Insulin by Jet-injection for Hyperglycemia in Diabetes

Study Overview
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Brief Summary
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The purpose of this study is to compare the pharmacokinetic and pharmacodynamic profile of the rapid-acting insulin analogue aspart (Novorapid®) injected subcutaneously by jet-injection to that of the same insulin injected with a conventional pen in the management of hyperglycemia in subjects with diabetes

Detailed Description
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Recently, we showed in both healthy, non-diabetic volunteers and in patients with type 1 (T1DM) and insulin-treated type 2 diabetes (T2DM) a 40-50% faster absorption of rapid-acting insulin analogues when administered by jet injection technology rather than by conventional insulin pen. The faster insulin action of insulin administration by jet injection may be especially advantageous for correction of hyperglycemia. To investigate this, a open-label randomised controlled cross-over study will be performed in 20 adult patients (18-75 years) with T1DM or T2DM on basal-bolus insulin treatment. The pharmacokinetic and pharmacodynamic profile of insulin aspart will be derived from the time-action profiles of insulin and glucose, respectively, in response to insulin (in a dose of 1.5 times the amount of insulin needed to reduce blood glucose to 6 mmol/l calculated by the insulin-sensitivity factor) after reaching hyperglycemia (18-23 mmol/l). All patients will be investigated twice, where on one occasion the jet-injector device will be used to inject insulin, and on the other occasion insulin will be injected with a conventional insulin pen. The order of these occasions will be randomised. Both devices will be operated by the patient after sufficient training. Ease of use will be evaluated.

Official Title
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The Effect of Rapid-acting Insulin Injected by Needle-free Jet-injection in the Management of Hyperglycemia in Patients With Diabetes

Conditions
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Diabetes Mellitus

Intervention / Treatment
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* Drug: insulin aspart


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: diabetes mellitus type 1 or 2 Age 18-75 years Body-Mass Index ≥25 kg/m2 and ≤40 kg/m2 Stable glycaemic control with HbA1c ≥48 (6.5%) and ≤86 mmol/mol (10%) Insulin treatment according to basal-bolus regimen, i.e. by multiple daily injections at least four times daily, or by subcutaneous insulin pump, for at least 12 months, use of metformin allowed Exclusion Criteria: Inability to provide informed consent Insulin requirement of <34 or >200 units per day Treatment with systemic corticosteroids, immunosuppressive or cytostatic drugs Known allergy to aspart insulin Use of oral antidiabetic drugs other than metformin Symptomatic diabetic neuropathy History of a major cardiovascular disease event (myocardial infarction, stroke, symptomatic peripheral artery disease, coronary bypass surgery, percutaneous coronary or peripheral artery angioplasty) in the previous 6 months Pregnancy or the intention to become pregnant Renal disease (creatinine >150 μmol/l or MDRD-GFR <30 ml/min/1.73m2) Liver disease (aspartate aminotransferase or alanine aminotransferase level of more than three times the upper limit of normal range) Presence of any other medical condition that might interfere with the study protocol anemia

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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 |
| --- | --- |
| Other: insujet is tested first<br>first procedure: experiment with the investigational product (Insujet pen)containing insulin aspart; second procedure: control device (conventional Novopen III insulin pen) contains insulin aspart. | Drug: insulin aspart<br>* After hyperglycaemia (18-23 mmol/l) has been reached (by decreasing or interrupting exogenous insulin administration 12-24 hours before the experiment), aspart insulin (in a dose of 1.5 times the amount of insulin needed to reduce blood glucose to 6 mmol/l calculated by the insulin-sensitivity factor) will be administered subcutaneously by Insujet pen or conventional insulin pen, on two separate occasions, or vice versa. The injection will be given by the subject under supervision of the research staff.<br>* Other names: Novorapid;|
| Other: insujet is tested second<br>first procedure: experiment with the conventional Novopen III insulin pen containing insulin aspart; second procedure: investigational device (Insujet) contains insulin aspart. | Drug: insulin aspart<br>* After hyperglycaemia (18-23 mmol/l) has been reached (by decreasing or interrupting exogenous insulin administration 12-24 hours before the experiment), aspart insulin (in a dose of 1.5 times the amount of insulin needed to reduce blood glucose to 6 mmol/l calculated by the insulin-sensitivity factor) will be administered subcutaneously by Insujet pen or conventional insulin pen, on two separate occasions, or vice versa. The injection will be given by the subject under supervision of the research staff.<br>* Other names: Novorapid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| T-BG≥10 | the time in minutes until plasma glucose concentration has dropped with ≥ 10mmol/l (T-BG≥10). | participants will be followed for the duration of the study, an expected average of 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| T-BG5 and 8 (min) | the time in minutes until plasma glucose values drop below 8 an 5 mmol/l, respectively | participants will be followed for the duration of the study, an expected average of 4 weeks | 
| Rfall | the slope of the glucose fall (mmol • l-1 • min-1), calculated from the time- glucose curve | participants will be followed for the duration of the study, an expected average of 4 weeks | 
| BG-AUC 0-2h | the area under the time-glucose curve, reflecting post-injection hyperglycaemic burden, from 0 to 2h after insulin injection. | participants will be followed for the duration of the study, an expected average of 4 weeks | 
| BG-AUC 0-6h | the area under the time-glucose curve (mmol • min-1 • l-1), from 0 to 6h after insulin injection. | participants will be followed for the duration of the study, an expected average of 4 weeks | 
| C-INSmax (pmol/l) | maximal insulin concentration | participants will be followed for the duration of the study, an expected average of 4 weeks | 
| T-INSmax | time to maximal insulin concentration in minutes(C-INSmax) | participants will be followed for the duration of the study, an expected average of 4 weeks | 
| T-INSBL | the time until plasma insulin values drop below baseline values (minutes) | participants will be followed for the duration of the study, an expected average of 4 weeks | 
| INSAUC | area under the insulin concentration curve (pmol • min-1 • l-1)(from timepoint 0), reflects total insulin absorption | participants will be followed for the duration of the study, an expected average of 4 weeks | 
| T-INSAUC50% | time until 50% of insulin absorption in minutes(mean residence time, MRT) | participants will be followed for the duration of the study, an expected average of 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diabetes, insulin administration, hyperglycaemia, insulin aspart