Efficacy and Safety of Oral Semaglutide Versus Placebo in Subjects With Type 2 Diabetes Mellitus Treated With Diet and Exercise Only

Change in Mean Postprandial Increment Over All Meals in SMPG

Change from baseline (week 0) to week 26 in the average of the post-prandial increments over all meals. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.

Time frame: Week 0, week 26

Change in Fasting Insulin - Ratio to Baseline

Change from baseline (week 0) to week 26 in fasting insulin (pmol/L) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product

Time frame: Week 0, week 26

Change in Fasting Pro-insulin - Ratio to Baseline

Change from baseline (week 0) to week 26 in fasting pro-insulin (pmol/L) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product

Time frame: Week 0, week 26

Change in Fasting Glucagon - Ratio to Baseline

Change from baseline (week 0) to week 26 in fasting glucagon (pg/mL) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product

Time frame: Week 0, week 26

Change in HOMA-IR (Insulin Resistance) - Ratio to Baseline

Change from baseline (week 0) to week 26 in homeostatic model assessment index of insulin resistance (HOMA-IR) (%) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.

Time frame: Week 0, week 26

Change in HOMA-B (Beta-cell Function) - Ratio to Baseline

Change from baseline (week 0) to week 26 in homeostatic model assessment index of beta-cell function (HOMA-B) (%) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.

Time frame: Week 0, week 26

Change in CRP - Ratio to Baseline

Change from baseline (week 0) to week 26 in C-reactive protein (CRP) (mg/L) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.

Time frame: Week 0, week 26

Change in Body Weight (%)

Change from baseline (week 0) to week 26 in body weight. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.

Time frame: Week 0, week 26

Change in BMI

Change from baseline (week 0) to week 26 in body mass index (BMI). 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 or premature discontinuation of trial product.

Time frame: Week 0, week 26

Change in Waist Circumference

Change from baseline (week 0) to week 26 in waist circumference. 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 or premature discontinuation of trial product.

Time frame: Week 0, week 26

Change in Fasting Total Cholesterol - Ratio to Baseline

Change from baseline (week 0) to week 26 in fasting total cholesterol (mmol/L) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.

Time frame: Week 0, week 26

Change in Fasting LDL Cholesterol - Ratio to Baseline

Change from baseline (week 0) to week 26 in fasting low-density lipoprotein (LDL) cholesterol (mmol/L) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.

Time frame: Week 0, week 26

Change in Fasting HDL Cholesterol - Ratio to Baseline

Change from baseline (week 0) to week 26 in fasting high-density lipoprotein (HDL) cholesterol (mmol/L) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.

Time frame: Week 0, week 26

Change in Fasting Triglycerides - Ratio to Baseline

Change from baseline (week 0) to week 26 in triglycerides (mmol/L) 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 or premature discontinuation of trial product.

Time frame: Week 0, week 26

Participants Who Achieve HbA1c < 7.0 % (53 mmol/Mol) ADA Target (Yes/no)

Participants who achieved HbA1c \<7.0% (53 mmol/mol) (American Diabetes Association (ADA) target), at week 26 are presented. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.

Time frame: Week 26

Participants Who Achieve HbA1c ≤ 6.5 % (48 mmol/Mol) AACE Target (Yes/no)

Participants who achieved HbA1c ≤6.5% (48 mmol/mol) (American Association of Clinical Endocrinologists (AACE) target), at week 26 are presented. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.

Time frame: Week 26

Participants Who Achieve Body Weight Loss ≥ 5 % (Yes/no)

Participants who achieved body weight loss more than or equal to 5% of their baseline body weight (yes/no) at week 26 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 or premature discontinuation of trial product.

Time frame: Week 26

Participants Who Achieve Body Weight Loss ≥ 10 % (Yes/no)

Participants who achieved body weight loss more than or equal to 10% of their baseline body weight (yes/no) at week 26 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 or premature discontinuation of trial product.

