Research Study to Compare Semaglutide Tablets With Empagliflozin or Metformin Tablets in People With Type 2 Diabetes

Study Overview
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Brief Summary
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This study compares the medicines semaglutide with empagliflozin or metformin in people with newly diagnosed type 2 diabetes. This study will look mainly at how well participant's blood sugar and body weight are controlled when they are taking the study medicines. Participants will either get semaglutide tablets, empagliflozin tablets or metformin tablets. Which treatment participants will get is decided by chance. Currently, doses of 3 milligram (mg), 7 mg and 14 mg semaglutide tablets (Rybelsus) can be prescribed in some countries. 25 mg and 50 mg semaglutide tablets are new doses. 10 mg and 25 mg empagliflozin tablets (Jardiance) can be prescribed in some countries. 500 mg metformin tablets (STADA) can be prescribed in some countries. Participants will get 1 to 4 tablets per day for 104 weeks. The study will last for about 2 years and 7 weeks (111 weeks). Participants should not have been treated for weight management 90 days before screening or never been treated with any medicine for type 2 diabetes (except diabetes during pregnancy) before screening. Women cannot take part if pregnant, breast-feeding or plan to get pregnant during the study period.

Official Title
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Efficacy and Safety of First Line Use of Oral Semaglutide 25 mg or 50 mg Once Daily Versus Empagliflozin 25 mg or Versus Metformin 2000 mg in Newly Diagnosed Treatment naïve Patients With Type 2 Diabetes

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Semaglutide
* Drug: Empagliflozin
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female. Age ≥18 and <60 years at the time of signing the informed consent. Diagnosed with type 2 diabetes mellitus within 24 months from the day of screening. HbA1c of 7.0-10.0% (53-86 millimoles per mole [mmol/mol]) Body mass index ≥25.0 kilogram per square meter (kg/m^2) Exclusion Criteria: Treatment with any medication for the indication of diabetes. Prior insulin treatment for gestational diabetes is allowed. Treatment with any medication for the indication of weight management 90 days prior to screening. Renal impairment measured as estimated glomerular filtration rate (eGFR) <60 milliliters per minute per 1.73 meter sqaure (mL/min/1.73 m^2) at screening. Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus examination performed within 90 days before screening or in the period between screening and randomisation. Pharmacological pupil-dilation is a requirement unless using a digital fundus photography camera specified for non-dilated examination. C-peptide <1.5 nanograms per milliliter (ng/mL) at screening. Positive insulinoma associated-protein 2 (IA-2) antibodies ≥7.5 Units/mL or anti-glutamic acid decarboxylase (anti-GAD) antibodies greater than (>) 5.0 international units per milliliter (IU/mL). Impaired liver function, defined as Alanine aminotransferase (ALT) ≥2.5 times or Bilirubin >1.5 times upper normal limit at screening. History of major surgical procedures involving the stomach potentially affecting absorption of trial products (example subtotal or total gastrectomy, sleeve gastrectomy, gastric bypass surgery) or current presence of gastrointestinal implant. Presence of clinically significant gastrointestinal disorders affecting absorption of drugs and/or nutrients, as judged by the investigator. Any contraindications for empagliflozin or metformin according to local labelling at the investigator's discretion

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Semaglutide 25 mg<br>Participants will receive 25 mg oral semaglutide once daily in maintenance period after dose escalation period. | Drug: Semaglutide<br>* Administered as oral tablets.<br>|
| Experimental: Semaglutide 50 mg<br>Participants will receive 50 mg oral semaglutide once daily in maintenance period after dose escalation period. | Drug: Semaglutide<br>* Administered as oral tablets.<br>|
| Experimental: Empagliflozin 25 mg<br>Participants will 25 mg empagliflozin oral once daily in maintenance period after dose escalation period. | Drug: Empagliflozin<br>* Administered as oral tablets.<br>|
| Experimental: Metformin 2000 mg<br>Participants will receive metformin 1000 mg orally twice daily (total 2000 mg) in maintenance period after dose escalation period. | Drug: Metformin<br>* Administered as oral tablets.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in glycated haemoglobin (HbA1c) | Measured in Percentage (%)-points. | From randomisation (week 0) to week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in body weight | Measured in kilograms (kg). | From randomisation (week 0) to week 52 | 
