Happy Face | Via a paper diary, the children perceived insulin therapy injection pain by using a four-grade facial visual analogue scale (VAS): very sad face, sad face, happy face or very happy face. | Week 0 and Week 8 |