PIONEER 1: Efficacy and Safety of Oral Semaglutide Versus Placebo in Subjects With Type 2 Diabetes Mellitus Treated With Diet and Exercise Only

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02906930
• Collaborator: (none)
• Enrollment: 703
• Locations: 105
• Arms: 4
• Actual Duration (Months): 14.6
• Patients Per Site: 6.7
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This trial is conducted globally. The aim of this trial is to investigate efficacy and safety of oral semaglutide versus placebo in subjects with type 2 diabetes mellitus treated with diet and exercise only.

Condition or Disease	Intervention/Treatment	Phase
Diabetes; Diabetes Mellitus, Type 2	Drug: semaglutide; Drug: placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 703 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Oral Semaglutide Versus Placebo in Subjects With Type 2 Diabetes Mellitus Treated With Diet and Exercise Only.
• Actual Study Start Date: Sep 20, 2016
• Actual Primary Completion Date: Oct 30, 2017
• Actual Study Completion Date: Dec 8, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 3 mg oral semaglutide	Drug: semaglutide; Oral administration once daily.
Experimental: 7 mg oral semaglutide	Drug: semaglutide; Oral administration once daily.
Experimental: 14 mg oral semaglutide	Drug: semaglutide; Oral administration once daily.
Placebo Comparator: Placebo	Drug: placebo; Oral administration once daily.

Outcome Measures

Primary Outcome Measures

1. Change in HbA1c [Week 0, week 26]

   Change from baseline (week 0) to week 26 in glycosylated haemoglobin (HbA1c). The endpoint was evaluated based on data from the in-trial observation period. The in-trial observation period - time period from when a subject was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product. The primary endpoint was also analysed based on data from the on-treatment without rescue medication observation period. The on-treatment without rescue medication observation period - time period when a subject was on treatment with trial product, excluding any period after initiation of rescue medication.

Secondary Outcome Measures

1. Change in Body Weight (kg) [Week 0, week 26]

   Change from baseline (week 0) to week 26 in body weight. The endpoint was evaluated based on data from the in-trial observation period. The in-trial observation period - time period from when a subject was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product. The primary endpoint was also analysed based on data from the on-treatment without rescue medication observation period. The on-treatment without rescue medication observation period - time period when a subject was on treatment with trial product, excluding any period after initiation of rescue medication.

2. Change in Fasting Plasma Glucose [Week 0, week 26]

   Change from baseline (week 0) to week 26 in fasting plasma glucose. The endpoint was evaluated based on data from the in-trial observation period. The in-trial observation period - time period from when a subject was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.

3. Change in Mean 7-point SMPG Profile [Week 0, week 26]

   Change from baseline (week 0) to week 26 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. 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.

4. Change in Mean Postprandial Increment Over All Meals in SMPG [Week 0, week 26]

   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.

5. Change in Fasting Insulin - Ratio to Baseline [Week 0, week 26]

   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

6. Change in Fasting Pro-insulin - Ratio to Baseline [Week 0, week 26]

   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

7. Change in Fasting Glucagon - Ratio to Baseline [Week 0, week 26]

   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

8. Change in HOMA-IR (Insulin Resistance) - Ratio to Baseline [Week 0, week 26]

   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.

9. Change in HOMA-B (Beta-cell Function) - Ratio to Baseline [Week 0, week 26]

   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.

10. Change in CRP - Ratio to Baseline [Week 0, week 26]

    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.

11. Change in Body Weight (%) [Week 0, week 26]

    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.

12. Change in BMI [Week 0, week 26]

    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.

13. Change in Waist Circumference [Week 0, week 26]

    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.

14. Change in Fasting Total Cholesterol - Ratio to Baseline [Week 0, week 26]

    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.

15. Change in Fasting LDL Cholesterol - Ratio to Baseline [Week 0, week 26]

    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.

16. Change in Fasting HDL Cholesterol - Ratio to Baseline [Week 0, week 26]

    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.

17. Change in Fasting Triglycerides - Ratio to Baseline [Week 0, week 26]

    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.

18. Participants Who Achieve HbA1c < 7.0 % (53 mmol/Mol) ADA Target (Yes/no) [Week 26]

    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.

19. Participants Who Achieve HbA1c ≤ 6.5 % (48 mmol/Mol) AACE Target (Yes/no) [Week 26]

    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.

20. Participants Who Achieve Body Weight Loss ≥ 5 % (Yes/no) [Week 26]

    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.

21. Participants Who Achieve Body Weight Loss ≥ 10 % (Yes/no) [Week 26]

    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.

22. Participants Who Achieve HbA1c < 7.0 % (53 mmol/Mol) Without Hypoglycaemia (Severe or BG-confirmed Symptomatic Hypoglycaemia) and Without Body Weight Gain (Yes/no) [Week 26]

    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

23. Participants Who Achieve HbA1c Reduction ≥ 1.0% (10.9 mmol/Mol) and Weight Loss ≥ 3% (Yes/no) [Week 26]

    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.

