Reproducibility of insulin injected by needle-free jet-injection for glycaemic management in healthy volunteers

Using a specific jet injector for the administration of a rapid-acting insulin
analogue has been shown to advance the absorption of insulin from the
subcutaneous area into the bloodstream by 40-50%, when compared to conventional
injection by insulin pens. The reproducibility of the jet stream method has not
been previously determined in vivo. It is also unknown how the efficacy of
injecting regular insulin by jet stream compares to that of rapid-acting
analogues injected by conventional pen. We 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. This is important
because rapid acting insulin analogs are not worldwide available but are very
important in maintaining stable blood glucose values and preventing diabetic
complications.

1. To compare the pharmacologic reproducibility of the rapid-acting insulin
analogue aspart (Novorapid®) injected by jet-injection to that of the same
insulin injected with a conventional pen.
2. To compare pharmacokinetic and -dynamic profile of regular insulin injected
by jet injection to that of aspart insulin injected by conventional pen.

Double-blind double-dummy randomized controlled parallel/cross-over study

All subjects will participate to two identical study days, after being
randomized to the jet injector (J-I) study-arm or the conventional pen (C-P)
study-arm. Subjects randomized to J-I will receive a standardized dose of
aspart insulin subcutaneously by jet injection and a placebo administration
(injection with a pen identical to a conventional pen but without actual
contents) by conventional pen. Subsequently, glucose 20% will be given
intravenously to maintain plasma glucose at fasting levels (normoglycemic
clamp). Those randomized to C-P will receive the dose of aspart by conventional
pen and the placebo administration by jet injection. The pharmacokinetic and
pharmacodynamic profile of insulin aspart will be derived from the time-action
profiles of plasma insulin levels and glucose requirements, respectively.
Within-subject variability will be calculated for the pharmacokinetic and -
dynamic profiles for both administration routes. All subjects will be asked to
participate to one additional clamp study until 20 subjects have been enrolled,
during which regular insulin will be administered by jet injection. The
pharmacological profile will be compared to the profile obtained in patients
randomized to C-P and obtained in a previous study.

All participants will undergo a standard physical examination to determine
eligibility. For each experiment, two cannulae will be inserted intravenously,
one for blood sampling, the other for glucose 20% as needed to maintain
normoglycemia after insulin injection. A total of 148 ml of blood will be drawn
during each experiment for laboratory measurements, i.e. 296 ml for two
experiments or 444 ml for three experiments. The risk of hypoglycemia after
insulin injection is negligible since plasma glucose levels will be measured at
5-10-min intervals and glucose will be infused should plasma glucose levels
(tend to) fall below 4.8 mmol/l. Intravenous glucose may cause local irritation
and occasionally phlebitis.