Efficacy and Safety of Oral Semaglutide Versus Liraglutide and Versus Placebo in Subjects With Type 2 Diabetes Mellitus

Study Overview
=================
Brief Summary
-----------------
This trial is conducted globally. The aim of this trial is to investigate efficacy and safety of oral Semaglutide versus Liraglutide and versus Placebo in Subjects with Type 2 Diabetes Mellitus.

Official Title
-----------------
Efficacy and Safety of Oral Semaglutide Versus Liraglutide and Versus Placebo in Subjects With Type 2 Diabetes Mellitus

Conditions
-----------------
Diabetes, Diabetes Mellitus, Type 2

Intervention / Treatment
-----------------
* Drug: semaglutide
* Drug: liraglutide
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial Male or female, age above or equal to 18 years at the time of signing informed consent. For Japan only: Male or female, age at least 20 years at the time of signing informed consent Diagnosed with type 2 diabetes mellitus for at least 90 days prior to day of screening. HbA1c (glycosylated haemoglobin) of 7.0-9.5 % (53-80.3 mmol/mol) (both inclusive) Stable daily dose of metformin (above or equal to 1500 mg or maximum tolerated dose as documented in the subject medical record) alone or in combination with a stable daily dose of a SGLT-2 (sodium-glucose co-transporter-2) inhibitor for at least 90 days prior to day of screening (fixed-dose combinations are allowed) Exclusion Criteria: Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using an adequate contraceptive method (adequate contraceptive measure as required by local regulation or practice).For certain specific countries: Additional specific requirements apply Any disorder, which in the investigator's opinion might jeopardise subject's safety or compliance with the protocol Family or personal history of Multiple Endocrine Neoplasia Type 2 (MEN 2) or Medullary Thyroid Carcinoma (MTC) History of pancreatitis (acute or chronic) History of major surgical procedures involving the stomach and potentially affecting absorption of trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery) Any of the following: myocardial infarction (MI), stroke or hospitalisation for unstable angina or transient ischaemic attack within the past 180 days prior to the day of screening Subjects presently classified as being in New York Heart Association (NYHA) Class IV Planned coronary, carotid or peripheral artery revascularisation known on the day of screening Subjects with ALT (alanine aminotransferase) above 2.5 × upper normal limit (UNL) Renal impairment defined as estimated Glomerular Filtration Rate (eGFR) below 60 mL/min/1.73 m^2 as per Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria in a period of 90 days before the day of screening. An exception is short-term insulin treatment for acute illness for a total of below or equal to 14 days Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus photography or dilated fundoscopy performed within 90 days prior to randomisation History or presence of malignant neoplasms within the last 5 years (except basal and squamous cell skin cancer and carcinoma in situ) History of diabetic ketoacidosis

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral Semaglutide<br> | Drug: semaglutide<br>* Oral semaglutide once-daily.<br>|
| Active Comparator: Liraglutide<br> | Drug: liraglutide<br>* Subcutaneous (s.c.) injection once-daily.<br>|
| Placebo Comparator: Placebo<br> | Drug: placebo<br>* Placebo once-daily.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c (Week 26) | Change from baseline (week 0) in glycosylated haemoglobin (HbA1c) was evaluated at week 26. The endpoint was evaluated based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. The endpoint was also evaluated based on the data from the on-treatment without rescue medication observation period, which was the time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication and/or premature trial product discontinuation. | Week 0, week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Body Weight (Week 26) | Change from baseline (week 0) in body weight was evaluated at week 26. The endpoint was evaluated based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. The endpoint was also evaluated based on the data from the on-treatment without rescue medication observation period, which was the time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication and/or premature trial product discontinuation. | Week 0, week 26 | 
| Change in HbA1c (Week 52) | Change from baseline (week 0) in HbA1c was evaluated at 52 weeks. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 52 | 