24. Time to Additional Anti-diabetic Medication [Weeks 0-26]

    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.

25. Time to Rescue Medication [Weeks 0-26]

    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.

26. Number of Treatment-emergent Adverse Events (TEAEs) [Approximately upto week 31]

    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.

27. Change in Amylase - Ratio to Baseline [Week 0, week 26]

    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.

28. Change in Lipase - Ratio to Baseline [Week 0, week 26]

    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.

29. Change in Pulse Rate [Week 0, week 26]

    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.

30. Change in Systolic Blood Pressure (SBP) [Week 0, week 26]

    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.

31. Change in Diastolic Blood Pressure (DBP) [Week 0, week 26]

    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.

32. Change in Electrocardiogram (ECG) Evaluation [Week 0, week 26]

    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.

33. Change in Physical Examination [Week 0, week 26]

    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.

34. Change in Eye Examination Category [Week 0, week 26]

    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.

35. Occurrence of Anti-semaglutide Binding Antibodies (Yes/no) [Weeks 0-31]

    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.

36. Occurrence of Anti-semaglutide Neutralising Antibodies (Yes/no) [Weeks 0-31]

    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.

37. Occurrence of Anti-semaglutide Binding Antibodies Cross Reacting With Native GLP-1 (Yes/no) [Weeks 0-31]

    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.

38. Occurrence of Anti-semaglutide Neutralising Antibodies Cross Reacting With Native GLP-1 (Yes/no) [Weeks 0-31]

    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.

39. Anti-semaglutide Binding Antibody Levels [Weeks 0-31]

    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.

40. Number of Treatment-emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemic Episodes During Exposure to Trial Product [Weeks 0-31]

    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.

41. Participants With Treatment-emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemic Episodes During Exposure to Trial Product [Weeks 0-31]

    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.

42. SNAC Plasma Concentrations [Weeks 0-26]

    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.

43. Semaglutide Plasma Concentrations for Population PK Analysis [Weeks 0 - 26]

    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.

44. Change in SF-36v2 (Acute Version) Health Survey: Scores From the 8 Domains, the Physical Component Summary (PCS) and the Mental Component Summary (MCS) [Week 0, week 26]

    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.

45. IWQOL-Lite Clinical Trial Version: Total Score of the 22 Items (Used for Validation of the Questionnaire) [Week 0, week 26]

    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.

46. PGI-S Item: Scores of the Two Individual Items (Used for Validation of the IWQOL Questionnaire) [Week 26]

    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.

47. PGI-C Item: Scores of the Two Individual Items (Used for Validation of the IWQOL Questionnaire) [Week 26]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 above or equal to 20 years at the time of signing informed consent. For Algeria only: Male or female, age above or equal to 19 years at the time of signing informed consent - Diagnosed with type 2 diabetes mellitus for at least 30 days prior to day of screening - HbA1c (glycosylated haemoglobin) between 7.0-9.5% (53-80 mmol/mol) (both inclusive) - Treatment with diet and exercise for at least 30 days prior to day of screening 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 Japan only: Adequate contraceptive measures are abstinence (not having sex), diaphragm, condom (by the partner), intrauterine device, sponge, spermicide or oral contraceptives.For Czech Republic only: Adequate contraceptive measures are always one highly reliable method (such as intrauterine device, sterilisation of one of the partners, hormonal birth control methods) plus one supplementary barrier method (such as condom, diaphragm) with a spermicide. In justified cases, this combination may be replaced with a double-barrier method with a spermicide. Total sexual abstinence may also be considered contraception. (Please note: hormonal contraception should always be discussed with a gynaecologist) - 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 or medullary thyroid carcinomas - History of pancreatitis (acute or chronic) - History of major surgical procedures involving the stomach potentially affecting absorption of trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery) - Any of the following: myocardial infarction, stroke or hospitalisation for unstable angina or transient ischaemic attack within the past 180 days prior to the day of screening and randomisation - Subjects presently classified as being in New York Heart Association Class

