A Study of LY3532226 in Participants With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate the safety and tolerability of the study drug known as LY3532226 in participants with type 2 diabetes mellitus (T2DM). Blood tests will be performed to check how much LY3532226 gets into the bloodstream and how long it takes the body to eliminate it. This is a 2-part study and will last approximately 16 weeks excluding screening period for each part, respectively.

Official Title
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A Phase 1b, 2-Part, Investigator- and Participant-Blind, Multiple-Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LY3532226 in Participants With Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: LY3532226
* Drug: Placebo
* Drug: Dulaglutide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with type 2 diabetes mellitus (T2DM) for at least 3 months before screening Have the following glycosylated hemoglobin (HbA1c) levels at screening: HbA1c >/= 7.0% to </= 10.0% for participants treated with diet and exercise alone and participants treated with metformin alone, and HbA1c >/= 6.0% to </= 9.5% for participants treated with dipeptidyl peptidase inhibitor-4 (DPP-4) (with/without metformin) inhibitors and participants treated with metformin and sodium-glucose cotransporter-2 (SGLT-2) inhibitor Participants treated with diet and exercise alone or on a stable dose of metformin for at least 3 months Participants with body weight up to 150 kilograms (kg) and body mass index (BMI) of 23.0 to 45.0 kilograms per meter squared (kg/m²) Male participants who agree to use effective methods of contraception and female participants not of childbearing potential Exclusion Criteria: Participants who have uncontrolled diabetes defined as an episode of ketoacidosis or hyperosmolar state requiring hospitalization in the 6 months prior to screening Have a clinically significant abnormality ECG Have obesity induced by other endocrine disorders such as Cushing's syndrome or Prader-Willi syndrome Are on any glucose-lowering medications other than metformin, SGLT-2 inhibitors and/or DPP4 Have received chronic systemic glucocorticoid therapy (>2 weeks) in the past 6 months Have an average weekly alcohol intake that exceeds 21 units per week (males 65 years of age or lesser) and 14 units per week (females and males 65 years of age or older) Smoke more than 10 cigarettes, or cigarette equivalent, per day

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY3532226 + Dulaglutide (Part A)<br>LY3532226 administered subcutaneously (SC) followed by dulaglutide administered SC. | Drug: LY3532226<br>* Administered SC.<br>Drug: Dulaglutide<br>* Administered SC.<br>* Other names: Trulicity;|
| Placebo Comparator: Placebo + Dulaglutide (Part A)<br>Placebo administered SC followed by dulaglutide administered SC. | Drug: Placebo<br>* Administered SC.<br>Drug: Dulaglutide<br>* Administered SC.<br>* Other names: Trulicity;|
| Active Comparator: Dulaglutide + Placebo (Part B)<br>Dulaglutide administered SC in combination with placebo given SC. | Drug: Placebo<br>* Administered SC.<br>Drug: Dulaglutide<br>* Administered SC.<br>* Other names: Trulicity;|
| Experimental: LY3532226 + Dulaglutide (Part B)<br>LY3532226 administered SC in combination with Dulaglutide given SC. | Drug: LY3532226<br>* Administered SC.<br>Drug: Dulaglutide<br>* Administered SC.<br>* Other names: Trulicity;|
| Experimental: LY3532226 + Placebo (Part B)<br>LY3532226 administered SC in combination with placebo given SC. | Drug: LY3532226<br>* Administered SC.<br>Drug: Placebo<br>* Administered SC.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Number of Participants with One or More Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Event(s) (SAEs) Considered by the Investigator to be Related to Study Drug Administration | A summary of TEAEs and SAEs, regardless of causality, will be reported in the Reported Adverse Events module | Baseline up to Week 16 | 
| Part B: Change from Baseline in Total Clamp Disposition Index (cDI) | Change from Baseline in Total cDI | Baseline up to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY3532226 | PK: Cmax of LY3532226 | Predose on Day 1 through Week 16 | 
| Part A: PK: Area Under the Concentration Versus Time Curve (AUC) of LY3532226 | PK: AUC of LY3532226 | Predose on Day 1 through Week 16 | 
| Part B: Change from Baseline in Insulin Secretion Rate (ISR) from hyperglycaemic clamp | Change from Baseline in ISR from hyperglycaemic clamp | Baseline through Week 12 | 
| Part B: Change from Baseline in β-cell Glucose Sensitivity (GS) from hyperglycaemic clamp | Change from Baseline in β-cell GS from hyperglycaemic clamp | Baseline through Week 12 | 
| Part B: Change from Baseline in Hyperinsulinemic Euglycemic Clamp M-value | Change from Baseline in Hyperinsulinemic Euglycemic Clamp M-value | Baseline through Week 12 | 
| Part A & B: Change from Baseline in Fasting and Post meal Glucose during Standardized Mixed-meal Tolerance Test (sMMTT) | Change from Baseline in Fasting and Post meal Glucose during sMMTT | Baseline through Week 16 | 
| Part A & B: Change from Baseline in Glycosylated Haemoglobin (HbA1c) | Change from Baseline in HbA1c | Baseline through Week 16 | 
| Part A & B: Change from Baseline in Glucagon Concentration at Fasting and Post meal during sMMTT | Change from Baseline in Glucagon Concentration at Fasting and Post meal during sMMTT | Baseline through Week 16 |