Time frame: Week 26

Participants Who Achieve HbA1c < 7.0 % (53 mmol/Mol) Without Hypoglycaemia (Severe or BG-confirmed Symptomatic Hypoglycaemia) and Without Body 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 week 26 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 or premature discontinuation of trial product

Time frame: Week 26

Participants Who Achieve HbA1c Reduction ≥ 1.0% (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 week 26 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 or premature discontinuation of trial product.

Time frame: Week 26

Time to Additional Anti-diabetic Medication

Presented results are the number of participants who had taken additional anti-diabetic medication anytime during the period from week 0 to week 26. 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 26), 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 or premature discontinuation of trial product.

Time frame: Weeks 0-26

Time to Rescue Medication

Presented results are the number of participants who had taken rescue medication anytime during the period from week 0 to week 26. 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 or premature trial product discontinuation.

Time frame: Weeks 0-26

Number of Treatment-emergent Adverse Events (TEAEs)

Treatment emergent adverse events (TEAEs) were recorded from week 0 to week 31 (26-week treatment period + 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.

Time frame: Approximately upto week 31

Change in Amylase - Ratio to Baseline

Change from baseline (week 0) to week 26 in amylase (units/litre (U/L)) 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.

Time frame: Week 0, week 26

Change in Lipase - Ratio to Baseline

Change from baseline (week 0) to week 26 in lipase (U/L) 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.

Time frame: Week 0, week 26

Change in Pulse Rate

Change from baseline (week 0) in pulse rate was evaluated at week 26. 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.

Time frame: Week 0, week 26

Change in Systolic Blood Pressure (SBP)

Change from baseline (week 0) in SBP was evaluated at week 26. 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.

Time frame: Week 0, week 26

Change in Diastolic Blood Pressure (DBP)

Change from baseline (week 0) in DBP was evaluated at week 26. 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.

Time frame: Week 0, week 26

Change in Electrocardiogram (ECG) Evaluation

Change from baseline (week 0) in ECG was evaluated at week 26. 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. 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 or premature discontinuation of trial product.

Time frame: Week 0, week 26

Change in Physical Examination

Participants with physical examination findings, normal, abnormal NCS and abnormal CS at baseline (week -2) and week 26 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 or premature discontinuation of trial product. Results are presented for the following examinations: 1) Cardiovascular system; 2) Nervous system (central and peripheral); 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.

Time frame: Week 0, week 26

Change in Eye Examination Category

Participants with eye examination (fundoscopy) findings, normal, abnormal NCS and abnormal CS at baseline (week -2), and week 26 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 or premature discontinuation of trial product.

Time frame: Week 0, week 26

Occurrence of Anti-semaglutide Binding Antibodies (Yes/no)

This outcome measure is only applicable for the oral semaglutide treatment arms (3 mg, 7 mg and 14 mg). Number of participants who measured with anti-semaglutide binding antibodies anytime during post-baseline visits (week 0 to week 31) 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 or premature discontinuation of trial product.

Time frame: Weeks 0-31

Occurrence of Anti-semaglutide Neutralising Antibodies (Yes/no)

This outcome measure is only applicable for the oral semaglutide treatment arms (3 mg, 7 mg and 14 mg). Number of participants who measured with anti-semaglutide neutralising antibodies anytime during post-baseline visits (week 0 to week 31) 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 or premature discontinuation of trial product.

Time frame: Weeks 0-31

Occurrence of Anti-semaglutide Binding Antibodies Cross Reacting With Native GLP-1 (Yes/no)

This outcome measure is only applicable for the oral semaglutide treatment arms (3 mg, 7 mg and 14 mg). 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 (week 0 to week 31) 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 or premature discontinuation of trial product.

Time frame: Weeks 0-31

Occurrence of Anti-semaglutide Neutralising Antibodies Cross Reacting With Native GLP-1 (Yes/no)

This outcome measure is only applicable for the oral semaglutide treatment arms (3 mg, 7 mg and 14 mg). Number of participants who measured with anti-semaglutide neutralising antibodies cross reacting with native GLP-1 anytime during post-baseline visits (week 0 to week 31) 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 or premature discontinuation of trial product.