1. • Planned coronary, carotid or peripheral artery revascularisation known on the day of screening - Subjects with alanine aminotransferase above 2.5 x upper normal limit - Renal impairment defined as estimated glomerular filtration rate below 60 mL/min/1.73 m^2 as per Chronic Kidney Disease Epidemiology Collaboration formula - Treatment with any medication for the indication of diabetes or obesity 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 in-situ carcinomas)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Lancaster	California	United States	93534
2	Novo Nordisk Investigational Site	Los Angeles	California	United States	90057
3	Novo Nordisk Investigational Site	Montclair	California	United States	91763
4	Novo Nordisk Investigational Site	North Hollywood	California	United States	91606
5	Novo Nordisk Investigational Site	Riverside	California	United States	92506
6	Novo Nordisk Investigational Site	San Diego	California	United States	92111
7	Novo Nordisk Investigational Site	San Jose	California	United States	95148
8	Novo Nordisk Investigational Site	San Mateo	California	United States	94401
9	Novo Nordisk Investigational Site	Doral	Florida	United States	33166
10	Novo Nordisk Investigational Site	Hialeah	Florida	United States	33012
11	Novo Nordisk Investigational Site	Miami	Florida	United States	33143
12	Novo Nordisk Investigational Site	Miami	Florida	United States	33173
13	Novo Nordisk Investigational Site	Miami	Florida	United States	33186
14	Novo Nordisk Investigational Site	Palm Harbor	Florida	United States	34684-3609
15	Novo Nordisk Investigational Site	Pembroke Pines	Florida	United States	33026
16	Novo Nordisk Investigational Site	Port Charlotte	Florida	United States	33952
17	Novo Nordisk Investigational Site	Spring Hill	Florida	United States	34609
18	Novo Nordisk Investigational Site	Tampa	Florida	United States	33607
19	Novo Nordisk Investigational Site	Woodstock	Georgia	United States	30189-4255
20	Novo Nordisk Investigational Site	Honolulu	Hawaii	United States	96814
21	Novo Nordisk Investigational Site	Blackfoot	Idaho	United States	83221
22	Novo Nordisk Investigational Site	Nampa	Idaho	United States	83686-6011
23	Novo Nordisk Investigational Site	Skokie	Illinois	United States	60077
24	Novo Nordisk Investigational Site	Muncie	Indiana	United States	47304
25	Novo Nordisk Investigational Site	Louisville	Kentucky	United States	40213
26	Novo Nordisk Investigational Site	Metairie	Louisiana	United States	70002
27	Novo Nordisk Investigational Site	Hyattsville	Maryland	United States	20782
28	Novo Nordisk Investigational Site	Kalamazoo	Michigan	United States	49009
29	Novo Nordisk Investigational Site	Rochester	Michigan	United States	48307
30	Novo Nordisk Investigational Site	Troy	Michigan	United States	48098
31	Novo Nordisk Investigational Site	Elkhorn	Nebraska	United States	68022
32	Novo Nordisk Investigational Site	Brooklyn	New York	United States	11215
33	Novo Nordisk Investigational Site	West Seneca	New York	United States	14224
34	Novo Nordisk Investigational Site	Asheboro	North Carolina	United States	27203
35	Novo Nordisk Investigational Site	Charlotte	North Carolina	United States	28277
36	Novo Nordisk Investigational Site	Greensboro	North Carolina	United States	27408
37	Novo Nordisk Investigational Site	Fargo	North Dakota	United States	58104
38	Novo Nordisk Investigational Site	Cincinnati	Ohio	United States	45255
39	Novo Nordisk Investigational Site	Willoughby Hills	Ohio	United States	44094
40	Novo Nordisk Investigational Site	Norman	Oklahoma	United States	73069
41	Novo Nordisk Investigational Site	Oklahoma City	Oklahoma	United States	73112
42	Novo Nordisk Investigational Site	Philadelphia	Pennsylvania	United States	19140
43	Novo Nordisk Investigational Site	Spartanburg	South Carolina	United States	29303
44	Novo Nordisk Investigational Site	Dallas	Texas	United States	75230
45	Novo Nordisk Investigational Site	Houston	Texas	United States	77058
