J2A-MC-GZPT A Phase 3 Study to Investigate the Efficacy and Safety of Orfor-glipron Once Daily in Participants Who Have Obesity or Overweight and Osteoar-thritis of the Knee: A Multicenter, Randomized, Double-Blind, Parallel-Arm, Pla-cebo-Controlled Trial List of Intervention-Specific Appendices (ISAs): ISA1 (GZT1): A Study to Investigate Efficacy and Safety of Orforglipron Once Daily in Participants Who Have Obesity or Overweight and Osteoarthritis of the Knee ISA2 (GZT2): A Study to Investigate Efficacy and Safety of Orforglipron Once Daily in Participants Who Have Obesity or Overweight and Osteoarthritis of the Knee

The primary objective of this study is to demonstrate the superiority of orforglipron administered once daily at the maximum tolerated dose compared to placebo in reducing pain associated with knee osteoarthritis, as measured by change in the WOMAC pain subscale score. This objective addresses a clinically significant need for effective pharmacological interventions targeting pain relief in patients with obesity or overweight who have concomitant knee osteoarthritis, a population in which mechanical stress and inflammatory processes contribute to progressive joint deterioration and functional impairment.

This clinical trial enrolled a total of **620 participants** diagnosed with **osteoarthritis** of the knee. The study population included both **male** and **female** subjects, comprising **adults** and **elderly** individuals. Participants presented with **obesity** or **overweight** and had a documented history of unsuccessful weight loss attempts through dietary interventions. A vulnerable population was included in the trial. Key eligibility requirements specified that participants must have osteoarthritis of the knee and demonstrate willingness to discontinue certain pain medications throughout the study duration. The trial population was selected based on their weight status, previous weight management efforts, and diagnosis of knee osteoarthritis.

This is a Phase 3, multicenter, randomized, double-blind, parallel-arm, placebo-controlled clinical trial designed to investigate the efficacy and safety of orforglipron administered once daily in participants with obesity or overweight and osteoarthritis of the knee. The study employs a randomized design in which participants are assigned to receive either the investigational medicinal product or placebo. The double-blind methodology ensures that neither participants nor investigators are aware of treatment allocation during the conduct of the trial. The investigational product, orforglipron (LY3502970), is an oral, nonpeptide small-molecule GLP-1 receptor agonist formulated as a tablet for oral use. The active substance is orforglipron hemicalcium. A matching placebo is administered to the control group to maintain blinding.

The primary objective is to demonstrate that orforglipron once daily at the maximum tolerated dose is superior to placebo in reducing the WOMAC pain subscale score. The primary endpoint is the change from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Score. This validated instrument assesses pain severity in participants with osteoarthritis of the knee.

Eligible participants must have obesity or overweight and must have previously attempted weight loss through dietary modification without success. Participants are required to have a confirmed diagnosis of osteoarthritis of the knee. A key inclusion criterion is the willingness to discontinue certain pain medications for the entire duration of the study. The maximum treatment period is 72 weeks. Participant involvement extends from the initial screening visit through the completion of the treatment phase and follow-up assessments. The estimated recruitment start date is December 2025, with an estimated end date of May 2028.

The study involves a sequence of scheduled visits to assess efficacy, safety, and tolerability. The screening visit serves to determine eligibility based on inclusion and exclusion criteria and to obtain informed consent. Following randomization, participants attend regular follow-up visits throughout the treatment period for administration of study medication, collection of efficacy and safety data, and monitoring of adverse events. The end-of-study visit marks the completion of participant involvement and includes final assessments of efficacy and safety parameters. Early termination from the study may occur due to withdrawal of consent, adverse events, protocol violations, or investigator discretion based on safety concerns.

The experimental medication under investigation is Orforglipron, also known by the sponsor product code LY3502970. The active substance is orforglipron hemicalcium, a chemical compound classified as an oral, nonpeptide small-molecule GLP-1 receptor agonist. Orforglipron is manufactured by ELI LILLY AND COMPANY LIMITED and is formulated as a tablet for oral use. The dosage is expressed in milligrams, with the specific dose to be determined as the maximum tolerated dose during the trial. The maximum treatment period is 72 weeks. Multiple tablet formulations are utilized in this clinical trial to accommodate different dosing requirements.

A placebo formulation matching the appearance of Orforglipron tablets is administered to participants in the control arm of the study. The placebo is designed to be indistinguishable from the active treatment to maintain blinding throughout the trial. The placebo is administered via the same route and with the same frequency as the experimental medication to ensure consistency in study procedures.

Efficacy will be assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Score as the primary endpoint. The evaluation will focus on the change from baseline in this score to determine whether orforglipron once daily at the maximum tolerated dose demonstrates superiority over placebo in reducing pain associated with osteoarthritis of the knee in participants who have obesity or overweight.