| Change in fasting plasma glucose (FPG) | Measured in millimoles per liter (mmol/L). | From randomisation (week 0) to week 52 | 
| Change in 7 point self measured plasma glucose (SMPG) mean profile | Measured in mmol/L. | From randomisation (week 0) to week 52 | 
| Change in 7-point self-measured plasma glucose (SMPG) mean post prandial increments | Measured in mmol/L. | From randomisation (week 0) to week 52 | 
| Relative change in body weight | Measured in Percentage (%). | From randomisation (week 0) to week 52 | 
| Change in waist circumference | Measured in centimeters (cm). | From randomisation (week 0) to week 52 | 
| HbA1c less than or equal to (≤) 6.5% (Yes/No) | Measured as count of participants. | At week 52 | 
| HbA1c less than (<) 7% (Yes/No) | Measured as count of participants. | At week 52 | 
| Body weight reduction greater than equal to ( ≥) 5% (Yes/No) | Measured as count of participants. | At week 52 | 
| Body weight reduction ≥10% (Yes/No) | Measured as count of participants. | At week 52 | 
| Body weight reduction ≥15% (Yes/No) | Measured as count of participants. | At week 52 | 
| HbA1c <7.0% and body weight reduction ≥5% (Yes/No) | Measured as count of participants. | At week 52 | 
| Change in systolic blood pressure | Measured in millimeters of mercury (mmHg). | From randomisation (week 0) to week 52 | 
| Change in diastolic blood pressure | Measured in mmHg. | From randomisation (week 0) to week 52 | 
| Change in High-sensitivity C-reactive protein (hsCRP) | Measured in milligrams per liter (mg/L). | From randomisation (week 0) to week 52 | 
| Time to rescue medication | Measured in days. | From randomisation (week 0) to week 104 | 
| Change in HbA1c | Measured in %-points. | From randomisation (week 0) to week 104 | 
| Change in body weight | Measured in kg. | From randomisation (week 0) to week 104 | 
| Change in FPG | Measured in mmol/L. | From randomisation (week 0) to week 104 | 
| Change in 7 point SMPG mean profile | Measured in mmol/L. | From randomisation (week 0) to week 104 | 
| Change in 7-point SMPG mean post prandial increments | Measured in mmol/L | From randomisation (week 0) to week 104 | 
| Relative change in body weight | Measured in Percentage. | From randomisation (week 0) to week 104 | 
| Change in waist circumference | Measured in cm. | From randomisation (week 0) to week 104 | 
| HbA1c ≤6.5% (Yes/No) | Measured as count of participants. | At week 104 | 
| HbA1c <7.0% (Yes/No) | Measured as count of participants. | At week 104 | 
| Body weight reduction ≥5% (Yes/No) | Measured as count of participants. | At week 104 | 
| Body weight reduction ≥10% (Yes/No) | Measured as count of participants. | At week 104 | 
| Body weight reduction ≥15% (Yes/No) | Measured as count of participants. | At week 104 | 
| HbA1c <7.0% and body weight reduction ≥5% (Yes/No) | Measured as count of participants. | At week 104 | 
| Change in systolic blood pressure | Measured in mmHg. | From randomisation (week 0) to week 104 | 
| Change in diastolic blood pressure | Measured in mmHg. | From randomisation (week 0) to week 104 | 
| Change in hsCRP | Measured in mg/L. | From randomisation (week 0) to week 104 | 
| Treatment emergent adverse events | Measured as count of events. | From randomisation (week 0) to week 52 | 
| Number of severe (level 3) or clinically significant (level 2) hypoglycaemic episodes | Measured as count of episodes. | From randomisation (week 0) to week 52 | 
| Treatment emergent adverse events | Measured as count of events. | From randomisation (week 0) to follow-up visit (week 109) | 
| Number of severe (level 3) or clinically significant (level 2) hypoglycaemic episodes | Measured as count of episodes. | From randomisation (week 0) to follow-up visit (week 109) | 
| Change in Control of Eating Questionnaire (CoEQ) score - Craving Control domain | CoEQ is a 19-item multidimensional patient reported outcome (PRO) that assesses the experience of hunger, satiety, and severity and type of food cravings. CoEQ consists of 4 subscales that measure craving control (5 items), positive mood (4 items), craving for sweet (4 items), craving for savoury food (4 items), and 2 single items that address hunger and satiety. Each item is evaluated on a 0-10 (i.e., 11-point) numeric rating scale. The total score for each subscale is calculated as the sum of the item scores divided by the number of items in the subscale. Scores ranges are thus: Craving Control 0-50/5 = 0-10); Positive Mood (0-40/4 = 0-10); Craving Sweet (0-40/4 = 0-10); Craving Savoury food (0-40/4 = 0-10); single items that address hunger and satiety (0-10). For the craving control subscale, the subscale score is reversed so that a higher score represents a greater level of craving control. | From randomisation (week 0) to week 52 | 
