Efficacy, Safety, and Tolerability of AZD5004 in Obesity or Overweight Patients with Comorbidities: A Phase IIb Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this Phase IIb randomized, double-blind, placebo-controlled study is to evaluate the **efficacy** of AZD5004 in achieving weight loss in participants living with obesity or overweight with at least one comorbidity. Specifically, the study aims to determine whether AZD5004 is superior to placebo for weight loss at 26 weeks and to assess its superiority in the proportion of participants achieving a weight loss of at least 5% from baseline at week 26. This is clinically relevant as effective weight management can significantly reduce the risk of obesity-related comorbidities and improve overall health outcomes.

Secondary objectives include:

• Determining whether AZD5004 is superior to placebo for weight loss at 36 weeks.
• Evaluating the superiority of AZD5004 over placebo in the proportion of participants achieving a weight loss of at least 5% from baseline at 36 weeks.
• Assessing the superiority of AZD5004 for absolute weight loss compared to placebo.
• Evaluating the effect of AZD5004 versus placebo on the proportion of participants achieving weight loss of at least 10% and 15%.

The clinical trial involves a total of **274 participants** who are living with **obesity** or are **overweight** with at least one comorbidity. The study population includes both male and female subjects, aged 18 years and older, with a **Body Mass Index (BMI)** of at least 30 kg/m², or a BMI of at least 27 kg/m² accompanied by a diagnosis of at least one weight-related comorbidity such as hypertension, dyslipidemia, cardiovascular disease, or obstructive sleep apnea. Participants were selected based on their ability to provide informed consent and maintain a stable body weight for three months prior to screening. The trial includes individuals from a vulnerable population, and lifestyle considerations such as the use of contraception are required for both male and female participants. The selection criteria ensure a diverse and representative sample of individuals affected by obesity or overweight conditions, allowing for a comprehensive evaluation of the investigational product's efficacy in promoting weight loss.

The clinical trial is a **Phase IIb randomized, double-blind, placebo-controlled study** designed to evaluate the efficacy, safety, and tolerability of **AZD5004** in participants living with obesity or overweight with at least one comorbidity. The trial aims to determine whether AZD5004 is superior to placebo for weight loss at 26 weeks, with primary endpoints including the percent change in body weight from baseline and the proportion of participants achieving a weight loss of at least 5% from baseline at week 26. Secondary endpoints extend to week 36, assessing further weight loss metrics.

Participants will be involved in the trial for a maximum treatment period of 36 weeks. The trial will commence with a screening visit to confirm eligibility based on criteria such as age, body mass index (BMI), and the presence of weight-related comorbidities like hypertension or dyslipidemia. Following successful screening, participants will be randomized to receive either AZD5004 or a matching placebo, administered orally in the form of a film-coated tablet. The trial will include regular follow-up visits to monitor safety, efficacy, and adherence to the treatment regimen. The end-of-study visit will conclude the participant's involvement, with assessments to evaluate the overall outcomes of the intervention.

Participants are expected to maintain a stable body weight for three months prior to screening and adhere to specific contraceptive measures if applicable. Conditions that may lead to early termination from the study include significant protocol deviations, adverse events, or withdrawal of consent. The estimated recruitment start date is November 4, 2024, with the trial expected to conclude by November 28, 2025. The study is not classified as low intervention and is conducted under the sponsorship of AstraZeneca AB, utilizing a synthetic small molecule as the investigational medicinal product.

The clinical trial involves the administration of **AZD5004**, a synthetic small molecule developed by AstraZeneca AB. AZD5004 is provided in the form of a **film-coated tablet** and is intended for **oral use**. The active substance, AZD5004, is of chemical origin. The trial does not specify a maximum daily dose or total dose amount, but the maximum treatment period is set at 36 weeks. The trial aims to evaluate the efficacy, safety, and tolerability of AZD5004 in participants living with obesity or overweight with comorbidity. The pharmaceutical form of the tablet ensures ease of administration and compliance monitoring will be conducted to ensure adherence to the dosing schedule.

In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind, placebo-controlled study. The placebo is designed to match the AZD5004 film-coated tablet in appearance but does not contain the active substance. The use of a placebo allows for the assessment of the true efficacy of AZD5004 by comparing outcomes between the treatment and control groups. The placebo administration follows the same route and schedule as the experimental medication to maintain the study's blinding integrity.

The efficacy of AZD5004 in the clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints include the percent change in body weight from baseline at Week 26 and the proportion of participants achieving a weight loss of at least 5% from baseline at the same time point. Secondary endpoints will further evaluate efficacy by measuring the percent change in body weight from baseline at Week 36, the proportion of participants with weight loss of at least 5% at Week 36, and the absolute change in body weight at both Week 26 and Week 36. Additionally, the trial will assess the proportion of participants achieving weight loss of at least 10% and 15% at both Week 26 and Week 36.

These efficacy parameters will be collected and analyzed at specified time points, namely Week 26 and Week 36, to determine the effectiveness of AZD5004 compared to placebo. The trial is designed as a Phase IIb randomized, double-blind, placebo-controlled study, focusing on participants living with obesity or overweight with comorbidity. The primary objective is to establish whether AZD5004 is superior to placebo in achieving significant weight loss over the course of the trial.