Abbreviations: AE = adverse event; AUC = area under the concentration versus time curve; BGmax = maximal plasma glucose concentration; Cmax = maximal concentration; IMG = intramuscular glucagon; PD = pharmacodynamics; PG = plasma glucose; PK = pharmacokinetics; SAE = serious adverse event; TEAE = treatment-emergent adverse event; Tmax = time to maximal concentration.

(Estimands were not included in this older sample protocol.)

Key aspects of the trial design are summarised below.

Number of Arms: 4

Trial Blind Schema: Open Label

Blinded Roles: Not applicable.

Number of Participants:

Seventy-five patients may be enrolled in order to have at least 66 patients (at least 30 patients with T1DM and T2DM, respectively) complete both periods with evaluable primary outcome. If patients discontinue from the study before completion of both periods with evaluable primary outcome for any reason, the patient may be replaced. Replacement should not occur beyond 75 patients enrolled, if it is expected to have at least 66 patients complete the study.

Duration

Total planned duration of trial intervention for each participant:

2 days

Total planned duration of trial participation for each participant:

6 weeks

Patients will undergo a screening examination within 28 days prior to enrollment. Patients will be administered a single dose in Periods 1 and 2, which will be separated by a washout period of 3 to 14 days. Patients will return for a follow-up visit 26 to 30 days after the last study treatment. Patients will undergo a screening examination within 28 days prior to enrollment. Patients will be administered a single dose in Periods 1 and 2, which will be separated by a washout period of 3 to 14 days. Patients will return for a follow-up visit 26 to 30 days after the last study treatment.

Committees:

Not Applicable.

There is no anticipated therapeutic benefit for the patients participating in this study

This study will expose patients to an insulin-induced hypoglycemia meant to simulate hypoglycemia in a controlled setting. The procedure of insulin-induced hypoglycemia targeting nadir glucose around 50 mg/dL is adopted from a previously completed trial, specifically Study IGBC, which demonstrated the safe use of this method. This is an inpatient procedure in which the patients will be under constant supervision of the clinical research unit (CRU) staff with frequent glucose monitoring. Safety provisions have been considered in that IV glucose will be administered if the patient experiences signs and symptoms of severe hypoglycemia and gauged to require intervention during the experimental procedure, at the discretion of the investigator.

Potential risks associated with LY900018, derived from the known risks of currently existing injected glucagon therapy and from the safety profile observed from clinical trials conducted for LY900018, include nausea, vomiting, allergic reactions, increased blood pressure (BP) and heart rate, headache, dysgeusia, and nasal or ocular events (Glucagon G Novo for Injection Package Insert, 2016; Glucagon G Novo for Injection Interview Form, 2015; GLUCAGON for Injection ITO Package Insert, 2016; GLUCAGON for Injection ITO Interview Form, 2016).

Nausea and Vomiting: Glucagon therapy, including LY900018, may cause nausea and vomiting.

Allergic Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with glucagon therapy, including LY900018. Patients who have had hypersensitivity reactions to injectable glucagon, or LY900018 or any of its excipients will be excluded from all clinical studies.

Increased Blood Pressure and Heart Rate: Glucagon exerts positive inotropic and chronotropic effects. A temporary increase in both BP and heart rate may occur after the administration of glucagon, including LY900018.

Headache and Dysgeusia: Use of LY900018 may cause headache and altered taste.

Nasal Symptoms: Use of LY900018 may cause a variety of nasal symptoms, such as runny nose, stuffy nose, nasal discomfort, cough, and sneezing.

Ocular Symptoms: Use of LY900018 may cause a variety of ocular symptoms, such as watery eyes, redness of eyes, and itchy eyes.

No additional potential risks of LY900018 were identified in preclinical safety pharmacology and toxicity studies (Reno et al. 2015).

More information about the known and expected benefits, risks, serious adverse events (SAEs), and reasonably anticipated adverse events (AEs) of LY900018 are to be found in the Investigator’s Brochure (IB).

More detailed information about the known and expected benefits and risks of GlucaGen® may be found in the Summary of Product Characteristics (GlucaGen Summary of Product Characteristics, 2015).