46	Novo Nordisk Investigational Site	Mesquite	Texas	United States	75149
47	Novo Nordisk Investigational Site	San Antonio	Texas	United States	78215
48	Novo Nordisk Investigational Site	San Antonio	Texas	United States	78224
49	Novo Nordisk Investigational Site	San Antonio	Texas	United States	78228-3419
50	Novo Nordisk Investigational Site	San Antonio	Texas	United States	78230
51	Novo Nordisk Investigational Site	Sugar Land	Texas	United States	77479
52	Novo Nordisk Investigational Site	Waco	Texas	United States	76710
53	Novo Nordisk Investigational Site	Bountiful	Utah	United States	84010
54	Novo Nordisk Investigational Site	Norfolk	Virginia	United States	23510-2015
55	Novo Nordisk Investigational Site	Richmond	Virginia	United States	23219
56	Novo Nordisk Investigational Site	Salem	Virginia	United States	24153-6404
57	Novo Nordisk Investigational Site	Algiers		Algeria	16000
58	Novo Nordisk Investigational Site	Algiers		Algeria	16003
59	Novo Nordisk Investigational Site	Algiers		Algeria	16049
60	Novo Nordisk Investigational Site	Algiers		Algeria
61	Novo Nordisk Investigational Site	Sofia		Bulgaria	1233
62	Novo Nordisk Investigational Site	Sofia		Bulgaria	1431
63	Novo Nordisk Investigational Site	Broumov		Czechia	550 01
64	Novo Nordisk Investigational Site	Chrudim		Czechia	537 01
65	Novo Nordisk Investigational Site	Mlada Boleslav		Czechia	293 50
66	Novo Nordisk Investigational Site	Olomouc		Czechia	77900
67	Novo Nordisk Investigational Site	Prague 1		Czechia	11694
68	Novo Nordisk Investigational Site	Como		Italy	22042
69	Novo Nordisk Investigational Site	Palermo		Italy	90129
70	Novo Nordisk Investigational Site	Pisa		Italy	56124
71	Novo Nordisk Investigational Site	Rome		Italy	00168
72	Novo Nordisk Investigational Site	Siena		Italy	53100
73	Novo Nordisk Investigational Site	Suita-shi, Osaka		Japan	565-0853
74	Novo Nordisk Investigational Site	Tokyo		Japan	103-0027
75	Novo Nordisk Investigational Site	Tokyo		Japan	103-0028
76	Novo Nordisk Investigational Site	Tokyo		Japan	104-0031
77	Novo Nordisk Investigational Site	Tokyo		Japan	160-0008
78	Novo Nordisk Investigational Site	Yokohama-shi, Kanagawa		Japan	236-0004
79	Novo Nordisk Investigational Site	Ciudad Madero	Tamaulipas	Mexico	89440
80	Novo Nordisk Investigational Site	Aguascalientes		Mexico	20230
81	Novo Nordisk Investigational Site	Targoviste	Dambovita	Romania	130086
82	Novo Nordisk Investigational Site	Targoviste	Dambovita	Romania	130095
83	Novo Nordisk Investigational Site	Ploiesti	Prahova	Romania	100018
84	Novo Nordisk Investigational Site	Bucharest		Romania	010825
85	Novo Nordisk Investigational Site	Bucharest		Romania	011234
86	Novo Nordisk Investigational Site	Dzerzhinskiy		Russian Federation	140091
87	Novo Nordisk Investigational Site	Kazan		Russian Federation	420073
88	Novo Nordisk Investigational Site	Novosibirsk		Russian Federation	630099
89	Novo Nordisk Investigational Site	Saint-Petersburg		Russian Federation	194358
90	Novo Nordisk Investigational Site	Saint-Petersburg		Russian Federation	199226
91	Novo Nordisk Investigational Site	Tomsk		Russian Federation	634050
92	Novo Nordisk Investigational Site	Voronezh		Russian Federation	394018
93	Novo Nordisk Investigational Site	Yaroslavl		Russian Federation	150003
94	Novo Nordisk Investigational Site	Yoshkar-Ola		Russian Federation	424004
95	Novo Nordisk Investigational Site	Belgrade		Serbia	11000
96	Novo Nordisk Investigational Site	Adana		Turkey	01250
97	Novo Nordisk Investigational Site	Istanbul		Turkey	34096
98	Novo Nordisk Investigational Site	Istanbul		Turkey	34147
99	Novo Nordisk Investigational Site	Istanbul		Turkey	34303
100	Novo Nordisk Investigational Site	Istanbul		Turkey	34371
101	Novo Nordisk Investigational Site	Istanbul		Turkey	34400
102	Novo Nordisk Investigational Site	Istanbul		Turkey	34718
103	Novo Nordisk Investigational Site	Istanbul		Turkey	34722
104	Novo Nordisk Investigational Site	Istanbul		Turkey	34752
105	Novo Nordisk Investigational Site	Istanbul		Turkey