| Change in Body Weight (Week 52) | Change from baseline (week 0) in body weight was evaluated at 52 weeks. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 52 | 
| Change in Body Weight (%) | Relative change from baseline (week 0) in body weight (kg) was evaluated at weeks 26 and 52. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, Week 26, Week 52 | 
| Change in Fasting Plasma Glucose | Change from baseline (week 0) in fasting plasma glucose (FPG) was evaluated at weeks 26 and 52. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Change in Body Mass Index | Change from baseline (week 0) in body mass index (BMI) was evaluated at weeks 26 and 52. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Change in Waist Circumference | Change from baseline (week 0) in waist circumference was evaluated at weeks 26 and 52. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Change in Total Cholesterol - Ratio to Baseline | Change from baseline (week 0) in total cholesterol (mmol/L) at weeks 26 and 52 is presented as ratio to baseline. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Change in Low-density Lipoprotein (LDL) Cholesterol - Ratio to Baseline | Change from baseline (week 0) in low-density lipoprotein (LDL) cholesterol (mmol/L) at weeks 26 and 52 is presented as ratio to baseline. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Change in Very Low Density Lipoprotein (VLDL) Cholesterol - Ratio to Baseline | Change from baseline (week 0) in VLDL cholesterol (mmol/L) at weeks 26 and 52 is presented as ratio to baseline. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Change in High-density Lipoprotein (HDL) Cholesterol - Ratio to Baseline | Change from baseline (week 0) in HDL cholesterol (mmol/L) at weeks 26 and 52 is presented as ratio to baseline. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Change in Triglycerides - Ratio to Baseline | Change from baseline (week 0) in triglycerides (mmol/L) at weeks 26 and 52 is presented as ratio to baseline. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Change in Free Fatty Acids - Ratio to Baseline | Change from baseline (week 0) in free fatty acids (FFA) (mmol/L) at weeks 26 and 52 is presented as ratio to baseline. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Change in SMPG - Mean 7-point Profile | Change from baseline (week 0) to week 26 and week 52 in mean 7-point self-measured plasma glucose (SMPG) profile. SMPG was recorded at the following 7 time points: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after dinner and at bedtime. Mean 7-point profile was defined as the area under the profile, calculated using the trapezoidal method, divided by the measurement time. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Change in SMPG - Mean Postprandial Increment Over All Meals | Change from baseline (week 0) in the average of the post-prandial increments over all meals was evaluated at weeks 26 and 52. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Participants Who Achieve HbA1c <7.0% (53 mmol/Mol) ADA Target (Yes/no) | Participants who achieved HbA1c <7.0% (American Diabetes Association (ADA) target) (yes/no), was evaluated at weeks 26 and 52. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 26, week 52 | 
| Participants Who Achieve HbA1c <6.5% (48 mmol/Mol) AACE Target (Yes/no) | Participants who achieved HbA1c less than or equal to 6.5% (American Association of Clinical Endocrinologists (AACE) target) (yes/no) at weeks 26 and 52 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 26, week 52 | 
| Participants Who Achieve Weight Loss ≥5% (Yes/no) | Participants who achieved weight loss more than or equal to 5% of their baseline body weight (yes/no) at weeks 26 and 52 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 26, week 52 | 
| Participants Who Achieve Weight Loss ≥ 10% (Yes/no) | Participants who achieved weight loss more than or equal to 10% of their baseline body weight (yes/no) at weeks 26 and 52 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 26, week 52 | 
| Participants Who Achieve HbA1c <7.0 % (53 mmol/Mol) Without Hypoglycaemia (Severe or BG Confirmed Symptomatic Hypoglycaemia) and no Weight Gain (Yes/no) | Participants who achieved HbA1c less than 7.0 % without severe or blood glucose (BG) confirmed symptomatic hypoglycaemia and without weight gain (yes/no) at weeks 26 and 52 are presented. Severe hypoglycaemia was defined as an episode requiring assistance of another person to actively administer carbohydrate or glucagon, or take other corrective actions. BG-confirmed symptomatic hypoglycaemia was defined as an episode with plasma glucose value <3.1 mmol/L with symptoms consistent with hypoglycaemia. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 26, week 52 | 
