J2A-MC-GZGS: A Phase 3, Open-Label Study of Once Daily Orforglipron Compared with Insulin Glargine in Adult Participants with Type 2 Diabetes and Obesity or Overweight at Increased Cardiovascular Risk (ACHIEVE-4)

The primary objective of this Phase 3, open-label study is to demonstrate that **LY3502970** is non-inferior to **insulin glargine** in the occurrence of major adverse cardiovascular events (MACE-4) in adult participants with **Type 2 Diabetes** and **obesity** or **overweight** at increased cardiovascular risk. This objective is clinically relevant as it aims to establish the cardiovascular safety profile of LY3502970, which could provide an alternative treatment option for patients with Type 2 Diabetes who are at heightened risk of cardiovascular complications.

The clinical trial involves a total of **1580 participants** who are being studied to evaluate the non-inferiority of LY3502970 compared to insulin glargine in the occurrence of MACE-4 events. The study population includes both **male and female** subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific health conditions, including **Type 2 Diabetes**, cardiovascular diseases, and chronic kidney disease. The trial population is characterized by individuals who are either overweight or obese. Participants are required to have been on a consistent dose of 1 to 3 oral diabetes medications for the past three months and must have high blood sugar levels, as indicated by a hemoglobin A1C of at least 7.0%. The study also includes a vulnerable population, although specific details about this group are not provided. Lifestyle factors such as diet and physical activity are not explicitly mentioned, but the inclusion criteria suggest a focus on individuals with established heart disease and metabolic conditions.

The clinical trial is designed to evaluate the efficacy and safety of **LY3502970** compared to **insulin glargine** in adult participants with **Type 2 Diabetes** and obesity or overweight, who are at increased cardiovascular risk. This is a Phase 3, open-label study with a primary objective to demonstrate that LY3502970 is non-inferior to insulin glargine in the occurrence of major adverse cardiovascular events (MACE-4). The trial is expected to run from July 2023 to August 2025, with the estimated recruitment start date being July 5, 2023, and the estimated end date being August 27, 2025.

The trial involves several study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as having Type 2 Diabetes, taking a consistent dose of 1 to 3 oral diabetes medications for the last three months, having heart disease, and having high blood sugar levels as measured by hemoglobin A1C (HbA1c at least 7.0%). Participants will then be randomized to receive either LY3502970 or insulin glargine. The study is open-label, meaning both the participants and the investigators will know which treatment is being administered.

Participants will be involved in the study for a maximum treatment period of one year, with regular follow-up visits to monitor their health status and any adverse events. The primary endpoint is the time to the first occurrence of any MACE-4 event, which includes myocardial infarction, stroke, hospitalization for unstable angina, or cardiovascular death. The study will conclude with an end-of-study visit to assess the overall outcomes and gather final data. Conditions that may lead to early termination from the study include significant adverse events or withdrawal of consent by the participant.

The clinical trial involves the administration of **LY3502970**, an experimental medication provided in the form of a capsule. The active substance in LY3502970 is a complex chemical compound, specifically 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4-ide hemicalcium. The medication is administered orally, and the dosing schedule is determined by the study protocol, with a maximum treatment period of one day. The specific dosage in milligrams is not predetermined, as the trial aims to assess the efficacy and safety of the compound.

**Insulin Glargine** is used as a comparator treatment in the study. It is provided as a solution for injection in a pre-filled pen, known as ABASAGLAR 100 units/mL KwikPen. This formulation allows for subcutaneous administration, and the pen contains multiple doses of the medication. The maximum daily dose is not specified, as it is adjusted based on the participant's needs and the study's requirements. Insulin Glargine is a well-established treatment for diabetes, and its inclusion in the trial serves to compare the efficacy of LY3502970 against a standard-of-care therapy.

Additional non-experimental treatments include **Dapagliflozin**, **Metformin**, **Ertugliflozin**, **Canagliflozin**, **Empagliflozin**, and **Sulfonamides, Urea Derivatives**. These medications are administered orally in the form of film-coated tablets or capsules. Each of these treatments has a specified maximum daily dose, such as 10 mg for Dapagliflozin and 2000 mg for Metformin, with the treatment period limited to one day. These medications are commonly used in the management of type 2 diabetes and are included in the trial to provide a comprehensive assessment of LY3502970's performance in comparison to existing therapies.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. The study design includes measures to track and document the administration of both experimental and non-experimental treatments, ensuring the integrity of the trial data.

The efficacy of the investigational product LY3502970 will be assessed in a Phase 3, open-label clinical trial involving adult participants with **Type 2 Diabetes** and obesity or overweight at increased cardiovascular risk. The primary endpoint for evaluating efficacy is the time to the first occurrence of any Major Adverse Cardiovascular Event (MACE-4), which includes myocardial infarction, stroke, hospitalization for unstable angina, or cardiovascular death. This endpoint is designed to demonstrate that LY3502970 is non-inferior to insulin glargine, with a non-inferiority margin of 1.8.