Sponsors and Collaborators

• Novo Nordisk A/S

Investigators

• Study Director: Global Clinical Registry (GCR, 1452), Novo Nordisk A/S

Study Documents (Full-Text)

• Study Protocol - Jun 20, 2018
• Statistical Analysis Plan - Jun 20, 2018

More Information

Additional Information:

• Clinical Trials at Novo Nordisk

Publications

• Aroda VR, Saugstrup T, Buse JB, Donsmark M, Zacho J, Davies MJ. Incorporating and interpreting regulatory guidance on estimands in diabetes clinical trials: The PIONEER 1 randomized clinical trial as an example. Diabetes Obes Metab. 2019 Oct;21(10):2203-2210. doi: 10.1111/dom.13804. Epub 2019 Jun 30. Review.
• Kolotkin RL, Williams VSL, Ervin CM, Williams N, Meincke HH, Qin S, von Huth Smith L, Fehnel SE. Validation of a new measure of quality of life in obesity trials: Impact of Weight on Quality of Life-Lite Clinical Trials Version. Clin Obes. 2019 Jun;9(3):e12310. doi: 10.1111/cob.12310. Epub 2019 Apr 16.

• Responsible Party: Novo Nordisk A/S
• ClinicalTrials.gov Identifier: NCT02906930
• Other Study ID Numbers: NN9924-4233; 2015-005622-19; U1111-1177-5112; JapicCTI-163384
• First Posted: Sep 20, 2016
• Last Update Posted: Jul 20, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2

Study Results

Participant Flow

Recruitment Details	The trial was conducted at 93 sites in 9 countries as follows: Algeria: 4 sites screened/4 sites randomised subjects; Bulgaria: 3/3; Czech Republic: 5 /5; Japan: 6/6; Mexico: 2/2; Russian Federation: 9/9; Serbia: 3/3; Turkey: 7/7; United States: 53/48.
Pre-assignment Detail	Data presented in "participant flow" is based on 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.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Period Title: Overall Study
STARTED	175	175	175	178
Full Analysis Set (FAS)	175	175	175	178
Safety Analysis Set (SAS)	175	175	175	178
COMPLETED	169	161	163	170
NOT COMPLETED	6	14	12	8

Baseline Characteristics

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo	Total
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.	Total of all reporting groups
Overall Participants	175	175	175	178	703
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	55 (11)	56 (11)	54 (11)	54 (11)	55 (11)
Sex: Female, Male (Count of Participants)
Female	86 49.1%	82 46.9%	89 50.9%	89 50%	346 49.2%
Male	89 50.9%	93 53.1%	86 49.1%	89 50%	357 50.8%
Race/Ethnicity, Customized (Count of Participants)
White	135 77.1%	131 74.9%	130 74.3%	132 74.2%	528 75.1%
Black or African American	6 3.4%	11 6.3%	10 5.7%	10 5.6%	37 5.3%
Asian	31 17.7%	30 17.1%	29 16.6%	31 17.4%	121 17.2%
American Indian or Alaska Native	1 0.6%	1 0.6%	1 0.6%	1 0.6%	4 0.6%
Native Hawaiian or other Pacific Islander	0 0%	0 0%	1 0.6%	0 0%	1 0.1%
Other	2 1.1%	2 1.1%	4 2.3%	4 2.2%	12 1.7%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	52 29.7%	31 17.7%	46 26.3%	51 28.7%	180 25.6%
Not Hispanic or Latino	116 66.3%	133 76%	122 69.7%	121 68%	492 70%
Not applicable	7 4%	11 6.3%	7 4%	6 3.4%	31 4.4%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = full analysis set (FAS) which comprised all randomised participants. Number Analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	175	175	175	178
In-trial	-0.9 (1.2)	-1.3 (1.0)	-1.5 (1.0)	-0.3 (1.2)
On-treatment without rescue medication	-0.9 (1.2)	-1.4 (0.9)	-1.6 (1.0)	-0.3 (1.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide 14 mg, Placebo
	Comments	The analysis was based on a pattern mixture model using multiple imputation to impute missing data for week 26, assuming that the missing data mechanism was missing at random within the groups used for the imputation. The imputed data sets were analysed using an analysis of covariance (ANCOVA) model with treatment and region as categorical fixed effects and baseline HbA1c value as covariate for each of the 1000 imputed complete data sets, and pooled by Rubin's rule to draw inference.
	Type of Statistical Test	Superiority
	Comments	This hypothesis was controlled for multiplicity. Results are based on the data from the in-trial observation period. The estimated treatment effect includes the effect of any additional anti-diabetic medication for all randomised subjects regardless of premature trial product discontinuation (treatment policy estimand).
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Unadjusted two-sided p-value for test of no difference from 0.
	Method	Pattern mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean treatment difference
	Estimated Value	-1.1
	Confidence Interval	(2-Sided) 95%; -1.3 to -0.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Oral Semaglutide 14 mg - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide 7 mg, Placebo
	Comments	The analysis was based on a pattern mixture model using multiple imputation to impute missing data for week 26, assuming that the missing data mechanism was missing at random within the groups used for the imputation. The imputed data sets were analysed using an ANCOVA model with treatment and region as categorical fixed effects and baseline HbA1c value as covariate for each of the 1000 imputed complete data sets, and pooled by Rubin's rule to draw inference.
	Type of Statistical Test	Superiority
	Comments	This hypothesis was controlled for multiplicity. Results are based on the data from the in-trial observation period. The estimated treatment effect includes the effect of any additional anti-diabetic medication for all randomised subjects regardless of premature trial product discontinuation (treatment policy estimand).
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Unadjusted two-sided p-value for test of no difference from 0.
	Method	Pattern mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean treatment difference
	Estimated Value	-0.9
	Confidence Interval	(2-Sided) 95%; -1.1 to -0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Oral Semaglutide 7 mg - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide 3 mg, Placebo
	Comments	The analysis was based on a pattern mixture model using multiple imputation to impute missing data for week 26, assuming that the missing data mechanism was missing at random within the groups used for the imputation. The imputed data sets were analysed using an ANCOVA model with treatment and region as categorical fixed effects and baseline HbA1c value as covariate for each of the 1000 imputed complete data sets, and pooled by Rubin's rule to draw inference.
	Type of Statistical Test	Superiority
	Comments	This hypothesis was controlled for multiplicity. Results are based on the data from the in-trial observation period. The estimated treatment effect includes the effect of any additional anti-diabetic medication for all randomised subjects regardless of premature trial product discontinuation (treatment policy estimand).
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Unadjusted two-sided p-value for test of no difference from 0.
	Method	Pattern mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean treatment difference
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -0.8 to -0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Oral Semaglutide 3 mg - Placebo