To demonstrate that 3 mg LY900018 is non-inferior to 1 mg IMG for the proportion of patients achieving treatment success from insulin-induced hypoglycemia using a non-inferiority margin of 10%

Abbreviations: AE = adverse event; AUC = area under the concentration versus time curve; BGmax = maximal plasma glucose concentration; Cmax = maximal concentration; IMG = intramuscular glucagon; PD = pharmacodynamics; PG = plasma glucose; PK = pharmacokinetics; SAE = serious adverse event; TEAE = treatment-emergent adverse event; Tmax = time to maximal concentration

Estimand description not available in this older protocol.

Abbreviations: AE = adverse event; AUC = area under the concentration versus time curve; BGmax = maximal plasma glucose concentration; Cmax = maximal concentration; IMG = intramuscular glucagon; PD = pharmacodynamics; PG = plasma glucose; PK = pharmacokinetics; SAE = serious adverse event; TEAE = treatment-emergent adverse event; Tmax = time to maximal concentration

Estimand description not available in this older protocol.

This study design involves an open-label assessment of 3 mg LY900018 compared to 1 mg of the marketed IMG (GlucaGen). The study will be open label because the different administration routes (ie, intranasal and IM) cannot be blinded. The use of a crossover design allows each patient to serve as his or her own control, thereby reducing variability. The washout period of 3 to 14 days is considered sufficient based on the short half-life of LY900018 (t1/2 = approximately 25 minutes). Since the critical role of glucagon in the treatment of severe hypoglycemia is to raise the PG level sufficiently to restore cognition to the point where oral carbohydrate can be ingested, treatment success is defined either as an increase in PG returning to normal level of ≥70 mg/dL or an increase of ≥20 mg/dL from the PG nadir within 30 minutes after receiving glucagon, without the patient receiving additional actions to increase glucose. It is believed that an expected PG nadir of approximately 50 mg/dL (approximately 5 minutes after stop of insulin infusion at 60 mg/dL) is low enough to generate clinical symptoms in most participants and is high enough to avoid impairment of consciousness. The primary analysis includes both patients with T1DM and T2DM since it is expected that the proportion of treatment success is similar between patients with T1DM and T2DM.

Not defined in protocol.

Male patients must use an effective method of contraception for the duration of the study and for 28 days following the last study treatment.

Female patients of childbearing potential must use one highly effective method of contraception (<1% failure rate; such as combined oral contraceptive pill, implanted contraceptives, or intrauterine device) or a combination of 2 effective methods of contraception (such as male or female condoms with spermicide [not approved in Japan], diaphragms with spermicide [not approved in Japan], or cervical sponges) during the study and for 28 days following the last study treatment. The patient may choose to use a double barrier method of contraception. Barrier protection methods without concomitant use of a spermicide are not a reliable or acceptable method. Thus, each barrier method must include use of a spermicide. It should be noted that the use of male and female condoms as a double barrier method is not considered acceptable due to the high failure rate when these methods are combined.

In both treatment periods, patients will fast for at least 8 hours prior to beginning the hypoglycemia induction procedure. Patients should not be given any calorie-containing food/drink during insulin-induced hypoglycemia and within 90 minutes of glucagon administration unless there is a safety concern. The patients will receive a carbohydrate-rich meal after completion of all pharmacokinetic (PK) blood sample collections, at 240 minutes post glucagon dose. Patients will be given access to calorie-free water up to 240 minutes post study treatment. While resident in the CRU, patients should not consume any food or caloric drinks other than that provided by the CRU. When not resident in the CRU, patients will be encouraged to follow their normal diets

Patients should refrain from caffeine-containing food/beverages (eg, cola, chocolate drinks, tea, and coffee) from Day -1 to discharge from CRU in each period. Patient alcohol intake should not exceed 21 units per week (males up to age 65) and 14 units per week (males over 65 and females) during the study. Patients must not consume alcohol from Day -2 to discharge from CRU in each period. Smoking will not be permitted when resident in the CRU.

Patients are encouraged to maintain their regular exercise habits for the duration of the study. However, patients should avoid strenuous exercise 48 hours prior to admission or study visit.

