Evaluation of Orismilast and Semaglutide Combination Therapy on Body Weight Reduction in Obese Patients: A Randomized, Placebo-Controlled Trial

The primary objective of this randomized, placebo-controlled study is to assess the **efficacy** of **orismilast** administered orally twice daily, either alone or in combination with open-label once-weekly subcutaneous **semaglutide**, in individuals with **obesity** over a 16-week treatment period. The primary aim is to evaluate the effects of 30 mg orismilast BID, with or without semaglutide 1.0 mg s.c. once weekly, on the percentual change from baseline in body weight. This is clinically relevant as it addresses the need for effective weight management strategies in the treatment of obesity, a condition associated with numerous comorbidities and increased mortality risk.

The clinical trial focuses on individuals diagnosed with **obesity**, encompassing both male and female participants. The study population includes adults aged between 18 and 75 years, with a **Body Mass Index (BMI)** of 30 kg/m² or higher. Participants have a documented history of at least one attempt to lose body weight. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that the study population is representative of individuals who have previously engaged in weight loss efforts, which may influence their lifestyle considerations such as diet and physical activity. The trial aims to assess the efficacy of orismilast, administered orally twice daily, with or without the addition of semaglutide, administered subcutaneously once weekly, over a 16-week period.

The clinical trial is designed to evaluate the efficacy of **orismilast**, administered orally twice daily, either alone or in combination with open-label once-weekly subcutaneous **semaglutide**, in individuals with **obesity**. This study is a randomized, placebo-controlled trial with a double-blind design for the orismilast component, ensuring that neither the participants nor the investigators know which treatment the participants are receiving, thus minimizing bias. The trial is set to last for a total of 16 weeks, with the primary endpoint being the percentage change in body weight from baseline to week 16.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (18-75 years), a body mass index (BMI) of 30 kg/m² or greater, and a history of at least one attempt to lose body weight. Following successful screening, participants will be randomized to receive either the active treatment or placebo. The study includes regular follow-up visits to monitor safety, adherence, and efficacy, with assessments of body weight, BMI, waist circumference, and other health markers. The end-of-study visit will occur at the conclusion of the 16-week treatment period, where final assessments will be conducted.

The expected length of participant involvement is approximately 16 weeks, aligning with the treatment duration. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with the study protocol, or withdrawal of consent by the participant. The trial aims to provide valuable insights into the weight management potential of orismilast, both as a standalone treatment and in combination with semaglutide, contributing to the understanding of therapeutic options for obesity management.

The clinical trial involves the administration of **Orismilast**, a **modified-release tablet** containing the active substance **orismilast**. This experimental medication is chemically synthesized and is provided by UNION THERAPEUTICS A/S. The dosage form is a modified-release tablet, designed to release the active ingredient over an extended period. Participants will receive a dose of 30 mg orally, twice daily (BID), with a maximum daily dose of 60 mg. The total maximum dose over the 16-week treatment period is 5040 mg. The administration route is oral, and compliance will be monitored through regular assessments.

The study also includes a **placebo** group, where participants will receive tablets identical in appearance to the orismilast tablets but without the active pharmaceutical ingredient. The active molecule in the placebo is replaced by lactose, ensuring that the placebo tablets are indistinguishable from the active treatment in terms of appearance and administration. The placebo is administered orally, twice daily, following the same schedule as the orismilast treatment to maintain blinding in the study.

Additionally, the trial incorporates the use of **Semaglutide**, a protein-based medication administered as a subcutaneous injection. Semaglutide is provided in a pharmaceutical form identified as PHF00231MIG and is administered once weekly at a dose of 1 mg. The maximum total dose over the 16-week period is 11 mg. This open-label component of the study allows for the evaluation of the combined effect of orismilast and semaglutide on weight management in individuals with obesity. Compliance with semaglutide administration will be monitored through scheduled visits and participant self-reports.

The efficacy of the clinical trial investigating the weight management potential of **orismilast** alone or in combination with subcutaneous semaglutide will be assessed through a series of primary and secondary endpoints. The primary endpoint is the percentage change in body weight from baseline to week 16. This will be measured to evaluate the effectiveness of 30 mg orismilast administered orally twice daily, with or without 1.0 mg semaglutide administered subcutaneously once weekly.

Secondary endpoints include various parameters related to body weight and metabolic health. These include the absolute change in body weight in kilograms from week 0 to week 16, and the proportion of participants achieving body weight reductions of ≥3%, ≥5%, ≥10%, and ≥15% at week 16. Additional secondary endpoints involve changes in high sensitivity C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), body mass index (BMI), waist-hip ratio, waist circumference, systolic and diastolic blood pressure, heart rate, and body composition metrics such as fat-free mass, total fat mass, visceral fat mass rating, and bone mass. These will be measured using bioimpedance analysis. Furthermore, changes in fasting serum/plasma concentrations of inflammatory biomarkers will be assessed.

The trial is designed to be conducted over a 16-week treatment period, with efficacy parameters collected at baseline and at the end of the treatment period. The data collected will be analyzed to determine the efficacy of the treatment regimens in achieving the desired weight management outcomes in individuals with obesity.