J2A-MC-GZPS: A Master Protocol to Investigate the Efficacy and Safety of Orforglipron Tablet Once Daily Compared with Placebo in Female Participants with Stress Urinary Incontinence Who Have Obesity or Overweight (RESTRAIN-SUI) ; J2A-MC-GZS1: A Study to Investigate Efficacy and Safety of Orforglipron Once Daily in Participants with Stress Urinary Incontinence Who Have Obesity or Overweight ; J2A-MC-GZS2: A Study to Investigate Efficacy and Safety of Orforglipron Once Daily in Participants with Stress Urinary Incontinence Who Have Obesity or Overweight

The primary objective of this clinical trial is to demonstrate the superiority of orforglipron compared to placebo in reducing the change in weekly incontinence episode frequency in female participants with stress urinary incontinence who have obesity or are overweight. This endpoint is clinically relevant as it directly measures the therapeutic impact on symptom burden and quality of life in this patient population, where excess body weight contributes to increased intra-abdominal pressure and pelvic floor dysfunction.

This clinical trial enrolled a total of **705 participants**, all of whom were **female**. The study population consisted of **adults** diagnosed with **stress urinary incontinence**. Participants were selected based on having a **body mass index** indicative of **obesity** or being **overweight**. The trial focused on **patients** with this specific type of urinary incontinence, ensuring a targeted population for evaluating the investigational treatment. No vulnerable populations were included in this study.

This clinical trial investigates the efficacy and safety of **Orforglipron** administered as an oral **tablet** once daily compared with **placebo** in female participants with **stress urinary incontinence** who have **obesity** or **overweight**. The study is designed as a **randomized**, **controlled** trial classified as a **Phase III** investigation. The active substance is **orforglipron hemicalcium**, an oral, nonpeptide small-molecule **GLP-1** receptor agonist. The trial is categorized as a Category 2 trial, as it assesses a non-authorized investigational medicinal product to evaluate safety and efficacy, as well as potential dosage regimens.

The primary objective of the trial is to demonstrate that orforglipron is superior to placebo in reducing the change in weekly **incontinence episode frequency**. The **primary endpoint** is the change from baseline in incontinence episode frequency. Principal inclusion criteria require participants to have a **body mass index** indicating obesity or overweight and a confirmed diagnosis of stress urinary incontinence. The trial employs a master protocol design that encompasses multiple substudies evaluating the investigational product under consistent methodological standards.

Participant involvement begins with a **screening visit** to assess eligibility according to the inclusion and exclusion criteria. Following successful screening, participants are randomized to receive either orforglipron tablets or matching placebo administered orally. The treatment period involves scheduled **follow-up visits** for monitoring of efficacy outcomes, safety assessments, and collection of clinical data. An **end-of-study visit** is conducted to evaluate final outcomes and ensure participant safety. The estimated recruitment start date is October 2025, with an estimated study completion date of October 2027, indicating an overall trial duration of approximately two years.

Participants may be subject to **early termination** from the study under specific conditions, including withdrawal of consent, protocol non-compliance, adverse events requiring discontinuation, or at the discretion of the investigator if continued participation is deemed not in the participant's best interest. The maximum treatment period is defined as one day per dosing cycle, with the total duration of participant involvement dependent on the specific substudy protocol and treatment schedule. All study procedures are conducted in accordance with established clinical research standards to ensure the integrity of the data and the safety of participants.

The experimental medication Orforglipron (sponsor product code LY3502970) is administered in tablet form for oral use. The active substance is orforglipron hemicalcium, also known as orforglipron calcium or LY3502970 hemicalcium, which is a chemical substance of synthetic origin. Orforglipron is characterized as an oral, nonpeptide small-molecule GLP-1 receptor agonist. The product is manufactured by ELI LILLY AND COMPANY LIMITED. Multiple tablet formulations of Orforglipron are utilized in this clinical trial, allowing for flexible dosing regimens. The medication is administered once daily via the oral route.

A placebo matching the Orforglipron formulation is used as the comparator treatment in this study. The placebo is designed to match the active medication to maintain blinding integrity throughout the trial. The placebo tablets are administered via the same route and with the same frequency as the active treatment to ensure comparability between study arms.

Efficacy will be assessed using the change from baseline in **Incontinence Episode Frequency** (IEF) as the primary endpoint. This parameter will be used to demonstrate the superiority of **orforglipron** compared to **placebo** in reducing weekly incontinence episode frequency in female participants with **stress urinary incontinence** who have obesity or overweight.