Efficacy and Safety of Orforglipron in Obesity or Overweight Patients With and Without Type 2 Diabetes: A Master Protocol Study

The primary objective of this study is to evaluate the **efficacy** and **safety** of orforglipron, a tablet administered once daily, compared to placebo in participants with **obesity** or **overweight**, with or without **type 2 diabetes**. This is conducted under a master protocol that supports two distinct studies. The first study focuses on participants with obesity or overweight and at least one weight-related comorbidity, excluding type 2 diabetes, to assess the impact of orforglipron on reducing body weight. The second study targets participants with obesity or overweight and type 2 diabetes, aiming to determine the effect of orforglipron on improving glycemic control. These objectives are clinically relevant as they address the management of obesity and overweight, conditions that are associated with significant health risks, including cardiovascular diseases and diabetes, thereby potentially improving patient outcomes and quality of life.

The clinical trial involves a total of **1002 participants** who are being studied to evaluate the efficacy and safety of orforglipron compared to placebo in individuals with **obesity** or **overweight**, with or without **type 2 diabetes**. The study population includes both male and female subjects, with an age range of 18 to 65 years. Participants were selected based on specific criteria, including a body mass index (BMI) of at least 25 kg/m², and for those in the GZP2 group, a diagnosis of type 2 diabetes with hemoglobin A1c levels between 7% and 10%. Additionally, all participants have a history of at least one unsuccessful dietary effort to lose weight. The trial does not include vulnerable populations. Lifestyle considerations such as diet and physical activity are relevant, given the focus on weight-related health conditions. The selection process ensures a representative sample of individuals who meet the inclusion criteria, allowing for a comprehensive assessment of the investigational drug's impact on weight reduction and glycemic control.

The clinical trial is designed to evaluate the **efficacy** and **safety** of **Orforglipron** in participants with **obesity** or **overweight**, with and without **type 2 diabetes**. This trial follows a randomized, double-blind, placebo-controlled design, ensuring that neither the participants nor the investigators know which treatment the participants are receiving, thus minimizing bias. The trial is structured into two main studies under a master protocol: one for participants without type 2 diabetes and another for those with type 2 diabetes. The trial is expected to commence recruitment in August 2025 and conclude by June 2027, with a maximum treatment period of 72 weeks for each participant.

Participants will undergo a screening period of approximately four weeks to determine eligibility based on specific inclusion criteria, such as body mass index (BMI) thresholds and the presence of weight-related comorbidities. Following successful screening, participants will be randomized into one of the two study groups. The primary endpoints include the percent change in body weight for participants without type 2 diabetes and the change in hemoglobin A1c (HbA1c) levels for those with type 2 diabetes, both measured from baseline to week 40.

Study visits are scheduled at regular intervals to monitor participants' health and treatment response. These visits include baseline assessments, periodic follow-up visits, and an end-of-study visit. The purpose of these visits is to collect data on the primary and secondary endpoints, ensure participant safety, and assess the overall effectiveness of the treatment. Participants are expected to remain in the study for the full duration unless they meet criteria for early termination, such as adverse events or withdrawal of consent.

Throughout the trial, participants will receive either the investigational product, **Orforglipron**, or a matching placebo, administered orally in tablet form. The trial's rigorous design and comprehensive monitoring aim to provide robust data on the potential benefits and risks of Orforglipron in managing obesity and type 2 diabetes.

The clinical trial involves the administration of **Orforglipron**, a chemical compound known as **orforglipron hemicalcium**. This experimental medication is provided in the form of a **tablet** and is intended for **oral use**. The pharmaceutical product is manufactured by Eli Lilly and Company Limited and is identified by the sponsor product code LY3502970. The maximum treatment period for Orforglipron is 72 weeks. The dosage and frequency of administration are not specified in the provided data, and the maximum daily and total dose amounts are indicated as zero, suggesting that specific dosing instructions will be provided separately. Participant compliance with the dosing regimen will be monitored throughout the trial.

In addition to the experimental medication, a **placebo** is utilized in the study to match the appearance of the Orforglipron tablet. The placebo serves as a comparator treatment to evaluate the efficacy and safety of Orforglipron in participants with obesity or overweight, with or without type 2 diabetes. The placebo is administered in a manner consistent with the experimental treatment to ensure blinding and maintain the integrity of the trial results. The pharmaceutical form, route, and frequency of administration for the placebo are designed to mimic those of the Orforglipron tablet, although specific details are not provided in the data.

The efficacy of **Orforglipron** in the clinical trial will be assessed through specific primary endpoints tailored to the participant groups. For participants in the GZP1 study, the primary endpoint is the percent change from baseline in body weight, measured at baseline and at week 40. For participants in the GZP2 study, the primary endpoint is the change from baseline in **Hemoglobin A1c (HbA1c)** levels, also measured at baseline and at week 40. These endpoints are designed to evaluate the effectiveness of Orforglipron in reducing body weight and improving glycemic control, respectively.

The collection and analysis of these efficacy parameters will be conducted at specified time points, ensuring a systematic approach to data gathering. The trial will involve a comparison between Orforglipron and a placebo, with participants allocated to each study from baseline to week 4. The trial is structured to provide a comprehensive assessment of Orforglipron's efficacy over a 40-week period, with the primary focus on weight reduction and glycemic control in participants with obesity or overweight, with or without type 2 diabetes.