3. Introduction

              3.1. Study Rationale

              A prandial insulin with faster-on and/or faster-off characteristics might reduce glycemic excursions and the incidence of postprandial hypoglycemia compared to currently available fast-acting insulin analogs. LY900014 is an ultra-rapid-acting insulin lispro formulation that has shown an increased early absorption compared to commercially available insulin lispro (Humalog®; Eli Lilly). LY900014 aims to closely mimic the physiological prandial insulin secretion pattern, which may more effectively control postprandial glucose excursions and allow increased flexibility of the time of dosing relative to a meal.

              This study aims to compare PK and PD profiles as well as the improved action of insulin lispro from LY900014 on the control of postprandial blood glucose in comparison to Humalog in patients with T1DM. The improved action of insulin lispro will be assessed by using standardized mixed-meal tolerance test (MMTTs). Furthermore, this study will explore the postprandial glucose profiles with LY900014 and Humalog injected at two different meal-to- dose time intervals either immediately before or 20 minutes following the start of the test meal, to optimize future use of this investigational medicinal product (IMP).

              3.2. Background

              The insulin analog insulin lispro (Humalog) has been shown to be absorbed more quickly than regular human insulin (Humalog package insert, 2015). In healthy volunteers given subcutaneous (SC) doses of insulin lispro ranging from 0.1 to 0.4 units (U)/kg, peak serum levels were seen 30 to 90 minutes after dosing (Humalog package insert, 2015). However, the general consensus is that rapid-acting insulin is still not rapid enough to match carbohydrate absorption profiles, which limits efficacy and dosing flexibility. An ultra-rapid-acting prandial insulin would shift the PK/GD of insulin analogs so that they have an even faster onset to better match carbohydrate absorption and also allow greater flexibility in the time of dosing relative to meals.

              LY900014 represents a new formulation that contains insulin lispro, treprostinil, citrate and other excipients. This formulation involves the novel use of a microdose of treprostinil ( C ) as an excipient to enhance the absorption of insulin lispro by local vasodilatation rather than as C an active pharmaceutical ingredient to elicit a systemic effect. Treprostinil is a prostacyclin analogue, administered either through inhalation ( C ), as an intravenous (IV) infusion or as a continuous SC administration for the treatment of symptomatic C pulmonary arterial hypertension (PAH) and has been approved in the US since 2002 and in Germany since 2006 (AMIS database [WWW]). Sodium citrate, an excipient that speeds insulin absorption (at least in part by enhancing vascular permeability), is also included in the formulation to further enhance the absorption of insulin lispro. Each of the other excipients (such as magnesium chloride) in the LY900014 formulation is listed in the US Food and Drug Administration

              (FDA)’s Generally Recognized as Safe Food Additives database and in the FDA’s Inactive Ingredients in Approved Drugs database. Furthermore, the excipient concentration in LY900014 is within the limits identified for approved drug products in the FDA Inactive Ingredients in Approved Drugs database. To date, LY900014 has been administered to approximately 89 patients with diabetes (60 T1DM and 29 T2DM) across 3 Phase 1b studies and approximately 107 healthy volunteers across these Phase 1 studies. The total insulin lispro exposure was similar between LY900014 and Humalog; however LY900014 demonstrated a faster and earlier insulin lispro absorption compared to Humalog. Additionally, through the use of multiple daily injections of LY900014 for up to 2 weeks in patients with either T1DM or T2DM, it was found that LY900014 was well tolerated. There were no serious adverse events (SAEs) related to study treatment or discontinuations from the studies because of a drug-related adverse event (AE). Small numbers of treatment-emergent adverse events were reported, and there were no notable increases in these events in relation to any of the LY900014 formulations compared to those in relation to Humalog. There were no reported cases of severe hypoglycemia. Additionally, there was no reported incidences of local or systemic allergic reactions.

              3.3. Benefit/Risk Assessment

              This study will not offer any direct benefits to the patients participating in the study. The data from previous studies in healthy patients and patients with T1DM and T2DM have shown that LY900014 was well tolerated and the adverse drug reactions are in keeping with those reported for Humalog.

              Potential risks associated with LY900014, derived from the known risks of insulin lispro (Humalog), are hypoglycemia, hypersensitivity reactions (localized allergy and/or systemic allergy), undesirable effects at the injection site (injection-site reactions and lipodystrophy), and peripheral edema (Humalog package insert, 2015).

              Notably, across all doses in the studies that have evaluated treprostinil ( CCI ) as a local vasodilator with or without insulin lispro, there was no clinically significant increase in those AEs associated with systemic absorption of treprostinil, as described in the CCI package insert (2014). The exposures of treprostinil in LY900014 in this study are expected to be undetectable compared to those observed in the dose ranges previously explored with SC bolus administration of treprostinil and are expected to be substantially lower than those observed in the treatment of PAH. No known potential risks are associated with the use of small amounts of treprostinil in the LY900014 formulation.

              In preclinical safety pharmacology and toxicity studies, or clinical pharmacology studies involving LY900014 or treprostinil alone, other than known risks associated with Humalog and CCI , no additional risks were identified. Additionally, local and systemic toxicity profiles of Humalog and CCI do not suggest the potential for additive or synergistic toxicity

              The study includes inpatient procedures during which participants will be continuously monitored. Patients will be without food intake from the start of the MMTT to completion of blood collection (approximately 420 minutes) unless required to treat hypoglycemia, (see Section

              9.5.6.2 for definition of hypoglycemia and Section 9.5.8 for treatment guidelines). If a patient experiences elevated blood glucose following food intake for more than 1 hour, insulin glulisine will be administered intravenously (see Section 9.5.8 for treatment guidelines). Patients will maintain their basal insulin regimen of site-provided insulin glargine during the entire study including the MMTT days unless safety issues arise; in this case, the investigator will discuss a change of the basal insulin regimen with the sponsor clinical pharmacologist (CP) and implement this change, if necessary, to prevent any medical problems.

              More information about the known and expected benefits, risks, serious adverse events (SAEs) and reasonably anticipated adverse events (AEs) of LY900014 are to be found in the Investigator’s Brochure (IB).

                                       4. Objectives and Endpoints

              Table ITRV.1 shows the objectives and endpoints of the study.

Section label: Study Rationale and Background