Time frame: Weeks 0-31

Anti-semaglutide Binding Antibody Levels

This outcome measure is only applicable for the oral semaglutide treatment arms (3 mg, 7 mg and 14 mg). It is based on the data from participants who were measured with anti-semaglutide antibodies anytime during post-baseline visits (week 0 to week 31). 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 or premature discontinuation of trial product.

Time frame: Weeks 0-31

Number of Treatment-emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemic Episodes During Exposure to Trial Product

Treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes were recorded during week 0 to week 31 (26-weeks treatment period + 5-weeks 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.

Time frame: Weeks 0-31

Participants With Treatment-emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemic Episodes During Exposure to Trial Product

Treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes were recorded from week 0 to week 31 (26-week treatment period + 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.

Time frame: Weeks 0-31

SNAC Plasma Concentrations

This outcome measure is only applicable for the oral semaglutide 3 mg, 7 mg and 14 mg treatment arms. Sodium N-\[8-(2-hydroxybenzoyl) amino\]caprylate (SNAC) plasma concentrations were measured after 25 and 40 minutes post-dose at weeks 4, 14 and 26. 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.

Time frame: Weeks 0-26

Semaglutide Plasma Concentrations for Population PK Analysis

This outcome measure is only applicable for the oral semaglutide 3 mg, 7 mg and 14 mg treatment arms. Semaglutide plasma concentrations were measured at weeks 4, 8, 14 and 26. 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.

Time frame: Weeks 0 - 26

Change in SF-36v2 (Acute Version) Health Survey: Scores From the 8 Domains, the Physical Component Summary (PCS) and the Mental Component Summary (MCS)

SF-36 is a 36-item patient-reported survey of patient health that measures the participant's overall health-related quality of life (HRQoL). SF-36v2™ (acute version) questionnaire measured eight domains of functional health and well-being as well as two component summary scores (physical component summary (PCS) and mental component summary (MCS)). The 0-100 scale scores (where higher scores indicated a better HRQoL) from the SF-36 were converted to norm-based scores to enable a direct interpretation in relation to the distribution of the scores in the 2009 U.S. general population. In the metric of norm-based scores, 50 and 10 corresponds to the mean and standard deviation respectively of the 2009 U.S. general population. Change from baseline (week 0) in the sub-domain scores and component summary (PCS and MCS) scores were evaluated at week 26. A positive change score indicates an improvement since baseline. Results are based on the data from the in-trial observation period.

Time frame: Week 0, week 26

IWQOL-Lite Clinical Trial Version: Total Score of the 22 Items (Used for Validation of the Questionnaire)

The Impact of Weight on Quality of Life Clinical Trials Version (IWQOL-Lite-CT) is designed to assess the impact of changes in weight on patients' quality of life within the context of clinical trials. IWQOL-Lite-CT is a 22-item questionnaire-based instrument used to assess the impact of body weight changes on participant's overall health-related quality of life (HRQoL). All IWQOL-Lite-CT composite scores range from 0 to 100, with higher scores reflecting better levels of functioning. 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 or premature discontinuation of trial product.

Time frame: Week 0, week 26

PGI-S Item: Scores of the Two Individual Items (Used for Validation of the IWQOL Questionnaire)

Patient global impression of status (PGI-S) is a 2-item questionnaire used to assess the participant's impression of physical functioning and mental health status during the clinical trial. The PGI-S contains two items evaluated on a 5-point graded response scale. 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 or premature discontinuation of trial product.

Time frame: Week 26

PGI-C Item: Scores of the Two Individual Items (Used for Validation of the IWQOL Questionnaire)

Patient global impression of change (PGI-C) is a 2-item questionnaire used to assess the participant's impression of change from baseline in physical functioning and mental health status. The PGI-C contains two items evaluated on a 7-point graded response scale. 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 or premature discontinuation of trial product.

Time frame: Week 26