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide 3 mg, Placebo
	Comments	The analysis was based on a mixed model for repeated measurements (MMRM) that assumed data to be missing at random. As dependent variables, the MMRM model included all post-baseline values collected at scheduled visits up to and including week 26. The independent effects were treatment and region as categorical fixed effects and the baseline HbA1c value as a covariate, all nested within visit, and an unstructured residual covariance matrix.
	Type of Statistical Test	Superiority
	Comments	This hypothesis was not controlled for multiplicity. Results are based on the data from the on-treatment without rescue medication observation period. The estimated treatment effect excludes the effect of any rescue medication (hypothetical estimand).
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Unadjusted two-sided p-value for test of no difference from 0.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean treatment difference
	Estimated Value	-0.7
	Confidence Interval	(2-Sided) 95%; -0.9 to -0.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Oral Semaglutide 3 mg - placebo

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide 7 mg, Placebo
	Comments	The analysis was based on a mixed model for repeated measurements (MMRM) that assumed data to be missing at random. As dependent variables, the MMRM model included all post-baseline values collected at scheduled visits up to and including week 26. The independent effects were treatment and region as categorical fixed effects and the baseline HbA1c value as a covariate, all nested within visit, and an unstructured residual covariance matrix.
	Type of Statistical Test	Superiority
	Comments	This hypothesis was not controlled for multiplicity. Results are based on the data from the on-treatment without rescue medication observation period. The estimated treatment effect excludes the effect of any rescue medication (hypothetical estimand).
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Unadjusted two-sided p-value for test of no difference from 0.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean treatment difference
	Estimated Value	-1.2
	Confidence Interval	(2-Sided) 95%; -1.5 to -1.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Oral Semaglutide 7 mg - placebo

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide 14 mg, Placebo
	Comments	The analysis was based on a mixed model for repeated measurements (MMRM) that assumed data to be missing at random. As dependent variables, the MMRM model included all post-baseline values collected at scheduled visits up to and including week 26. The independent effects were treatment and region as categorical fixed effects and the baseline HbA1c value as a covariate, all nested within visit, and an unstructured residual covariance matrix.
	Type of Statistical Test	Superiority
	Comments	This hypothesis was not controlled for multiplicity. Results are based on the data from the on-treatment without rescue medication observation period. The estimated treatment effect excludes the effect of any rescue medication (hypothetical estimand).
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Unadjusted two-sided p-value for test of no difference from 0.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean treatment difference
	Estimated Value	-1.4
	Confidence Interval	(2-Sided) 95%; -1.7 to -1.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Oral Semaglutide 14 mg - placebo

2. Secondary Outcome

Title	Change in Body Weight (kg)
Description	Change from baseline (week 0) to week 26 in body weight. The endpoint was evaluated based on data from the in-trial observation period. The in-trial observation period - time period from when a subject was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product. The primary endpoint was also analysed based on data from the on-treatment without rescue medication observation period. The on-treatment without rescue medication observation period - time period when a subject was on treatment with trial product, excluding any period after initiation of rescue medication.
Time Frame	Week 0, week 26