From the beginning of hypoglycemia induction to 240 minutes post study treatment, patients should remain recumbent or sitting on the bed. >

See Section 6.4 above.

The investigator or designee must confirm appropriate temperature conditions have been maintained, as communicated by the sponsor, during transit for all investigational product received and any discrepancies are reported and resolved before use of the study treatment.

All investigational products should be stored in an environmentally-controlled and monitored (manual or automated) area in accordance with the labeled storage conditions with access limited to the investigator and authorized site staff. Only participants enrolled in the study may receive investigational product or study materials, and only authorized site staff may supply or administer investigational product.

The investigator, institution, or the head of the medical institution (where applicable) is responsible for study treatment accountability, reconciliation, and record maintenance (such as receipt, reconciliation, and final disposition records)

Clinical trial materials will be labeled according to the country’s regulatory requirements. Lilly will supply LY900018 and GlucaGen to the clinical site. Study materials will be provided as open-label material.

Investigational products must be stored at the investigational site, according to the instructions provided on the product label, in a locked and secure place.

Unused investigational products will remain locked and securely stored, according to the instructions provided on the product label at the investigational site, until returned to the sponsor or its designee, according to written instruction from the sponsor

Prior to the study drug administration on Period 1 Day 1, patients will be randomly assigned to a treatment sequence (either LY900018 in Period 1 and IMG in Period 2, or vice versa).

The treatment sequence to be administered for each enrolled patient will be determined according to a randomization table.

This is an open-label study. However, the treatment assignment list for all randomized patients will not be shared with those responsible for doing either the treatment response assessments or making the decision to take additional action to raise patients’ PG concentrations post-glucagon administration. The intent is to minimize any potential bias in administering additional rescue treatment for hypoglycemia.

The following concomitant medications are prohibited to use during the course of the study: beta-blocker, indomethacin, warfarin, and anti-cholinergic drugs.

The following concomitant medications that affect gastric motility can be used during the study but should be washed out before 7 days of each period and not taken while in the CRU: pro-motility medications (eg, metoclopramide, domperidone), opiate medications (eg, morphine), and medications with anti-emetic effects (eg, promethazine, prochlorperazine).

In general, concomitant medication should be avoided; however, acetaminophen (1 g, maximum 2 g/24 hours) may be administered at the discretion of the investigator for treatment of headaches, etc. If the need for concomitant medication (other than acetaminophen) arises, inclusion or continuation of the patients may be at the discretion of the investigator after consultation with a Lilly clinical pharmacologist (CP) or CRP. Any medication used during the course of the study must be documented.

Patients on stable concomitant medication at the time of study entry should continue their regular, unchanged dose throughout the study. These medications include stable regimen for 3 months of the anti-hyperglycemic therapy (for example, insulins and OAMs) as well as anti-hypertensive and anti-lipidemic medications. In addition to the physical examination, investigators should review the insulin regimen for all patients enrolled into the study to confirm acceptability to undergo the procedure to induce hypoglycemia (see Schedule of Activities; Section 2).

For patients using basal insulin, the last basal insulin injection should occur no later than 12 hours prior to the insulin-induced hypoglycemia procedure, and the basal dose should not be changed. Patients may inject basal insulin any time after the last PK sample is collected on Day 1 in each period.

For patients using prandial insulin, the last prandial insulin injection should occur no later than 6 hours prior to the insulin-induced hypoglycemia procedure. Patients may inject prandial insulin after the last PK sample is collected and before the meal on Day 1 in each period. The first prandial insulin dose for an individual patient after insulin-induced hypoglycemia procedure should be determined by the investigator based on the PG before meal and carbohydrate intake.

For patients using an insulin pump, a continuous subcutaneous insulin infusion by pump should be discontinued prior to procedure to induce hypoglycemia. Patients may start subcutaneous insulin infusion after the last PK sample is collected and before the meal on Day 1 in each period. The insulin dose should be determined by the investigator based on the PG before meal and carbohydrate intake.

For patients using OAMs, the last dose should occur no later than 12 hours prior to the insulin-induced hypoglycemia procedure. Patients may start OAM after the last PK sample is collected on Day 1 in each period.

