A Phase 4, Randomized, Open-Label, Active-Controlled Study to Investigate the Efficacy and Safety of Switching From Weekly Dulaglutide to Weekly Tirzepatide in Adults With Type 2 Diabetes

The primary objective of this study is to demonstrate that switching from once weekly **dulaglutide** to once weekly **tirzepatide** is superior to continuing and escalating dulaglutide for the change in HbA1c from baseline to Week 40 in adults with **Type 2 Diabetes**. This is clinically relevant as achieving better glycemic control is crucial in managing Type 2 Diabetes, potentially reducing the risk of complications associated with the disease.

Secondary objectives include demonstrating that switching from once weekly dulaglutide to once weekly tirzepatide is superior to continuing and escalating dulaglutide for weight change from baseline to Week 40. This is important as weight management is a key component in the overall treatment strategy for Type 2 Diabetes, influencing both disease progression and the effectiveness of therapeutic interventions.

The clinical trial involves a total of **105 participants** diagnosed with **Type 2 Diabetes**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific criteria, including having a stable dose of dulaglutide for at least six months prior to screening and maintaining a stable body weight within 5% during the 90 days preceding screening. The trial also considers individuals who are either not on oral antihyperglycemic medication or on a stable dose of up to three such medications, including metformin, SGLT-2 inhibitors, and/or sulfonylureas, for at least three months before screening. Participants are required to have a **BMI** of 25 kg/m² or higher. The trial includes a vulnerable population, indicating that additional ethical considerations are in place to protect these participants. The study aims to evaluate the efficacy of switching from once-weekly dulaglutide to once-weekly tirzepatide in terms of HbA1c change from baseline to Week 40.

The clinical trial is designed as a **randomized**, open-label, active-controlled study to evaluate the efficacy and safety of switching from weekly **dulaglutide** to weekly **tirzepatide** in adults with **type 2 diabetes**. The primary objective is to demonstrate that switching to tirzepatide is superior to continuing and escalating dulaglutide for the change in Hemoglobin A1c (HbA1c) from baseline to Week 40. The trial is expected to last approximately 40 weeks, with participant involvement beginning from the screening visit and continuing through the end-of-study visit.

Participants will undergo a series of study visits, starting with an inclusion (screening) visit to confirm eligibility based on criteria such as having type 2 diabetes, specific HbA1c levels, and stable body weight. Following randomization, participants will attend regular follow-up visits to monitor safety and efficacy outcomes, including changes in HbA1c, weight, and other metabolic parameters. The end-of-study visit will conclude the trial, assessing the final outcomes and any adverse events.

The expected length of participant involvement is approximately 40 weeks, with conditions for early termination including significant protocol deviations, adverse events, or withdrawal of consent. The trial will adhere to ethical standards and regulatory requirements, ensuring minimal additional risk or burden to participants compared to standard clinical practice.

The clinical trial involves the administration of several experimental and non-experimental medications to evaluate their efficacy and safety in adults with **Type 2 Diabetes**. The primary experimental medication is **Tirzepatide**, a solution for injection, administered once weekly. The maximum daily dose is 15 mg, with a total maximum dose of 450 mg over a 40-week period. The route of administration is via injection, and participant compliance is monitored throughout the study.

**Dulaglutide** is used as a comparator treatment in the study. It is also a solution for injection, administered once weekly, with a maximum daily dose of 4.5 mg and a total maximum dose of 174 mg over a 40-week period. The administration route is injection, and dosing schedules are adhered to as per protocol.

Additional non-experimental treatments include **Pioglitazone**, administered orally in a pharmaceutical form coded as PHF00245MIG. The maximum daily dose is 45 mg, with a total maximum dose of 13,860 mg over a 44-week period. **Canagliflozin** is another oral medication, provided as a film-coated tablet, with a maximum daily dose of 300 mg and a total maximum dose of 92,400 mg over 44 weeks.

**Glucagon** is administered nasally, with a maximum daily dose of 6 mg and a total maximum dose of 1,848 mg over 44 weeks. **Loperamide**, combined with **Dimeticone**, is administered orally, with a maximum daily dose of 16 mg and a total maximum dose of 4,928 mg over 44 weeks. **Colesevelam** is also administered orally, with a maximum daily dose of 3.75 g and a total maximum dose of 1,155 g over 44 weeks.

**Metformin** is administered orally, with a maximum daily dose of 2,000 mg and a total maximum dose of 616,000 mg over 44 weeks. **Empagliflozin** is provided as a film-coated tablet, with a maximum daily dose of 25 mg and a total maximum dose of 7,700 mg over 44 weeks. **Ertugliflozin** and **Dapagliflozin** are also administered orally, with maximum daily doses of 15 mg and 10 mg, respectively, and total maximum doses of 4,620 mg and 3,080 mg over 44 weeks.

**Bromocriptine** is administered orally, with a maximum daily dose of 4.8 mg and a total maximum dose of 1,478.4 mg over 44 weeks. **Ondansetron** is administered orally, with a maximum daily dose of 24 mg and a total maximum dose of 7,392 mg over 44 weeks. **Insulins and Analogues** are administered as a solution for injection, with a maximum daily dose of 500 IU and a total maximum dose of 154,000 IU over 44 weeks.

Participant compliance is monitored through regular assessments and adherence checks to ensure the accuracy and reliability of the study outcomes. The trial is designed to assess the superiority of switching from **Dulaglutide** to **Tirzepatide** in terms of HbA1c change from baseline to Week 40.

The efficacy of the clinical trial will be assessed by evaluating the change in **Hemoglobin A1c (HbA1c)** levels from baseline to Week 40. This primary endpoint will determine the effectiveness of switching from weekly dulaglutide to weekly tirzepatide in adults with type 2 diabetes. Secondary endpoints include changes from baseline in weight, fasting serum glucose, waist circumference, and body mass index (BMI). Additionally, the percentage of participants achieving specific HbA1c targets (<7%, ≤6.5%, <5.7%) and weight loss milestones (≥5%, ≥10%, ≥15%) will be measured. A composite endpoint will also be evaluated, defined as achieving HbA1c ≤6.5%, weight loss ≥10%, and no hypoglycemia, characterized by blood glucose <54 mg/dL (<3.0 mmol/L) and/or severe hypoglycemia. The change in the Impact of Weight on Quality of Life-Clinical Trials Version (IWQOL-Lite-CT) - Physical Functioning Score will also be assessed.