| Participants Who Achieve HbA1c Reduction ≥1% (10.9 mmol/Mol) and Weight Loss ≥3% (Yes/no) | Participants who achieved HbA1c reduction more than or equal to 1% of their baseline HbA1c and weight loss of more than or equal to 3% of their baseline body weight (yes/no) at weeks 26 and 52 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 26, week 52 | 
| Time to Additional Anti-diabetic Medication | Presented results are the number of participants who had taken additional anti-diabetic medication anytime during the periods, from week 0 to week 26 and week 0 to week 52. Additional anti-diabetic medication was defined as any new anti-diabetic medication used for more than 21 days with the initiation at or after randomisation (week 0) and before (planned) end-of-treatment (week 52), and/or intensification of anti-diabetic medication (a more than 20% increase in dose relative to baseline) for more than 21 days with the intensification at or after randomisation and before (planned) end-of-treatment. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Weeks 0-52 | 
| Time to Rescue Medication | Presented results are the number of participants who had taken rescue medication anytime during the periods, from week 0 to week 26 and week 0 to week 52. Rescue medication was defined as any new anti-diabetic medication used as add-on to trial product and used for more than 21 days with the initiation at or after randomisation (week 0) and before last day on trial product, and/or intensification of anti-diabetic medication (a more than 20% increase in dose relative to baseline) for more than 21 days with the intensification at or after randomisation and before last day on trial product. Results are based on the data from the on-treatment without rescue medication observation period, which was the time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication and/or premature trial product discontinuation. | Weeks 0-52 | 
| Number of Treatment-emergent Adverse Events (TEAEs) During Exposure to Trial Product | Treatment emergent adverse events (TEAEs) were recorded from week 0 to week 57 (52-week treatment period plus the 5-week follow-up period). Adverse events (AEs) with onset during the on-treatment observation period were considered treatment-emergent. On-treatment observation period: Time period when a participant was on treatment with trial product, including any period after initiation of rescue medication. | Weeks 0-57 | 
| Change in Amylase - Ratio to Baseline | Change from baseline (week 0) in amylase (units/litre (U/L)) at weeks 26 and 52 is presented as ratio to baseline. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication. | Week 0, week 26, week 52 | 
| Change in Lipase - Ratio to Baseline | Change from baseline (week 0) in lipase (U/L) at weeks 26 and 52 is presented as ratio to baseline. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication. | Week 0, week 26, week 52 | 
| Change in Pulse Rate | Change from baseline (week 0) in pulse rate was evaluated at weeks 26 and 52. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication. | Week 0, week 26, week 52 | 
| Change in SBP and DBP | Change from baseline (week 0) in systolic blood pressure (SBP) and diastolic blood pressure (DBP) was evaluated at weeks 26 and 52. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication. | Week 0, week 26, week 52 | 
| Change in ECG Evaluation | Change from baseline (week 0) in electrocardiogram (ECG) was evaluated at weeks 26 and week 52. Change from baseline results are presented as shift in findings (normal, abnormal and not clinically significant (NCS) and abnormal and clinically significant (CS)) from week 0 to week 26 and week 52. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0, week 26, week 52 | 
| Change in Physical Examination | Participants with physical examination findings, normal, abnormal NCS and abnormal CS at baseline (weeks -2) and weeks 52 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. Results are presented for the following examinations: 1) Cardiovascular system; 2) Central and peripheral nervous system; 3) Gastrointestinal system, incl. mouth; 4) General appearance; 5) Head, ears, eyes, nose, throat, neck; 6) Lymph node palpation; 7) Musculoskeletal system; 8) Respiratory system; 9) Skin; 10) Thyroid gland. | Week -2, week 52 | 
| Change in Eye Examination Category | Participants with eye examination (fundoscopy) findings, normal, abnormal NCS and abnormal CS at baseline (week -2) and week 52 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week -2, Week 52 | 