See Section 7.2.

Not Applicable.

Not Applicable.

If the sponsor or investigator identifies a patient who did not meet enrollment criteria and was inadvertently enrolled, a discussion must occur between the Lilly CP/CRP and the investigator to determine if the patient may continue in the study. If both agree it is medically appropriate to continue, the investigator must obtain documented approval from the Lilly CP/CRP to allow the inadvertently enrolled patient to continue in the study with or without continued treatment with investigational product.

Following the review of the safety data from the first 6 patients to complete Period 2 Day 1, the study will be stopped if deemed necessary for patient safety in the opinion of the Investigator and sponsor (Section 10.3.7).

The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, regulatory, or other reasons consistent with applicable laws, regulations, and GCP

The primary efficacy measure is the proportion of patients achieving treatment success, defined as either an increase in PG to >70 mg/dL or an increase of >20 mg/dL from nadir within 30 minutes after administration of glucagon.

Assessments Secondary efficacy measures will be determined from the pharmacodynamic (PD) characterization of PG profiles, including evaluation of change from baseline PG concentrations.

Assessments Subjective hypoglycemia symptoms will be assessed using a self-reported assessment tool (Edinburgh Hypoglycemia Scale; Appendix 7) during the initiation of the hypoglycemia induction, as well as at various time points following the administration of either LY900018 or IMG (see Schedule of Activities; Section 2).

The ability of the patient to identify hypoglycemic symptoms and describe their frequency will be captured at Period 1 Day -1 (see Schedule of Activities; Section 2). This self-report assessment will be done using the Clarke Hypoglycemia Awareness Survey (Appendix 8).

A study investigator, or qualified designee, must be present at the bedside for clinical assessments of the patient during the insulin infusion and for the 120 minutes following the glucagon administration.

The bedside PG level, measured using a glucose analyzer (Antsense Duo, HORIBA Ltd. or equivalent), must be 90 to 250 mg/dL to start the procedure. If the bedside PG is outside of this range, the hypoglycemia induction should be rescheduled.

Hypoglycemia will be induced by IV infusion of diluted human regular insulin (0.3 U/mL) at a rate of 2 mU/kg/min. The infusion rate may be adjusted as necessary up to a rate of 3 mU/kg/min for T1DM or 4 mU/kg/min for T2DM to decrease bedside PG levels < 60 mg/dL; however, the rate of decrease in PG should not exceed 50 mg/dL per 30 minutes. When the bedside PG concentration reaches <90 mg/dL, the insulin infusion rate may be decreased to approximately 1.0 mU/kg/min at the investigator’s discretion. Once the bedside PG level is <60 mg/dL, the insulin infusion will be stopped. If the target bedside PG level cannot be achieved within 4 hours after the start of insulin infusion, the hypoglycemia induction procedure will be terminated before glucagon administration, and the patient may have a carbohydrate-rich meal and be discharged from the CRU after medical assessment. Additional safety assessments may be conducted at the investigator’s discretion. The patient may be rescheduled for a new dosing visit 1 to 7 days later.

For safety monitoring during the hypoglycemia induction procedure, bedside PG levels will be measured using the glucose analyzer no more than 10 minutes apart while PG is ≥ 90 mg/dL, and no more than 5 minutes apart when PG is < 90 mg/dL.

Blood samples will be collected at pre-hypoglycemia induction and end of insulin infusion (5 minutes prior to study treatment) for PG (PD, as measured by central laboratory) and/or glucagon (PK) measurements according to the Schedule of Activities (Section 2).

Approximately 5 minutes after the insulin infusion has stopped, glucagon (either 3 mg LY900018 or 1 mg IMG) will be administered according to randomization. Refer to Section 7 for details regarding treatments.

For 120 minutes after glucagon administration, bedside PG levels will be measured no more than 5 minutes apart when the PG is < 90 mg/dL, and no more than 10 minutes apart when PG is ≥ 90 mg/dL using a glucose analyzer (Antsense Duo, HORIBA Ltd. or equivalent).

Blood samples will be collected at predose and various time points post glucagon administration for PG (PD, as measured by central laboratory) and/or glucagon (PK) measurements according to the Schedule of Activities (Section 2).

