Illustration of study design for Protocol I8B-MC-ITRV.

              Patients will be required to attend the CRU on at least 8 occasions (no more than 10 occasions if dose-finding and/or one MMTT rescheduled) as noted in the Study Schedule (see Section 2):

                   Informed consent

                   Screening visit

                   Lead-in and insulin transition period (see Section 9.2.1)

                   4 inpatient CRU study visits (including dose finding assessment [see Section 9.2.2])

                   A follow-up visit

              Eligible patients who have satisfied the entry criteria and completed all screening procedures will return to the CRU at least 2 weeks prior to Period 1 Day -2 to begin a lead-in and insulin transition period. When patients visit the CRU to begin the lead-in period, patients will receive instruction on general diabetes education including measurement of self-monitored plasma glucose (SMPG) and receive instruction on the insulin transition (see Section 9.2.1). During the insulin transition period, patients will transition from their current basal insulin therapy to site- provided insulin glargine and Humalog CCI (see Section 9.2.1). Following insulin transition, patients will return to the CRU for the dose-finding assessment (see Section 9.2.2) on either the evening of Day -2, Period 1 or early morning of Day -1, Period 1. The dose-finding assessment will use Humalog administered immediately before a standardized liquid test meal (MMTT) to inform the dose of LY900014 and Humalog to be used during subsequent study MMTT assessments. Upon completion of the dose-finding assessment, patients will be randomised to 1 of 4 treatment sequences. Prior to the MMTT in each study period, patients will undergo a run-in period (see Section 9.2.3.1) to achieve a predetermined glucose target of 135 ±15 mg/dL (7.5 ±0.8 mmol/L). Once the glucose target has been attained, patients will proceed with the MMTT in which a single individualized SC dose of LY900014 or Humalog will be administered either immediately before the test meal or 20 minutes following the start of the test meal (see Section 9.2.3.2).

              Doses of LY900014 and Humalog during the 4 study periods will be separated by a minimum washout of approximately 21 hours. The maximum duration allowed for all 4 periods is approximately 6 weeks. Patients will continue using site-provided Humalog and insulin glargine during the washout periods between MMTTs (see Section 7.7 for use of concomitant medication and basal insulin). During the washout periods, patients will be instructed to perform regular blood glucose monitoring (see Section 9.5.7).

              Following completion of all study procedures in each Period, patients may be offered a meal and discharged from the CRU at the discretion of the principal investigator.

              Study governance considerations are described in detail in Appendix 3.

              5.2. Number of Participants

              Up to 36 patients may be enrolled so that approximately 30 patients complete the study. For purposes of this study, a patient completes the study when all scheduled procedures shown in the Schedule of Activities have been finished. Patients who drop out may be replaced, and the replacement patient will adopt all 4 assigned crossover treatments of the original patient’s randomization schedule.

              5.3. End of Study Definition

              End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of Activities (Section 2) for the last patient.

              5.4. Scientific Rationale for Study Design

              The study is a 4-period crossover design to reduce the variability of insulin PK and GD, as each patient will act as his/her own control. The total number of patients needed with a crossover design is less than the number needed with a parallel group design. A maximum duration of approximately 6 weeks is allowed for patients to complete all 4 assigned periods to minimize the risk of insulin resistance/changes in mean glycemic control during the study.

              Randomization and blinding are used to avoid bias introduced through an association between allocation order of investigational medicinal product (IMP) and patient characteristics. The Lilly clinical pharmacologist (CP)/Lilly study team will be unblinded.

              In each study period patients will undergo a run-in period before the MMTT using a variable insulin and glucose IV infusion. This run-in period will allow for improved comparability of the postprandial glucose response to a mixed meal after treatment with LY900014 and Humalog administered either immediately before the start of the meal, or 20 minutes following the start of the test meal. This run-in aims to achieve similar preprandial glucose levels for all patients before the start of the test meal and thereby reduces the variability of the postprandial glucose response. Insulin glulisine has been chosen for the IV optimization of blood glucose during the run-in because insulin glulisine does not cross-react with the insulin lispro–specific assay used for the PK analysis.

              Under this design, if two periods occur on consecutive days, the interval between the last bolus on the first day and the first bolus on the second day is much longer compared to the length of time that the treatment (LY900014 or Humalog) lasts in the bloodstream; therefore, no carryover effect is assumed. This enables PK and GD data from the breakfast meal tests of each period to be analyzed independently and separately.

              A minimum of approximately 21 hours washout between the test meals allows for a complete washout of study drug administered with the MMTT and glucose response and prevents carry- over effects.

              5.5. Justification for Dose

              The bolus dose of insulin lispro (LY900014 or Humalog) will be individualized per patient to cover the carbohydrate content in this standardized liquid test meal. This dose of insulin is reflective of a clinically relevant, individualized insulin dosing, similar to how patients would determine the insulin dose for the carbohydrate content in a meal. For each patient, the individualized prandial insulin lispro dose in LY900014 and Humalog for each test meal must be kept identical throughout the crossover periods.

                                              6. Study Population

              Eligibility of patients for study enrollment will be based on the results of screening medical history, physical examination, vital signs, clinical laboratory tests, and electrocardiogram (ECG).

              The nature of any conditions present at the time of the physical examination and any preexisting conditions will be documented.

              Screening may occur over a 14 day period prior to the lead-in site visit. Patients who are not entered within this time period, may be subjected to an additional medical assessment and/or clinical measurements to confirm their eligibility.

              Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, are not permitted.

              6.1. Inclusion Criteria

              Patients are eligible for inclusion in the study only if they meet all of the following criteria at screening and/or enrollment:

                     [1] are male or female patients with T1DM for at least 1 year. A diagnosis of T1DM is based on medical history with a fasting C-peptide <0.30 nmol/L.

                               a. Male patients:

                                      i. No male contraception required except in compliance with specific local government requirements

                               b. Female patients:

                                      i. Women of child-bearing potential who are abstinent (if this is complete abstinence, as their preferred and usual lifestyle) or in a same sex relationship (as part of their preferred and usual lifestyle) must agree to either remain abstinent or stay in a same sex relationship without sexual relationships with males.

                                      ii. Otherwise, women of child-bearing potential participating must agree to use one highly effective method of contraception until discharge from final treatment period.

                                             1. Women of child bearing potential must test negative for pregnancy prior to initiation of treatment as indicated by a negative serum pregnancy test at the screening visit followed by a negative urine pregnancy test within 24 hours prior to exposure in Period 1.

                                             2. A highly effective method of contraception includes a combined (estrogen and progestogen containing) or progestogen-only hormonal contraception administered orally, intravaginally, or transdermally and is associated with inhibition of ovulation. Alternatively, patients may use either an intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, or the partner should have been vasectomised.

                                     iii. Women not of childbearing potential may participate and include those who are:

                                             1. infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy or bilateral salpingectomy), congenital anomaly such as mullerian agenesis; or

                                             2. post-menopausal – defined as a woman being amenorrheic for more than 1 year without an alternative medical cause and a serum follicle- stimulating hormone (FSH) level compatible with postmenopausal status. A FSH level in the post- menopausal range may be used to confirm a post- menopausal state in women not using hormonal contraception or hormonal re

Section label: Inclusion Criteria