Reproducibility of Insulin Action When Administered by Needle-free Jet Injection

1. Introduction Insulin administration by a jet injector is a needle-free alternative to conventional administration of insulin by insulin pens or syringes. Jet injectors deliver insulin at a high velocity (typically >100m/s) across the skin in the subcutaneous tissue and dispense the insulin over a larger area than insulin injected with a syringe. This significantly accelerates absorption of rapid-acting insulin from the subcutaneous area into the systemic circulation.

Reproducibility of the insulin effect is an essential, but easily overlooked, issue for a product that needs to be administered so frequently in daily practice. When identical doses of aspart insulin were injected by a common syringe on two different days separated by at least a week, the intra-individual and inter-individual variability of various pharmacokinetic and -dynamic parameters was found to vary between 11-21% and 18-36%, respectively. Reproducibility has not been investigated when insulin was administered by jet injectors. The investigators previous studies indicated smaller between-subjects variability in insulin absorption after injection by this jet injector than after injection by conventional pen, providing some evidence that reproducibility is at least comparable, but potentially even better when using a jet injector.

The aim of the present research proposal is to compare the variability of the metabolic effect of insulin aspart when administered by jet injection to that when injected by conventional insulin pen, under controlled experimental conditions.

An additional aim is to investigate the pharmacokinetic and -dynamic comparability between regular soluble insulin injected by the jet stream device with aspart insulin administered by conventional pen. The reason the investigators wanted to investigate the comparability is that rapid-acting insulin analogs are not worldwide available and very costly compared to regular insulin. If you could achieve the same pharmacological benefits as rapid acting insulin with a less costly type of insulin, this would be of great benefit for patients with diabetes in less developed countries. 2. Hypotheses The variability of the metabolic effect of insulin administered subcutaneously by jet injection is similar to or better than that of insulin administered by a conventional insulin pen. The investigators also hypothesize that the metabolic effect of soluble insulin administered by jet injection is similar to that of insulin aspart administered by conventional insulin pen. 3. Study Population For this study, a total of 30 healthy volunteers will be recruited. Subjects are potentially eligible when they are between 18 and 50 years of age and in good clinical condition. Additional participants will be recruited in case of drop-out. 4. Investigational medicinal products Main study: Insulin aspart (Novorapid® Penfill 100 units/ml, 3 ml ampoule): rapid-acting analogue of human insulin.

Sub-study: Regular Human Insulin (Humulin® Penfill 100 units/ml, 3ml ampoule): human regular insulin. 5. Summary of known and potential risks and benefits Novorapid® insulin is indicated for the treatment of diabetes mellitus in adults, adolescents and children above the age of 2 years. The study comprises a risk of hypoglycemia. However, the risk of hypoglycaemia during the experiment is negligible, since glucose is measured at 5-10 minute intervals and additional glucose will be administered should glucose levels tend to drop below 4.8 mmol/l. Intravenous glucose 20% may cause local irritation and occasionally phlebitis. 6. Methods 6.1 Randomisation The study will have a randomised controlled parallel design. Randomisation will be done by a computer program with the use of blocks of two subjects, to randomize which of the two devices will contain insulin and which placebo solution. This will ensure that equal number of subjects will have the experiment with the investigational product (InsujetTM pen) or with the control device (Novopen® IV insulin pen).