Evaluation of Semaglutide in Patients with Non-Cirrhotic Non-Alcoholic Steatohepatitis and Fibrosis Stages 2 or 3: A Randomized, Placebo-Controlled Trial

The primary objective of this study is to evaluate the efficacy of **semaglutide** administered subcutaneously in improving liver histology compared to placebo in subjects with non-alcoholic steatohepatitis (NASH) and fibrosis stages 2 or 3. Additionally, the study aims to demonstrate that semaglutide lowers the risk of liver-related clinical events compared to placebo in the same patient population. These objectives are clinically relevant as they address the potential of semaglutide to modify disease progression and reduce liver-related complications in patients with NASH, a condition with limited treatment options.

Secondary objectives include:

• Demonstrating that semaglutide lowers body weight compared to placebo in subjects with NASH and fibrosis stages 2 or 3.
• Assessing improvements in patient-reported outcomes with semaglutide compared to placebo.
• Comparing the effects of semaglutide versus placebo on cardiovascular disease and cardio-metabolic factors.
• Evaluating the effect of semaglutide versus placebo on biomarkers related to fibrosis.

The clinical trial involves a total of **981 participants** diagnosed with **non-alcoholic steatohepatitis (NASH)**, specifically those with fibrosis stage 2 or 3. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on histological evidence of NASH and fibrosis, as confirmed by a central pathologist's evaluation of a baseline liver biopsy. The trial does not include a vulnerable population. Lifestyle factors such as diet and physical activity were not specified as part of the selection criteria. The study aims to assess the efficacy of semaglutide in improving liver histology and reducing liver-related clinical events compared to a placebo.

The clinical trial is designed to evaluate the efficacy of **semaglutide** in subjects with non-cirrhotic non-alcoholic steatohepatitis (NASH). This is a phase III, randomized, double-blind, placebo-controlled trial. The trial is divided into two parts, with the primary objective of Part 1 being to demonstrate improvement in liver histology compared to placebo, and Part 2 focusing on reducing the risk of liver-related clinical events. The trial is expected to run from April 2021 to April 2029, with participant involvement lasting up to 240 weeks.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age (≥18 years) and histological evidence of NASH and fibrosis stage 2 or 3. The baseline liver biopsy, which can be historical if obtained within 180 days prior to the screening, will be evaluated by a central pathologist. Following randomization, participants will receive either semaglutide or placebo via subcutaneous injection using a pre-filled pen. The trial includes regular follow-up visits to monitor safety and efficacy, with primary endpoints assessed at week 72 and secondary endpoints extending to week 240.

The study visits are structured to ensure comprehensive data collection and participant safety. The inclusion visit involves detailed assessments to confirm eligibility, while follow-up visits are scheduled to monitor treatment effects and any adverse events. The end-of-study visit will conclude the participant's involvement, with final assessments to evaluate the long-term impact of the treatment. Participants may be withdrawn from the study early if they experience significant adverse effects or if they fail to comply with the study protocol.

Throughout the trial, the use of semaglutide is carefully controlled, with the maximum treatment period set at 241 weeks. The trial employs a robust methodology to ensure the reliability of results, including the use of a placebo group and double-blinding to minimize bias. The trial's endpoints focus on both histological improvements and clinical outcomes, providing a comprehensive evaluation of semaglutide's potential benefits in treating NASH.

The clinical trial involves the administration of **semaglutide**, a solution for injection, in various formulations and dosages. The primary experimental medication is "Semaglutide B 1.34 mg/mL PDS290 3.0 mL," which is provided as a solution for injection in a pre-filled pen. This formulation is administered subcutaneously using a PDS290 pen-injector, which contains a 3 mL cartridge made of type 1 glass with a chlorobutyl rubber plunger and a bromobutyl/polyisoprene rubber disc. The administration schedule is designed for a maximum treatment period of 241 days. The dosing frequency and participant compliance are monitored throughout the trial.

Another experimental formulation is "Semaglutide D 2.0 mg/mL DV3396," also a solution for injection, administered subcutaneously. This formulation is delivered using a single-dose pre-filled pen, which includes a 1 mL glass syringe barrel with a staked needle, a chlorobutyl plunger, and a rigid needle shield. The pen contains either 0.5 mL or 0.75 mL of the solution. The treatment period for this formulation is also set for a maximum of 241 days.

The trial includes a placebo group, utilizing a "Cartridge (glass) in pre-filled pen (PDS290 pen-injector): Semaglutide B placebo PDS290 pen-injector, 1.5 mL and 3 mL." This placebo is designed to mimic the appearance and administration method of the active semaglutide formulations, ensuring blinding in the study. The placebo is administered subcutaneously, following the same schedule as the active treatments.

Additional formulations of semaglutide used in the trial include "Semaglutide B 2.27 mg/mL PDS290 3.0 mL," "Semaglutide B 3.2 mg/mL PDS290 3.0 mL," "Semaglutide D 1.0 mg/mL DV3396," "Semaglutide D 2.27 mg/mL DV3396," and "Semaglutide D 3.2 mg/mL DV3396." Each of these formulations is provided as a solution for injection, administered subcutaneously, and delivered using either a PDS290 pen-injector or a single-dose pre-filled pen, depending on the specific formulation. The maximum treatment period for all formulations is 241 days, with compliance monitored throughout the study.

The trial also includes another placebo group using "Pre-filled syringe (glass) in a pre-filled pen: Semaglutide placebo Ia DV3396 pen-injector, 0.5 mL and Semaglutide placebo Ib DV3396 pen-injector, 0.75 mL." This placebo is administered subcutaneously and is designed to match the administration method of the active semaglutide formulations, ensuring the integrity of the study's blinding process.

The efficacy of the clinical trial evaluating the effect of **semaglutide** in subjects with non-cirrhotic non-alcoholic steatohepatitis (NASH) will be assessed using both primary and secondary endpoints. The primary endpoints include the resolution of steatohepatitis without worsening of liver fibrosis and improvement in liver fibrosis without worsening of steatohepatitis, assessed from randomization (week 0) to week 72. Additionally, cirrhosis-free survival will be evaluated from randomization to week 240.

Secondary endpoints will measure various parameters, including changes in body weight, liver histology, and liver stiffness values, as well as biochemical markers such as ALT, AST, and cholesterol levels. These will be assessed at multiple time points, including weeks 72 and 240. The trial will also evaluate changes in patient-reported outcomes, such as the SF-36 Bodily Pain score, and the occurrence of major cardio-hepatic events. The assessments will be conducted using validated scales and laboratory tests to ensure accuracy and reliability of the data collected throughout the trial duration.