Dose-Response Study of NNC0487-0111 in Type 2 Diabetes Patients Inadequately Controlled with Metformin and/or SGLT2 Inhibitors

The primary objective of this study is to demonstrate and characterize the **dose-response relationship** of once-weekly subcutaneous (QW s.c.) and once-daily oral (QD) administration of NNC0487-0111. The study aims to compare the effect of varying doses to placebo on the change in **HbA1c** levels from baseline to week 36 in participants with **Type 2 Diabetes** (T2D) inadequately controlled with metformin with or without an SGLT2 inhibitor. This is clinically relevant as it seeks to optimize glycemic control in T2D patients, potentially improving their overall metabolic health and reducing the risk of diabetes-related complications.

The secondary objectives include: - Characterizing the dose-response relationship of varying doses of QW s.c. and QD oral NNC0487-0111, and comparing these to placebo for relative change in body weight from baseline to week 36 in participants with T2D inadequately controlled with metformin with or without an SGLT2 inhibitor. - Comparing the effect of varying doses of QW s.c. and QD oral NNC0487-0111 versus placebo on body weight, glycemic control, BMI, waist circumference, blood pressure, inflammation, and lipid metabolism in participants with T2D inadequately controlled with metformin with or without an SGLT2 inhibitor. - Comparing the safety and tolerability of varying doses of QW s.c. and QD oral NNC0487-0111 versus placebo in participants with T2D inadequately controlled with metformin with or without an SGLT2 inhibitor. - Comparing the effect of varying doses of QW s.c. and QD oral NNC0487-0111 versus placebo on chronic kidney disease (CKD) markers in participants with T2D inadequately controlled with metformin with or without an SGLT2 inhibitor.

The clinical trial involves a total of **100 participants** diagnosed with **Type 2 Diabetes**. The study population includes both male and female subjects, aged between 18 and 75 years. Participants were selected based on their diagnosis of type 2 diabetes mellitus at least 180 days prior to screening and must have been on a stable daily dose of metformin, with or without an SGLT2 inhibitor, for at least 90 days before screening. The participants' **HbA1c** levels range from 7.0% to 10.0% as assessed by a central laboratory at screening, and their body mass index is between 23.0 and less than 50.0 kg/m². The trial does not include a vulnerable population. Participants are required to adhere to the study protocol, including the use of a continuous glucose monitoring device. The selection criteria ensure that the study population is representative of individuals with inadequately controlled type 2 diabetes on their current medication regimen.

The clinical trial is designed to evaluate the **safety** and efficacy of once-weekly subcutaneous and once-daily oral administration of NNC0487-0111 in participants with **type 2 diabetes**. This is a randomized, double-blind, placebo-controlled trial, which aims to characterize the dose-response relationship and compare the effects of varying doses to placebo on the change in HbA1c from baseline to week 36. The trial is expected to last until October 31, 2025, with recruitment starting on August 23, 2024. Participants will be involved for a maximum of 36 weeks, during which they will undergo a series of study visits.

The sequence of study visits includes an initial screening visit to confirm eligibility based on criteria such as age, diagnosis of type 2 diabetes, stable antidiabetic medication regimen, and HbA1c levels. Following the screening, participants will be randomized to receive either the investigational product or placebo. Regular follow-up visits will be scheduled to monitor safety, efficacy, and adherence to the protocol, including the use of a continuous glucose monitoring device. The end-of-study visit will assess the primary endpoint of change in HbA1c, along with secondary endpoints such as changes in body weight, fasting plasma glucose, and other metabolic parameters.

Participant involvement may be terminated early if they experience significant adverse events, fail to adhere to the study protocol, or withdraw consent. The trial will ensure that all data collected is handled in accordance with regulatory standards, maintaining the confidentiality and integrity of participant information. The study will contribute valuable insights into the management of type 2 diabetes, potentially informing future therapeutic strategies.

The clinical trial involves the administration of several treatments to evaluate their safety and efficacy in participants with type 2 diabetes. The experimental medication **NNC0487-0111** is a polypeptide consisting of a glucagon-like peptide-1 receptor agonist and an amylin receptor agonist, connected by a linker with four glycine residues and a C18 fatty acid side chain. This compound is administered in two pharmaceutical forms: as a tablet for oral administration and as a solution for subcutaneous injection. The dosing schedule for both forms is once daily for the oral tablet and once weekly for the subcutaneous injection, with a maximum treatment period of 36 weeks. The trial aims to characterize the dose-response relationship and compare the effects of varying doses to placebo.

**Metformin embonate** is included as a non-experimental treatment in the study. It is administered orally in a pharmaceutical form identified as PHF00245MIG. The role of metformin embonate in the trial is to serve as a standard-of-care therapy, as participants are those inadequately controlled with metformin alone or in combination with an SGLT2 inhibitor. The dosing schedule and compliance monitoring for metformin embonate are consistent with standard clinical practice, although specific dosing details are not provided in the trial data.

**Dapagliflozin propanediol** is another non-experimental treatment used in the study, classified as an SGLT2 inhibitor. It is administered orally in a pharmaceutical form identified as PHF00082MIG. Similar to metformin embonate, dapagliflozin propanediol is part of the standard-of-care therapy for participants whose type 2 diabetes is inadequately controlled. The dosing schedule follows standard clinical guidelines, and participant compliance is monitored throughout the trial duration.

The trial also includes the use of **placebo** treatments, specifically Placebo A and Placebo C tablets. These are utilized to compare the effects of the experimental medication NNC0487-0111 and to assess the placebo effect in the study population. The placebo tablets are administered in a manner consistent with the experimental treatments, ensuring blinding and maintaining the integrity of the trial design.

The efficacy of the clinical trial will be assessed primarily through the change in **HbA1c** levels from baseline to week 36. This parameter serves as the primary endpoint to evaluate the effectiveness of the investigational product, NNC0487-0111, in participants with type 2 diabetes inadequately controlled with metformin with or without an SGLT2 inhibitor. Secondary endpoints include a range of metabolic and cardiovascular parameters such as relative change in body weight, change in fasting plasma glucose (FPG), change in body mass index (BMI), and change in systolic blood pressure (SBP). Additional secondary endpoints involve changes in lipid profiles, including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides. The trial will also monitor changes in high sensitivity C-Reactive Protein (hsCRP), urinary albumin/creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR) using creatinine-cystatin C based CKD-EPI.

Data collection will occur at specified intervals throughout the trial, with the primary endpoint being assessed at the conclusion of the 36-week treatment period. The trial will employ validated laboratory tests and continuous glucose monitoring (CGM) devices to ensure accurate and reliable measurement of these parameters. The analysis will focus on comparing the effects of varying doses of NNC0487-0111 to placebo, thereby characterizing the dose-response relationship. The trial is designed to provide comprehensive insights into the efficacy of the investigational product in managing type 2 diabetes and its associated metabolic conditions.