To accurately capture the PG profile, the site should not give patients any calorie-containing food/drink within 90 minutes of glucagon administration unless there is a safety concern.

If the patient loses consciousness or the bedside PG is declining too fast or symptoms consistent with the progression to severe hypoglycemia occur, the investigator may decide to start a glucose infusion to prevent a deterioration of the situation. Following the administration of glucagon, if a patient’s bedside PG concentration remains < 55 mg/dL at 30 minutes or < 60 mg/dL at 45 minutes postdose, IV glucose may be given as deemed clinically necessary. If IV glucose is given, the time and amount of glucose infusion will be recorded in the CRF.

Before discharge from the CRU, the glucose and insulin dosing and stability of the patient will be evaluated by the investigator to ensure patient safety. Patients will remain at the CRU for at least 6 hours following glucagon administration, during which time a carbohydrate-rich meal will be provided. The patient may stay at the CRU longer, at the discretion of the investigator

For each patient, vital sign measurements should be conducted according to the Schedule of Activities (Section 1.3).

Body temperature will be measured as specified in the Schedule of Activities (Section 1.3) and as clinically indicated.

Blood pressure and pulse rate should be measured after at least 5 minutes supine.

Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or posture-induced symptoms. If orthostatic measurements are required, patients should be supine for at least 5 minutes and stand for at least 2 minutes. If the patient feels unable to stand, supine vital signs only will be recorded. Additional vital signs may be measured during each study period if warranted.

For each patient, single and triplicate ECGs should be collected according to the Schedule of Activities (Section 1.3).

Any clinically significant findings from ECGs that result in a diagnosis and that occur after the patient receives the first dose of the investigational product should be reported to Lilly, or its designee, as an AE via CRF.

Single ECGs will be collected and stored locally at the investigator’s site.

Triplicate ECGs will be electronically transmitted to a central ECG laboratory designated by Lilly. The central ECG laboratory will perform a basic quality control check (for example, demographics and study details) then store the ECGs in a database. At a future time, the stored ECG data may be overread at the central ECG laboratory for further evaluation of machine-read measurements or to meet regulatory requirements. Triplicate ECGs collected 30 and 15 minutes prior to the start of insulin-induced hypoglycemia on Day 1 of each period will be used to I8R- establish a baseline. The consecutive triplicate ECGs will be obtained at approximately 1-minute intervals.

When scheduled at the same time point, ECGs must be recorded before collecting any blood samples. Patients must be supine for at least 5 minutes before ECG collection and remain supine but awake during ECG collection. Electrocardiograms may be obtained at additional times, when deemed clinically necessary.

Single ECGs will be interpreted by a qualified physician (the investigator or qualified designee) at the site as soon after the time of ECG collection as possible, and ideally while the patient is still present, to determine whether the patient meets entry criteria at the relevant visit(s) and for immediate patient management, should any clinically relevant findings be identified.

If a clinically significant finding is identified (including, but not limited to, changes in QT/corrected QT interval from baseline) after enrollment, the investigator will determine if the patient can continue in the study. The investigator, or qualified designee, is responsible for determining if any change in patient management is needed, and must document his/her review of the ECG printed at the time of collection. Any new clinically relevant finding should be reported as an AE.

The machine-read ECG intervals and heart rate may be used for data analysis and report writing purposes unless a cardiologist overread of the ECGs is conducted prior to completion of the final study report (in which case the overread data would be used).

For each patient, laboratory tests detailed in Section 13.1 should be conducted according to the Schedule of Activities (Section 1.3). Lilly or its designee will provide the investigator with the results of laboratory tests analyzed by a central vendor, if a central vendor is used for the study.

Nasal inspections with nasal speculum and injection-site assessments will be conducted according to the Schedule of Activities (Section 2). This inspection will ascertain whether sites are normal in appearance prior to and after drug administration

The Lilly CP or CRP/scientist will monitor safety data throughout the course of the study. Lilly will review SAEs within time frames mandated by company procedures. The Lilly CP or CRP will periodically review the following data:

• trends in safety data
• laboratory analytes
• AEs including monitoring of nasal cavity and IM injection site When appropriate, the Lilly CP or CRP will consult with the functionally independent Global Patient Safety therapeutic area physician or clinical research scientist.

Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility designated by the sponsor. Concentrations of glucagon will be assayed using a validated liquid chromatography with tandem mass spectrometry method. Bioanalytical samples collected to measure investigational product concentrations will be retained for a maximum of 1 year following last patient visit for the study.

A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of Activities (Section 1.3), where local regulations allow.

Samples will not be used to conduct unspecified disease or population genetic research either now or in the future. Samples will be used to investigate variable exposure or response to nasal glucagon (LY900018) and to investigate genetic variants thought to play a role in diabetes mellitus and related complications. Assessment of variable response may include evaluation of AEs or differences in efficacy.

All samples will be coded with the patient number. These samples and any data generated can be linked back to the patient only by the investigative site personnel.

Samples will be retained for a maximum of 15 years after the last patient visit, or for a shorter period if local regulations and/or ERBs impose shorter time limits, for the study at a facility selected by Lilly or its designee. This retention period enables use of new technologies, response to regulatory questions, and investigation of variable response that may not be observed until later in the development of LY900018 or after LY900018 is commercially available.

Molecular technologies are expected to improve during the 15-year storage period and therefore cannot be specifically named. However, existing approaches include whole genome or exome sequencing, genome wide association studies, multiplex assays, and candidate gene studies. Regardless of technology utilized, data generated will be used only for the specific research scope described in this section.

At times specified in the Schedule of Activities (see Section 2), venous blood samples will be collected and used to determine PG concentrations. The samples will be stored for up to a maximum of 1 year after last patient visit for the study at a facility selected by the sponsor.

Investigators are responsible for monitoring the safety of patients who have entered this study and for alerting Lilly or its designee to any event that seems unusual, even if this event may be considered an unanticipated benefit to the patient.

The investigator is responsible for the appropriate medical care of patients during the study.

Investigators must document their review of each laboratory safety report.

The investigator remains responsible for following, through an appropriate health care option, AEs that are serious or otherwise medically important, considered related to the investigational product or the study, or that caused the patient to discontinue the investigational product before completing the study. The patient should be followed until the event resolves, stabilizes with appropriate diagnostic evaluation, or is reasonably explained. The frequency of follow-up evaluations of the AE is left to the discretion of the investigator.

After the informed consent form is signed, study site personnel will record, via CRF, the occurrence and nature of each patient’s preexisting conditions, including clinically significant signs and symptoms of the disease under treatment in the study. Additionally, site personnel will record any change in the condition(s) and the occurrence and nature of any AEs.

The investigator will interpret and document whether or not an AE has a reasonable possibility of being related to study treatment, medical device, or a study procedure, taking into account the disease, concomitant treatment, or pathologies.

A “reasonable possibility” means that there is a potential cause and effect relationship between the investigational product, medical device, and/or study procedure and the AE.

Planned surgeries should not be reported as AEs unless the underlying medical condition has worsened during the course of the study.

An SAE is any AE from this study that results in one of the following:

• death
• initial or prolonged inpatient hospitalization
• a life-threatening experience (that is, immediate risk of dying)
• persistent or significant disability/incapacity
• congenital anomaly/birth defect
• important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes listed in the definition above
• when a condition related to the medical device necessitates medical or surgical intervention to preclude either permanent impairment of a body function or permanent damage to a body structure, the serious outcome of “required intervention” will be assigned.

Study site personnel must alert the Lilly CRP/CP, or its designee, of any SAE as soon as practically possible.

Additionally, study site personnel must alert Lilly Global Patient Safety, or its designee, of any SAE within 24 hours of investigator awareness of the event via a sponsor-approved method. If alerts are issued via telephone, they are to be immediately followed with official notification on study-specific SAE forms. This 24-hour notification requirement refers to the initial SAE information and all follow-up SAE information.

Although all AEs are recorded in the CRF after signing informed consent, SAE reporting to the sponsor begins after the patient has signed informed consent and has received investigational product. However, if an SAE occurs after signing informed consent, but prior to receiving investigational product, AND is considered reasonably possibly related to a study procedure then it MUST be reported.

