Phase 3 Randomized Open-Label Study of Orforglipron vs. Dapagliflozin in Adults with Type 2 Diabetes and Inadequate Glycemic Control on Metformin

The primary objective of this Phase 3, randomized, open-label study is to demonstrate that **orforglipron** is noninferior to **dapagliflozin** in achieving glycemic control in adult participants with **Type 2 Diabetes** who have inadequate glycemic control with **metformin**. This objective is clinically relevant as it seeks to establish orforglipron as a viable alternative to dapagliflozin, potentially expanding treatment options for patients with Type 2 Diabetes who require additional glycemic management beyond metformin. No secondary objectives are specified for this study.

The clinical trial involves a total of **622 participants** diagnosed with **Type 2 Diabetes**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including having been on stable diabetes treatment with metformin for at least 90 days prior to the study and maintaining a stable body weight during this period. They are required to agree not to initiate any intensive diet or exercise programs aimed at weight loss, aside from standard lifestyle or dietary measures for diabetes management. The trial includes a vulnerable population, ensuring a comprehensive assessment of the treatment's efficacy across diverse demographic groups. The primary objective is to evaluate whether orforglipron is noninferior to dapagliflozin in terms of glycemic control.

The clinical trial is designed to evaluate the efficacy and safety of **orforglipron** compared to **dapagliflozin** in adult participants with **Type 2 Diabetes** who have inadequate glycemic control with **metformin**. This is a Phase 3, randomized, open-label study. The trial will involve a comparison between the investigational product, orforglipron, and the comparator, dapagliflozin, with the primary endpoint being the change from baseline in Hemoglobin A1c (HbA1c). The trial is expected to commence recruitment on February 5, 2024, and conclude by July 28, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as having Type 2 Diabetes and stable treatment with metformin for at least 90 days prior to the study. Following randomization, participants will attend regular follow-up visits to monitor their health status and treatment efficacy. The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted. The expected duration of participant involvement is aligned with the trial's overall timeline, subject to individual health conditions and adherence to study protocols.

Participants may be withdrawn from the study early if they experience significant adverse effects, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial will adhere to rigorous scientific and ethical standards to ensure the reliability of the data collected and the safety of all participants involved.

The clinical trial involves the administration of **Orforglipron**, an investigational medication, which is provided in the form of a capsule. The active substance in Orforglipron is **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. The dosing schedule and specific dosage amounts are not specified in the provided data, and the maximum treatment period is indicated as 9999 days, suggesting an extended duration of administration. Participant compliance with the dosing regimen will be monitored throughout the study.

**Dapagliflozin** is used as a comparator treatment in this study. It is administered in a pharmaceutical form denoted as PHF00082MIG, which is also taken orally. The maximum daily dose for Dapagliflozin is set at 10 mg. This medication is a standard-of-care therapy for managing Type 2 Diabetes and is included to evaluate the efficacy of Orforglipron in comparison to an established treatment. The maximum treatment period for Dapagliflozin is also 9999 days, aligning with the investigational drug's duration.

**Metformin** is another non-experimental treatment used in the study, provided in the same pharmaceutical form as Dapagliflozin, PHF00082MIG, and administered orally. The maximum daily dose for Metformin is 3000 mg. Metformin is a widely used medication for Type 2 Diabetes and serves as a background therapy for participants in the trial. The treatment period for Metformin is similarly extended to 9999 days, ensuring consistent administration throughout the study duration.

The efficacy of the investigational medicinal product, orforglipron, will be assessed in a Phase 3, randomized, open-label clinical trial. The primary endpoint for evaluating efficacy is the change from baseline in **Hemoglobin A1c (HbA1c)** levels. This parameter is a well-established biomarker for assessing glycemic control in individuals with Type 2 diabetes. The trial aims to demonstrate that orforglipron is noninferior to dapagliflozin in managing glycemic levels in adult participants with Type 2 diabetes who have inadequate glycemic control with metformin.