Effect of Insulin Detemir on Use of Energy in Type 1 Diabetes

Study Overview
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Brief Summary
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This trial is conducted in Europe. The purpose of this trial is to investigate if there is any change in the mechanism of energy expenditure (i.e. the way in which energy is used) in patients with type 1 diabetes, whilst taking two different, commercially available insulins for the treatment of their diabetes.

Detailed Description
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The study had been temporarily halted due to an unplanned interim analysis. The Sponsor is now aware that a further interim analysis has been performed by the site and therefore a decision has been made not to recommence the study

Official Title
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A 32-week National, Single-centre, Open-labelled, Randomised, Crossover Trial Comparing Energy Expenditure With Insulin Detemir Versus NPH Insulin Using a Basal-Bolus Regimen With Insulin Aspart as Mealtime Insulin in Subjects With Type 1 Diabetes

Conditions
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Diabetes, Diabetes Mellitus, Type 1

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 diabetes for more than 12 months Current treatment: Basal-bolus insulin regimen for more than three months (i.e. at least one daily injection of long-acting insulin (including insulin glargine) and fast-acting insulin with each main meal) HbA1c (glycosylated haemoglobin A1c) between 7.0 and 11.0% Able and willing to maintain consistent physical activity level throughout the entire study period Able and willing to maintain consistent eating habits throughout the entire study period Exclusion Criteria: Proliferative retinopathy that has required acute treatment within the last six months Recurrent major hypoglycaemia or hypoglycaemic unawareness as judged by the Investigator Liver, kidney or heart problems as judged by the Investigator Pregnancy, breast-feeding, the intention of becoming pregnant or not using adequate contraceptive measures Known or suspected allergy to trial products or related products Receipt of any investigational drug within one month prior to this trial

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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment period 1<br>Insulin detemir for 16 weeks (treatment period 1) followed by insulin NPH treatment for 16 weeks (treatment period 2) in addition to meal-time insulin aspart | Drug: insulin detemir<br>* Treat-to-target dose tritation (dose adjusted individually), s.c. (under the skin) injection<br>Drug: insulin NPH<br>* Treat-to-target dose tritation (dose adjusted individually), s.c. (under the skin) injection<br>Drug: insulin aspart<br>* Treat-to-target dose tritation (dose adjusted individually), s.c. (under the skin) injection<br>|
| Experimental: Treatment period 2<br>Insulin NPH for 16 weeks (treatment period 1) followed by insulin detemir treatment for 16 weeks (treatment period 2) in addition to meal-time insulin aspart | Drug: insulin detemir<br>* Treat-to-target dose tritation (dose adjusted individually), s.c. (under the skin) injection<br>Drug: insulin NPH<br>* Treat-to-target dose tritation (dose adjusted individually), s.c. (under the skin) injection<br>Drug: insulin aspart<br>* Treat-to-target dose tritation (dose adjusted individually), s.c. (under the skin) injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Energy Expenditure, Double-labelled Water Method | Total energy expenditure (TEE) measured after each treatment period by the double-labelled water (DLW) method. This technique required subjects to label their body water using oral administration of water labelled with 2 stable isotopes (2H218O). The clearance of 2H and 18O was measured over a two week period with daily collections of urine. The difference between the clearance of 2H and 18O is a measure of CO2 production rate. This can be converted to provide a measure of energy expenditure. | Weeks 14-16, weeks 30-32 | 
| Total Energy Expenditure, Dietary Record Method | The total energy expenditure (TEE) measured after each treatment period by the dietary record method. The calculation of energy balance is accomplished by compiling an accurate record of food intake over a period of time and measuring any changes in body weight that occur during that time. Data from the 7-day food diary was used to calculate TEE. | Weeks 14-16, weeks 30-32 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Component of Total Energy Expenditure: Resting Energy Expenditure (REE) | Resting energy expenditure (REE) is a component of TEE (total energy expenditure). It was measured at 2 different timepoints during the trial using indirect calorimetry (measurement of O2 consumption/CO2 production) after an overnight fast when subjects would be metabolising a mixture of carbohydrate and free fatty acid. This technique allowed the calculation of the rate of carbohydrate and lipid oxidation. | Week 14, week 30 | 
| Component of Total Energy Expenditure: Diet Induced Thermogenesis (DIT) | Diet induced thermogenesis (DIT) is a component of TEE (total energy expenditure) and is the energy expenditure following feeding for anabolic processes. Subjects fasted overnight and rested for 1 hour. Multiple measurements of REE (resting energy expenditure) were taken. A fixed 600 kcal liquid meal was given and REE was measured over the next 3 hours. DIT was calculated as area under the curve of total REE-resting REE for the 3-hour period and was then converted to a per day measurement by taking into account each individual's average daily food intake. | Week 14, week 30 | 
| Component of Total Energy Expenditure: Physical Activity Thermogenesis | Physical activity thermogenesis is a component of TEE (total energy expenditure). Subjects were asked not to change their physical activity levels. Physical activity thermogenesis can be calculated as the difference between TEE minus (REE + DIT), as long as volitional exercise is unchanged. Volitional exercise was assessed using Actiheart 3-D monitor readings. Subjects were asked to measure their normal activity for between 1 and 5 days prior to their visits at week 16 and week 32). | Week 16, week 32 | 
| Component of Total Energy Expenditure: Non-exercise Activity Thermogenesis (NEAT) | Non-exercise activity thermogenesis is a component of TEE (total energy expenditure). Thermic efficiency was assessed by measuring O2 consumption/CO2 production while the subject exercised on a bike for 20 minutes while hooked up to a device that recorded their respiration (visit in week 14 and week 30). If thermic efficiency was unchanged and volitional exercise was unchanged, then any change in physical activity thermogenesis was due to changes in NEAT. | Week 16, week 32 | 
| Body Weight | Body weight after each treatment period. | Week 16, week 32 | 
| Lean Body Mass | Lean body mass was measured using Bioelectrical Impedance Analysis (BIA), a method used for estimating body composition. | Week 16, week 32 | 
| Fat Mass | Fat mass was measured using Bioelectrical Impedance Analysis (BIA), a method used for estimating body composition. | Week 16, week 32 | 
| Waist:Hip Ratio | At each time-point, 3 measurements each of waist and hip circumference were taken, then an average across the three measurements was calculated for both and the ratio was calculated as the waist average in cm divided by hip average in cm, and multiplied by 100. | Week 16, week 32 | 
| Hormonal Assessment: Adiponectin | Adiponectin levels after each treatment period. | Week 14, week 30 | 
| Hormonal Assessment: Insulin-like Growth Factor-1 | Insulin-like growth factor-1 (IGF-1) levels after each treatment period. | Week 14, week 30 | 
| Hormonal Assessment: Resistin | Resistin levels after each treatment period. | Week 14, week 30 | 
| Hormonal Assessment: Leptin | Leptin levels after each treatment period. | Week 14, week 30 | 
| Glycosylated Haemoglobin A1c (HbA1c) | Glycosylated haemoglobin A1c (HbA1c) after each treatment period. | Week 16, week 32 | 
| Fasting Plasma Glucose | Fasting plasma glucose (FPG) after each treatment period. | Week 16, week 32 | 
| Hypoglycaemic Episodes | Total number of hypoglycaemic episodes experienced in the study. | Weeks 0-32 | 
| Hypoglycaemic Episodes, Diurnal/Nocturnal | Total number of hypoglycaemic episodes during the day (diurnal) and the night (nocturnal) experienced in the study. | Weeks 0-32 |