Investigators are not obligated to actively seek AEs or SAEs in patients once they have discontinued from and/or completed the study (the patient summary CRF has been completed). However, if the investigator learns of any SAE, including a death, at any time after a patient has been discharged from the study, and he/she considers the event reasonably possibly related to the study treatment or study participation, the investigator must promptly notify Lilly.

Pregnancy (maternal or paternal exposure to investigational product) does not meet the definition of an AE. However, to fulfill regulatory requirements any pregnancy should be reported following the SAE process to collect data on the outcome for both mother and fetus>

Lilly collects product complaints on investigational products used in clinical trials in order to ensure the safety of study participants, monitor quality, and to facilitate process and product improvements. Patients should be instructed to contact the investigator as soon as possible if he or she has a complaint or problem with the investigational product so that the situation can be assessed.

See Separate Reporting Form Instructions.

See Separate Reporting Form Instructions

See Separate Reporting Form Instructions.

See Separate Reporting Form Instructions.

See Section 9.1 & 9.2.

Not Applicable

Not applicable.

Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its designee. Efficacy, PK, and PD analyses will be conducted on the full analysis set. This set includes all data from all randomized patients receiving at least one dose of the investigational product according to the treatment allocation. Safety analyses will be conducted for all enrolled patients, whether or not they completed all protocol requirements. If a patient receives a glucose infusion to prevent the progression to severe hypoglycemia (see Section 9.2.4), data after IV glucose infusion may be excluded from the efficacy and PD analyses. Details will be described in the statistical analysis plan (SAP). Any change to the data analysis methods described in the protocol will require an amendment ONLY if it changes a principal feature of the protocol. Any other change to the data analysis methods described in the protocol, and the justification for making the change, will be described in the SAP and/or in the clinical study report. Additional exploratory analyses of the data will be conducted as deemed appropriate. Study results may be pooled with the results of other studies for population PK analysis purposes to avoid issues with post-hoc analyses and incomplete disclosures of analyses.

The primary objective is to demonstrate that 3 mg LY900018 is non-inferior to 1 mg IMG for the proportion (NIM=10%) of Japanese patients with T1DM or T2DM who achieve treatment success without receiving additional actions to increase the PG concentration. Treatment success is defined as either an increase in PG to ≥70 mg/dL or an increase of ≥20 mg/dL from PG nadir within 30 minutes after receiving study treatment. The nadir is defined as the minimum PG concentration at the time of or within 10 minutes following glucagon administration.

The primary analysis will be a treatment group comparison of the primary outcome. The percentage of treatment successes in each treatment group and the difference in percentages will be computed. A 2-sided 95% confidence interval (CI) will be obtained from the 1-sample mean of the paired differences in primary outcome (1=outcome observed; 0=outcome not observed) across 2 treatment visits. Non-inferiority of LY900018 will be declared if the upper limit of a 2-sided 95% CI constructed on the difference in percentages (IMG - LY900018) is less than the NIM of 10%.

Primary efficacy analysis will only include patients who complete both treatment visits with evaluable primary outcome. The following will be considered as non-evaluable primary efficacy outcomes and will be excluded from the analysis related to primary efficacy outcome:

• Patients with at least 1 treatment visit in which the lowest PG concentration at the time of or within 10 minutes following glucagon administration is ≥70 mg/dL;
• Patients who receive an external measure to raise PG concentration either before glucagon administration or within the first 10 minutes of glucagon administration.

Plasma glucose concentrations assessed through a central laboratory will be used to assess treatment success. Additional analysis will be performed if deemed necessary. The details will be provided in the SAP).

See SAP for details.

Descriptive statistics will be used to summarize the baseline, various postdose time points, and absolute change from baseline in PG values by treatment group. Additional analysis will be performed if deemed necessary. The details will be provided in the SAP. If a patient receives additional intervention to raise PG concentrations, measurements taken after the time of intervention will be excluded from the analysis. >}

Descriptive statistics will be used to summarize the baseline, various postdose time points, and absolute change from baseline in total score and each subscale score of Edinburgh Hypoglycemia Scale by treatment group. Additional analysis will be performed if deemed necessary. The details will be provided in the SAP.