| Occurrence of Anti-semaglutide Binding Antibodies (Yes/no) | This outcome measure is only applicable for the oral semaglutide 14 mg treatment arm. Number of participants who measured with anti-semaglutide binding antibodies anytime during post-baseline visits (weeks 0-57) are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Weeks 0-57 | 
| Occurrence of Anti-semaglutide Neutralising Antibodies (Yes/no) | This outcome measure is only applicable for the oral semaglutide 14 mg treatment arm. Number of participants who measured with anti-semaglutide neutralising antibodies anytime during post-baseline visits (weeks 0-57) are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Weeks 0-57 | 
| Occurrence of Anti-semaglutide Binding Antibodies Cross Reacting With Native GLP-1 (Yes/no) | This outcome measure is only applicable for the oral semaglutide 14 mg treatment arm. Number of participants who measured with anti-semaglutide binding antibodies cross reacting with native glucagon-like peptide-1 (GLP-1) anytime during post-baseline visits (weeks 0-57) are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Week 0-57 | 
| Occurrence of Anti-semaglutide Neutralising Antibodies Cross Reacting With Native GLP-1 (Yes/no) | This outcome measure is only applicable for the oral semaglutide 14 mg treatment arm. Number of participants who measured with anti-semaglutide neutralising antibodies cross reacting with native GLP-1 anytime during post-baseline visits (weeks 0-57) are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Weeks 0-57 | 
| Anti-semaglutide Binding Antibody Levels | This outcome measure is only applicable for the oral semaglutide 14 mg treatment arm. It is based on the data from participants who were measured with anti-semaglutide antibodies anytime during post-baseline visits (weeks 0-57). Results are presented as percentage of bound radioactivity-labelled semaglutide /total added radioactivity-labelled semaglutide (%B/T). Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. | Weeks 0-57 | 
| Number of Treatment-emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemic Episodes | Treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes were recorded during weeks 0-57 (52-week treatment period plus the 5-week follow-up period). Hypoglycaemic episodes with onset during the on-treatment observation period were considered treatment-emergent. On-treatment observation period was defined as the time period when a subject was on treatment with trial product, including any period after initiation of rescue medication. Severe hypoglycaemia was defined as an episode requiring assistance of another person to actively administer carbohydrate or glucagon, or take other corrective actions. BG-confirmed symptomatic hypoglycaemia: Confirmed by a glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. | Weeks 0-57 | 
| Participants With Treatment-emergent Severe or BG-confirmed Symptomatic Hypoglycaemic Episodes | Treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes were recorded from week 0 to week 57 (52-week treatment period plus the 5-week follow-up period). Hypoglycaemic episodes with onset during the on-treatment observation period were considered treatment-emergent. On-treatment observation period was defined as the time period when a subject was on treatment with trial product, including any period after initiation of rescue medication. Severe hypoglycaemia was defined as an episode requiring assistance of another person to actively administer carbohydrate or glucagon, or take other corrective actions. BG-confirmed symptomatic hypoglycaemia: Confirmed by a glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. | Weeks 0-57 | 
| Change in DTSQs: Individual Items and Total Treatment Satisfaction Score (6 of the 8 Items Summed) | Change from baseline (week 0) in Diabetes Treatment Satisfaction Questionnaire - status version (DTSQs) was evaluated at week 26 (wk 26) and week 52 (wk 52). The DTSQs items are scored on a 7-point graded response scale ranging from 6 to 0. Higher scores indicate higher levels of treatment satisfaction for DTSQs items 1, 4 -8. For items 2 and 3 a higher score indicates a higher patient perceived experience of hyperglycaemia and hypoglycaemia, respectively. Thus, lower scores indicate a perception of blood glucose levels being none of the time unacceptably high (item 2) or low (item 3). The domain score of total treatment satisfaction (total treatment satisfaction score) was computed by adding the six items scores 1, 4-8. The score has a minimum of 0 and a maximum of 36. A higher treatment satisfaction score indicates a higher level of treatment satisfaction. | Week 0, week 26, week 52 |