Randomized, Double-blind, Crossover, PK and GD Study of CSII in Subjects With Type 1 Diabetes

Previous clinical studies of insulin coadministered with rHuPH20 have demonstrated insulin
pharmacokinetics (PK) that better replicate the natural insulin response to a meal in
healthy individuals. Specifically, coadministration of insulin with rHuPH20 accelerates the
onset of insulin action (early t50% max), the time of peak insulin concentration (tmax), and
the offset of insulin action (late t50%max). rHuPH20 coadministration also increases the
peak insulin concentration, increases early insulin exposure, and reduces late postprandial
insulin exposure. In healthy volunteers, this acceleration of insulin exposure results in
accelerated glucose metabolism, as measured by glucose infusion rates during a euglycemic
clamp. In subjects with Type 1 and Type 2 diabetes mellitus, the acceleration of insulin
exposure has been shown to reduce postprandial hyperglycemia, as measured by peak blood
glucose, two-hour postprandial glucose, and total area of glucose excursions >140 mg/d
occurring in response to a standardized liquid test meal.

This study is designed to compare the PK of insulin analogs when they are infused with and
without rHuPH20. In addition to comparisons of various PK and glucodynamic measures, safety
and tolerability of insulin analogs alone and with rHuPH20 during continuous infusion of
each study drug in subjects with Type 1 diabetes mellitus will be evaluated.