All investigational product and protocol procedure AEs will be listed, and, if the frequency of events allows, safety data will be summarized using descriptive methodology.

The incidence of symptoms for each treatment will be presented by severity and by association with investigational product as perceived by the investigator. Symptoms reported to occur prior to enrollment will be distinguished from those reported as new or increased in severity during the study.

The number of investigational product-related SAEs will be reported.

Nasal/respiratory and anosmia AEs will be identified using preferred terms and summarized by treatment group; the details will be provided in the SAP.

The scoring for each response to Nasal and Non-nasal Score Questionnaire will follow the scale displayed on the questionnaire (‘None’=0, ‘Mild’=1, ‘Moderate’=2, ‘Severe’=3). The total score of the questionnaire will be calculated as the sum of the scores for each question. Descriptive statistics will be used to summarize the baseline, various postdose time points, and absolute change from baseline in total score of Nasal and Non-nasal Score Questionnaire by treatment group. See Appendix 6 for a copy of the questionnaire. Additional analysis will be performed if deemed necessary. The details will be provided in the SAP.

Safety parameters that will be assessed include safety laboratory parameters, vital signs, and triplicated ECG parameters. The parameters will be listed and summarized using standard descriptive statistics. Additional analysis will be performed if warranted upon review of the data. The details will be provided in the SAP>

Exploratory analyses may be performed to evaluate exposure-response relationship if needed.

The frequency and percentage of patients with preexisting (baseline) ADA, ADA at any time point after baseline, and patients with TE ADA to glucagon may be tabulated.

Treatment-emergent ADA are defined as those with a titer 2-fold (1 dilution) greater than the minimum required dilution of the assay, if no ADA were detected at baseline; or those with a 4-fold (2 dilutions) increase in titer compared to baseline, if ADA were detected at baseline. For patients with TE ADA, the distribution of maximum titers may be described. The frequency of neutralizing antibodies may also be tabulated.

The relationship between the presence of antibodies to glucagon and efficacy, PK parameters, PD response, and safety results may be assessed.

Access to safety data is scheduled to occur after the first 6 patients complete Period 2 Day 1. The purpose of this review is to initiate remaining patients’ dosing. The investigator and the Lilly sponsor team will make the determination regarding initiation of remaining patients’ dose, based upon their review of the data.

Ethical Review

The investigator must give assurance that the ethical review board (ERB) was properly constituted and convened as required by International Council for Harmonization (ICH) guidelines and other applicable laws and regulations.

Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the study may begin at the investigative site(s). Lilly or its representatives must approve the ICF before it is used at the investigative site(s). All ICFs must be compliant with the ICH guideline on good clinical practice (GCP).

The study site’s ERB(s) should be provided with the following:

• the current Investigator’s Brochure or Package Insert and updates during the course of the study
• ICF
• relevant curricula vitae

Protocol Signatures

After reading the protocol, each principal investigator will sign the protocol signature page and send a copy of the signed page to a Lilly representative

Final Report Signature

The final report coordinating investigator or designee will sign the clinical study report for this study, indicating agreement that, to the best of his or her knowledge, the report accurately describes the conduct and results of the study.

The investigator with the most enrolled patients will serve as the final report coordinating investigator. If this investigator is unable to fulfill this function, another investigator will be chosen by Lilly to serve as the final report coordinating investigator.

The sponsor’s responsible medical officer and statistician will sign/approve the final clinical study report for this study, confirming that, to the best of his or her knowledge, the report accurately describes the conduct and results of the study.

Recruitment

Lilly or its designee is responsible for the central recruitment strategy for patients. Individual investigators may have additional local requirements or processes. Study-specific recruitment material should be approved by Lilly.

Protocol Signatures

The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best of his or her knowledge, the protocol accurately describes the planned design and conduct of the study.

Final Report Signature

The sponsor’s responsible medical officer and statistician will sign/approve the final clinical study report for this study, confirming that, to the best of his or her knowledge, the report accurately describes the conduct and results of the study.