Evaluation of Retatrutide (LY3437943) Efficacy and Safety in Obesity, Overweight, and Knee Osteoarthritis: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate the **efficacy** and **safety** of retatrutide in participants who have **obesity** or **overweight**, including subsets of participants with **knee osteoarthritis**. This is clinically relevant as it aims to address the management of obesity and overweight, which are significant risk factors for various comorbidities, including osteoarthritis. The study will assess the impact of retatrutide, administered as a solution for injection, on these conditions, providing insights into its potential as a therapeutic option.

The clinical trial involves a total of **1860 participants** who are being evaluated for the efficacy and safety of retatrutide in individuals with **obesity** or **overweight**, including those with **knee osteoarthritis**. The study population comprises both male and female subjects, with an age range that includes adults and older adults. Participants were selected based on specific criteria, including being overweight and having a history of unsuccessful dietary weight loss efforts. For those with knee osteoarthritis, additional criteria such as experiencing index knee pain for more than 12 weeks prior to screening, being over 50 years of age, having morning stiffness in the index knee lasting less than 30 minutes, or experiencing crepitus in the index knee were considered. The trial includes a vulnerable population, indicating careful consideration of ethical standards in participant selection. Lifestyle factors such as diet and physical activity are relevant, given the focus on weight-related conditions. The study aims to provide insights into the treatment of these conditions, with a particular emphasis on the subset of participants with knee osteoarthritis.

The clinical trial is designed to evaluate the **efficacy** and safety of **retatrutide** in participants with **obesity** or **overweight**, including those with knee **osteoarthritis**. This is a randomized, double-blind, placebo-controlled trial. The trial will involve the administration of **retatrutide** as a **solution for injection** via subcutaneous injection. The trial is expected to commence on July 15, 2023, and conclude by November 10, 2025, with the total duration of participant involvement being approximately 1 year.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as being overweight and having a history of unsuccessful dietary weight loss efforts. For those in the knee osteoarthritis subset, additional criteria include index knee pain for more than 12 weeks and specific symptoms like morning stiffness or crepitus. Following the screening, participants will be randomized to receive either the investigational product or a placebo. The primary endpoints include the percent change from baseline in body weight and changes in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Score for the knee osteoarthritis subset.

Throughout the trial, participants will attend regular follow-up visits to monitor safety and efficacy outcomes. These visits will include assessments of body weight and knee pain, as well as any adverse events. The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted. Participants may be withdrawn from the study early if they experience significant adverse effects or if they fail to comply with the study protocol. The trial is conducted under the sponsorship of Eli Lilly and Company Limited, with **retatrutide** being the investigational product under evaluation.

The clinical trial involves the administration of **Retatrutide**, an investigational medication, which is 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 administration of Retatrutide is conducted once weekly, with the dosing schedule designed to evaluate its efficacy and safety in participants without Type 2 Diabetes who have obesity or are overweight. The maximum treatment period for Retatrutide is set at one week, with no specified maximum daily or total dose amount. The investigational product is not a pediatric formulation and is not classified as an orphan drug. The sponsor of the trial is Eli Lilly and Company Limited.

In addition to the experimental treatment, a **placebo injection** is utilized as a comparator in this double-blind, placebo-controlled trial. The placebo is administered in a manner consistent with the experimental treatment to maintain the study's blinding. The placebo does not contain any active pharmaceutical ingredients and serves as a control to assess the efficacy and safety of Retatrutide. The administration route and frequency for the placebo are identical to those of the investigational product, ensuring consistency in the trial protocol.

The efficacy of the investigational medicinal product, **Retatrutide**, will be assessed in a randomized, double-blind, placebo-controlled clinical trial. The primary endpoints for evaluating efficacy include the percent change from baseline in body weight and the change from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Score for the GOA1 subset of participants with knee osteoarthritis. These endpoints will be measured using validated scales and methods appropriate for the assessment of body weight and osteoarthritis-related pain.

The trial is designed to evaluate the efficacy and safety of **Retatrutide** in participants who have obesity or are overweight, including those with knee osteoarthritis. The study will involve the administration of **Retatrutide** as a solution for injection via subcutaneous injection. The trial will follow a structured schedule for measuring and collecting data on the specified endpoints, although specific timepoints for these assessments are not detailed in the provided information. The trial is expected to conclude by November 10, 2025, with recruitment having started on July 15, 2023.