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = FAS which comprised all randomised participants. Number Analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	175	175	175	178
In-trial	-1.5 (3.3)	-2.6 (4.1)	-4.0 (4.2)	-1.4 (3.5)
On-treatment without rescue medication	-1.8 (3.3)	-2.8 (4.0)	-4.3 (4.2)	-1.6 (3.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide 14 mg, Placebo
	Comments	The analysis was based on a pattern mixture model using multiple imputation to impute missing data for week 26, assuming that the missing data mechanism was missing at random within the groups used for the imputation. The imputed data sets were analysed using an ANCOVA model with treatment and region as categorical fixed effects and baseline body weight value as covariate for each of the 1000 imputed complete data sets, and pooled by Rubin's rule to draw inference.
	Type of Statistical Test	Superiority
	Comments	This hypothesis was controlled for multiplicity. Results are based on the data from the in-trial observation period. The estimated treatment effect includes the effect of any additional anti-diabetic medication for all randomised subjects regardless of premature trial product discontinuation (treatment policy estimand).
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Unadjusted two-sided p-value for test of no difference from 0.
	Method	Pattern mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean treatment difference
	Estimated Value	-2.3
	Confidence Interval	(2-Sided) 95%; -3.1 to -1.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Oral Semaglutide 14 mg - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide 7 mg, Placebo
	Comments	The analysis was based on a pattern mixture model using multiple imputation to impute missing data for week 26, assuming that the missing data mechanism was missing at random within the groups used for the imputation. The imputed data sets were analysed using an ANCOVA model with treatment and region as categorical fixed effects and baseline body weight value as covariate for each of the 1000 imputed complete data sets, and pooled by Rubin's rule to draw inference.
	Type of Statistical Test	Superiority
	Comments	This hypothesis was controlled for multiplicity. Results are based on the data from the in-trial observation period. The estimated treatment effect includes the effect of any additional anti-diabetic medication for all randomised subjects regardless of premature trial product discontinuation (treatment policy estimand).
Statistical Test of Hypothesis	p-Value	0.0866
	Comments	Unadjusted two-sided p-value for test of no difference from 0.
	Method	Pattern mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean treatment difference
	Estimated Value	-0.9
	Confidence Interval	(2-Sided) 95%; -1.9 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Oral Semaglutide 7 mg - Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide 3 mg, Placebo
	Comments	The analysis was based on a pattern mixture model using multiple imputation to impute missing data for week 26, assuming that the missing data mechanism was missing at random within the groups used for the imputation. The imputed data sets were analysed using an ANCOVA model with treatment and region as categorical fixed effects and baseline body weight value as covariate for each of the 1000 imputed complete data sets, and pooled by Rubin's rule to draw inference.
	Type of Statistical Test	Superiority
	Comments	This hypothesis was controlled for multiplicity. Results are based on the data from the in-trial observation period. The estimated treatment effect includes the effect of any additional anti-diabetic medication for all randomised subjects regardless of premature trial product discontinuation (treatment policy estimand).
Statistical Test of Hypothesis	p-Value	0.8692
	Comments	Unadjusted two-sided p-value for test of no difference from 0.
	Method	Pattern mixed model
	Comments
Method of Estimation	Estimation Parameter	Mean treatment difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.9 to 0.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Oral Semaglutide 3 mg - Placebo

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide 3 mg, Placebo
	Comments	The analysis was based on a MMRM that assumed data to be missing at random. As dependent variables, the MMRM model included all post-baseline values collected at scheduled visits up to and including week 26. The independent effects were treatment and region as categorical fixed effects and the baseline body weight value as a covariate, all nested within visit, and an unstructured residual covariance matrix.
	Type of Statistical Test	Superiority
	Comments	This hypothesis was not controlled for multiplicity. Results are based on the data from the on-treatment without rescue medication observation period. The estimated treatment effect excludes the effect of any rescue medication (hypothetical estimand).
Statistical Test of Hypothesis	p-Value	0.7075
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean treatment difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -1.0 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Oral Semaglutide 3 mg - Placebo

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide 7 mg, Placebo
	Comments	The analysis was based on a MMRM that assumed data to be missing at random. As dependent variables, the MMRM model included all post-baseline values collected at scheduled visits up to and including week 26. The independent effects were treatment and region as categorical fixed effects and the baseline body weight value as a covariate, all nested within visit, and an unstructured residual covariance matrix.
	Type of Statistical Test	Superiority
	Comments	This hypothesis was not controlled for multiplicity. Results are based on the data from the on-treatment without rescue medication observation period. The estimated treatment effect excludes the effect of any rescue medication (hypothetical estimand).
Statistical Test of Hypothesis	p-Value	0.0138
	Comments	Unadjusted two-sided p-value for test of no difference from 0.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean treatment difference
	Estimated Value	-1.0
	Confidence Interval	(2-Sided) 95%; -1.8 to -0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Oral Semaglutide 7 mg - Placebo

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide 14 mg, Placebo
	Comments	The analysis was based on a MMRM that assumed data to be missing at random. As dependent variables, the MMRM model included all post-baseline values collected at scheduled visits up to and including week 26. The independent effects were treatment and region as categorical fixed effects and the baseline body weight value as a covariate, all nested within visit, and an unstructured residual covariance matrix.
	Type of Statistical Test	Superiority
	Comments	This hypothesis was not controlled for multiplicity. Results are based on the data from the on-treatment without rescue medication observation period. The estimated treatment effect excludes the effect of any rescue medication (hypothetical estimand).
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Unadjusted two-sided p-value for test of no difference from 0.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean treatment difference
	Estimated Value	-2.6
	Confidence Interval	(2-Sided) 95%; -3.4 to -1.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Oral Semaglutide 14 mg - Placebo

3. Secondary Outcome

Title	Change in Fasting Plasma Glucose
Description	Change from baseline (week 0) to week 26 in fasting plasma glucose. The endpoint was evaluated based on data from the in-trial observation period. The in-trial observation period - time period from when a subject 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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	166	160	160	166
Mean (Standard Deviation) [mmol/L]	-0.89 (2.67)	-1.52 (2.28)	-1.92 (2.04)	-0.18 (2.37)

4. Secondary Outcome

Title	Change in Mean 7-point SMPG Profile
Description	Change from baseline (week 0) to week 26 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. 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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	149	146	141	147
Mean (Standard Deviation) [mmol/L]	-1.8 (2.3)	-2.1 (2.0)	-2.3 (2.4)	-0.5 (2.6)

