Phase 3 Randomized Double-Blind Trial Comparing Efficacy and Safety of Retatrutide (LY3437943) Versus Tirzepatide (LY3298176) in Adults with Obesity

The primary objective of this Phase 3, randomized, double-blind study is to evaluate the **efficacy** and safety of **Retatrutide** compared to **Tirzepatide** in adults with **obesity**. Specifically, the study aims to demonstrate that the maximum tolerated dose (MTD) of Retatrutide is superior to the MTD of Tirzepatide in terms of change in body weight. This is clinically relevant as obesity is a significant risk factor for various comorbidities, and effective weight management is crucial for reducing these risks and improving overall health outcomes.

The clinical trial involves a total of **625 participants** diagnosed with **obesity**. The study population includes both male and female subjects, with an age range that spans from young adults to middle-aged individuals. Participants were selected based on their history of at least one self-reported unsuccessful dietary effort to reduce body weight, highlighting a significant lifestyle consideration related to diet. The trial includes a vulnerable population, ensuring a comprehensive assessment across diverse demographic groups. The selection criteria emphasize the inclusion of individuals who have previously attempted weight loss through dietary means, providing a relevant context for evaluating the efficacy of the investigational treatment. The trial aims to compare the effectiveness of retatrutide MTD against tirzepatide MTD in achieving weight reduction.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy and safety of **Retatrutide** compared to **Tirzepatide** in adults with **obesity**. The primary objective is to demonstrate that Retatrutide at maximum tolerated dose (MTD) is superior to Tirzepatide MTD in terms of percent change from baseline in body weight. The trial is expected to commence recruitment on November 1, 2024, and conclude by November 16, 2026, with a total duration of approximately two years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as having obesity and a history of at least one unsuccessful dietary effort to reduce body weight. Following successful screening, participants will be randomized to receive either Retatrutide or Tirzepatide, both administered as a **solution for injection** via **subcutaneous injection**. The trial will include multiple follow-up visits to monitor safety and efficacy outcomes, with the final visit marking the end of the study. The expected length of participant involvement is up to 80 weeks, corresponding to the maximum treatment period.

Conditions that may lead to early termination from the study include adverse events, non-compliance with study procedures, or withdrawal of consent. The trial will adhere to rigorous methodological standards to ensure the reliability and validity of the findings, contributing valuable data to the understanding of obesity treatment options.

The clinical trial involves the administration of **Retatrutide**, an experimental medication formulated as a **solution for injection**. The active substance in Retatrutide is LY3437943 sodium, a protein-based compound. The pharmaceutical form is a solution intended for subcutaneous injection. The dosing schedule for Retatrutide is not explicitly defined in terms of milligrams per day, as the maximum daily dose amount is set to zero. However, the treatment period is specified to last up to 80 weeks. The administration of Retatrutide is facilitated by a device that does not possess a CE mark, and participant compliance is monitored throughout the trial duration.

In this study, **Tirzepatide** serves as the comparator treatment. Like Retatrutide, Tirzepatide is also a solution for injection, with its active substance being a protein-based compound. The pharmaceutical form is consistent with that of Retatrutide, designed for subcutaneous injection. The dosing parameters for Tirzepatide mirror those of Retatrutide, with a maximum daily dose amount of zero and a treatment period extending up to 80 weeks. The administration of Tirzepatide is also supported by a non-CE marked device, ensuring consistency in the method of delivery across the trial. Compliance monitoring is similarly applied to participants receiving Tirzepatide.

The efficacy of the clinical trial will be assessed by evaluating the primary endpoint, which is the percent change from baseline in body weight. This trial aims to demonstrate that **Retatrutide** at its maximum tolerated dose (MTD) is superior to **Tirzepatide** at its MTD in achieving weight reduction in adults with obesity. The assessment of efficacy will involve measuring body weight changes from the baseline throughout the trial period. The trial is designed as a Phase 3, randomized, double-blind study, ensuring that neither the participants nor the investigators know which treatment the participants are receiving, thus minimizing bias in the efficacy assessment.