Efficacy and Safety Evaluation of AZD9550 and AZD6234 Co-administration in Obesity or Overweight Patients with Comorbidities: A Phase IIb Randomized Study

The primary objective of this Phase IIb randomized, double-blind, placebo-controlled study is to evaluate the efficacy of the co-administration of **AZD9550** and **AZD6234** in achieving superior weight loss compared to placebo. This is measured by the percent change in body weight from baseline and the proportion of participants achieving a weight loss of at least 5%. This objective is clinically relevant as it addresses the need for effective weight management strategies in individuals with obesity or overweight conditions, which are often associated with multiple comorbidities.

Secondary objectives include:

• Determining whether the combination treatment is superior to monotherapy with either AZD9550 or AZD6234 for weight loss.
• Assessing the effect of the combination treatment versus monotherapy on the proportion of participants achieving weight loss of at least 5%.
• Evaluating the effect of the combination treatment versus placebo and monotherapy on the proportion of participants achieving weight loss of at least 10% and 15%.
• Assessing the immunogenicity profile of the combination treatment and monotherapies.
• Evaluating the safety and tolerability of the combination treatment compared with placebo and monotherapy.

The clinical trial involves a total of **320 participants** who are being studied to assess the efficacy of a combination treatment for **obesity** or overweight conditions, which are often correlated with various co-morbidities. The study population includes both male and female participants, aged between **18 to 75 years**. Participants were selected based on specific criteria, including a **BMI** of 30 kg/m² or higher, or 27 kg/m² with at least one weight-related comorbidity. All participants are required to have maintained a stable body weight for three months prior to screening. The trial includes individuals who are capable of providing informed consent and adhere to local contraceptive regulations. Female participants must have negative pregnancy tests at both screening and baseline. The trial population is inclusive of a vulnerable population, ensuring a comprehensive assessment of the treatment's impact across diverse demographic groups.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy, safety, and tolerability of the co-administration of AZD9550 and AZD6234 in participants with obesity or overweight conditions associated with comorbidities. The primary objective is to determine whether the combination treatment is superior to placebo in achieving weight loss, measured as a percent change in body weight from baseline. The trial will also assess the proportion of participants achieving a weight loss of at least 5% from baseline. Secondary endpoints include absolute changes in body weight, weight loss of 10% and 15%, and the safety and tolerability of the treatments.

The trial is expected to last for 36 weeks, with participant involvement beginning from the screening visit and continuing through the end-of-study visit. The screening visit will confirm eligibility based on criteria such as age, body mass index (BMI), and stable body weight. Participants must be between 18 to 75 years of age, with a BMI of at least 30 kg/m² or 27 kg/m² with a weight-related comorbidity. Female participants must have negative pregnancy tests at screening and baseline. Following the screening, participants will be randomized to receive either the combination treatment, monotherapy, or placebo.

Study visits will occur at regular intervals to monitor safety, efficacy, and adherence to the treatment protocol. These visits will include assessments of body weight, vital signs, and any adverse events. The end-of-study visit will conclude the participant's involvement, with a final evaluation of the primary and secondary endpoints. Participants may be withdrawn from the study early if they experience significant adverse effects, fail to adhere to the study protocol, or withdraw consent. The trial is anticipated to start recruitment in February 2025 and conclude by June 2026.

The clinical trial involves the administration of several experimental and non-experimental treatments. **AZD9550** is a synthetic peptide administered as a solution for injection. It is delivered subcutaneously, with a dosing unit of mg/ml. The maximum treatment period is 36 weeks. The specific dosage and frequency are not detailed in the provided data.

**AZD6234** is another synthetic peptide used in the trial, also administered as a solution for injection via the subcutaneous route. The dosing unit is mg/ml, and the treatment duration is up to 36 weeks. The exact dosage and administration frequency are not specified.

The trial includes a **placebo** for AZD9550, which serves as a comparator treatment. The placebo is not associated with any active substance and does not have a specified pharmaceutical form or route of administration.

Similarly, a **placebo** for AZD6234 is used in the study. Like the placebo for AZD9550, it lacks an active substance, pharmaceutical form, and specified route of administration.

**Glucose** is utilized as an auxiliary treatment in the trial. It is administered intravenously, with a maximum daily dose of 9999 mg/kg. The treatment period can extend up to 36 weeks.

**Calcium Carbonate**, combined with **Ascorbic Acid** and **Calcium Lactate Gluconate**, is administered orally. The maximum daily dose is 4 grams, and the treatment duration is up to 36 weeks.

**Calcium Gluconate** is administered via IV infusion. The maximum daily dose is 9999 grams, with a treatment period of up to 36 weeks.

**Glucagon** is administered nasally, with a maximum daily dose of 3 mg. The treatment period is up to 36 weeks.

**Ondansetron Hydrochloride** is administered orally, with a maximum daily dose of 16 mg. The treatment duration is up to 36 weeks.

**Cyclizine Hydrochloride** is also administered orally, with a maximum daily dose of 200 mg. The treatment period is up to 36 weeks.

**Calcium Citrate** is administered orally, with a maximum daily dose of 4 grams. The treatment duration is up to 36 weeks.

Participant compliance with the dosing schedule is monitored throughout the trial, although specific methods of compliance monitoring are not detailed in the provided data.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints related to weight loss in participants living with obesity or overweight with comorbidity. The primary endpoints include the percent change in body weight from baseline after 36 weeks of treatment and the proportion of participants achieving a weight loss of at least 5% from baseline after 36 weeks. Secondary endpoints will further assess the absolute change in body weight, the percent and absolute change in body weight, and the proportion of participants achieving weight loss of at least 10% and 15% from baseline after 36 weeks. Additionally, the prevalence, incidence, and titres of anti-drug antibodies (ADAs) to AZD9550 and AZD6234, both in combination and as monotherapies, will be evaluated after 36 weeks of treatment. The safety and tolerability of the combination therapy compared with placebo and monotherapy will also be assessed.