| Change in CoEQ score - Craving for Savory domain | CoEQ is a 19-item multidimensional PRO that assesses the experience of hunger, satiety, and severity and type of food cravings. CoEQ consists of 4 subscales that measure craving control (5 items), positive mood (4 items), craving for sweet (4 items), craving for savoury food (4 items), and 2 single items that address hunger and satiety. Each item is evaluated on a 0-10 (i.e., 11-point) numeric rating scale. The total score for each subscale is calculated as the sum of the item scores divided by the number of items in the subscale. Scores ranges are thus: Craving Control 0-50/5 = 0-10); Positive Mood (0-40/4 = 0-10); Craving Sweet (0-40/4 = 0-10); Craving Savoury food (0-40/4 = 0-10); single items that address hunger and satiety (0-10). For the craving savoury food subscale, higher score represents a greater level of craving. | From randomisation (week 0) to week 52 | 
| Change in Impact of Weight on Quality of Life-Lite Clinical Trials (IWQOL-Lite-CT) score - Physical function domain | IWQOL-Lite-CT measures weight-related physical and psychosocial functioning. The measure consists of 20 items yielding 3 composite scores, and 1 total score. Higher scores indicate better levels of functioning. Composite scores (score range): Physical composite (0-100), Psychosocial composite (0 100), Physical Function composite (0-100). Total score range (0-100). | From randomisation (week 0) to week 52 | 
| Change in American Heart Association (AHA) Life's Simple 7 summary score | The AHA recommends focusing on 7 cardiovascular health factors (smoking, BMI, physical activity, diet, total cholesterol, blood pressure, and fasting blood glucose) for early or primary prevention of cardiovascular disease. The 7 health factors are each categorized as ideal, intermediate, or poor. Scales range from 0 (minimum) to 14 (maximum). Higher score represents a greater level of health. | From randomisation (week 0) to week 52 | 
| Change in CoEQ score - Craving Control domain | CoEQ is a 19-item multidimensional PRO that assesses the experience of hunger, satiety, and severity and type of food cravings. CoEQ consists of 4 subscales that measure craving control (5 items), positive mood (4 items), craving for sweet (4 items), craving for savoury food (4 items), and 2 single items that address hunger and satiety. Each item is evaluated on a 0-10 (i.e., 11-point) numeric rating scale. The total score for each subscale is calculated as the sum of the item scores divided by the number of items in the subscale. Scores ranges are thus: Craving Control 0-50/5 = 0-10); Positive Mood (0-40/4 = 0-10); Craving Sweet (0-40/4 = 0-10); Craving Savoury food (0-40/4 = 0-10); single items that address hunger and satiety (0-10). For the craving control subscale, the subscale score is reversed so that a higher score represents a greater level of craving control. | From randomisation (week 0) to week 104 | 
| Change in CoEQ score - Craving for Savory domain | CoEQ is a 19-item multidimensional PRO that assesses the experience of hunger, satiety, and severity and type of food cravings. CoEQ consists of 4 subscales that measure craving control (5 items), positive mood (4 items), craving for sweet (4 items), craving for savoury food (4 items), and 2 single items that address hunger and satiety. Each item is evaluated on a 0-10 (i.e., 11-point) numeric rating scale. The total score for each subscale is calculated as the sum of the item scores divided by the number of items in the subscale. Scores ranges are thus: Craving Control 0-50/5 = 0-10); Positive Mood (0-40/4 = 0-10); Craving Sweet (0-40/4 = 0-10); Craving Savoury food (0-40/4 = 0-10); single items that address hunger and satiety (0-10). For the craving savoury food subscale, higher score represents a greater level of craving. | From randomisation (week 0) to week 104 | 
| Change in IWQOL-Lite-CT score - Physical function domain | IWQOL-Lite-CT measures weight-related physical and psychosocial functioning. The measure consists of 20 items yielding 3 composite scores, and 1 total score. Higher scores indicate better levels of functioning. Composite scores (score range): Physical composite (0-100), Psychosocial composite (0 100), Physical Function composite (0-100). Total score range (0-100). | From randomisation (week 0) to week 104 | 
| Change in AHA Life's Simple 7 summary score | The AHA recommends focusing on 7 cardiovascular health factors (smoking, BMI, physical activity, diet, total cholesterol, blood pressure, and fasting blood glucose) for early or primary prevention of cardiovascular disease. The 7 health factors are each categorized as ideal, intermediate, or poor. Scales range from 0 (minimum) to 14 (maximum). Higher score represents a greater level of health. | From randomisation (week 0) to week 104 |