5. Secondary Outcome

Title	Change in Mean Postprandial Increment Over All Meals in SMPG
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	149	148	141	147
Mean (Standard Deviation) [mmol/L]	-0.4 (2.3)	-0.8 (2.0)	-1.2 (2.1)	-0.3 (2.0)

6. Secondary Outcome

Title	Change in Fasting Insulin - Ratio to Baseline
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	157	152	159	163
Geometric Mean (Geometric Coefficient of Variation) [Ratio of fasting insulin]	1.12 (59.2)	1.07 (49.2)	0.98 (45.0)	0.97 (59.2)

7. Secondary Outcome

Title	Change in Fasting Pro-insulin - Ratio to Baseline
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	162	158	156	165
Geometric Mean (Geometric Coefficient of Variation) [Ratio of fasting pro-insulin]	0.84 (71.5)	0.74 (74.3)	0.62 (75.5)	0.89 (76.5)

8. Secondary Outcome

Title	Change in Fasting Glucagon - Ratio to Baseline
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	161	158	159	163
Geometric Mean (Geometric Coefficient of Variation) [Ratio of fasting glucagon]	1.00 (28.2)	0.90 (27.1)	0.89 (25.7)	0.95 (25.4)

9. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	156	152	159	161
Geometric Mean (Geometric Coefficient of Variation) [Ratio of HOMA-IR]	1.00 (74.6)	0.88 (66.7)	0.76 (60.4)	0.92 (75.0)

10. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	156	152	159	160
Geometric Mean (Geometric Coefficient of Variation) [Ratio of HOMA-B]	1.40 (73.2)	1.51 (60.5)	1.60 (58.4)	1.01 (61.9)

11. Secondary Outcome

Title	Change in CRP - Ratio to Baseline
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	165	159	158	165
Geometric Mean (Geometric Coefficient of Variation) [Ratio of CRP]	0.89 (87.5)	0.72 (118.2)	0.81 (123.7)	0.99 (108.3)

12. Secondary Outcome

Title	Change in Body Weight (%)
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	168	160	160	168
Mean (Standard Deviation) [Percentage change]	-1.67 (4.08)	-2.85 (4.57)	-4.71 (5.00)	-1.37 (3.58)

13. Secondary Outcome

Title	Change in BMI
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	168	160	160	168
Mean (Standard Deviation) [kg/m^2]	-0.6 (1.2)	-0.9 (1.5)	-1.5 (1.5)	-0.5 (1.2)

14. Secondary Outcome

Title	Change in Waist Circumference
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	167	159	158	167
Mean (Standard Deviation) [cm]	-2.0 (4.8)	-2.3 (5.0)	-4.1 (4.9)	-0.9 (4.4)

15. Secondary Outcome

Title	Change in Fasting Total Cholesterol - Ratio to Baseline
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	165	159	158	166
Geometric Mean (Geometric Coefficient of Variation) [Ratio of fasting total cholesterol]	0.98 (15.6)	0.98 (18.4)	0.96 (19.0)	1.01 (17.9)

16. Secondary Outcome

Title	Change in Fasting LDL Cholesterol - Ratio to Baseline
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	165	159	158	165
Geometric Mean (Geometric Coefficient of Variation) [Ratio of fasting LDL cholesterol]	0.95 (27.8)	0.97 (28.8)	0.95 (31.6)	1.00 (26.2)

17. Secondary Outcome

Title	Change in Fasting HDL Cholesterol - Ratio to Baseline
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	165	159	158	166
Geometric Mean (Geometric Coefficient of Variation) [Ratio of fasting HDL cholesterol]	1.03 (14.6)	1.05 (14.9)	1.02 (14.7)	1.03 (14.0)

18. Secondary Outcome

Title	Change in Fasting Triglycerides - Ratio to Baseline
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	165	159	158	166
Geometric Mean (Geometric Coefficient of Variation) [Ratio of fasting triglycerides]	1.01 (35.8)	0.90 (41.1)	0.91 (37.8)	1.00 (39.2)

19. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	167	160	160	168
Yes	92 52.6%	110 62.9%	123 70.3%	52 29.2%
No	75 42.9%	50 28.6%	37 21.1%	116 65.2%

20. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	167	160	160	168
Yes	60 34.3%	76 43.4%	102 58.3%	30 16.9%
No	107 61.1%	84 48%	58 33.1%	138 77.5%

21. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	168	160	160	168
Yes	33 18.9%	43 24.6%	66 37.7%	25 14%
No	135 77.1%	117 66.9%	94 53.7%	143 80.3%

22. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	168	160	160	168
Yes	4 2.3%	13 7.4%	23 13.1%	2 1.1%
No	164 93.7%	147 84%	137 78.3%	166 93.3%

23. Secondary Outcome

Title	Participants Who Achieve HbA1c < 7.0 % (53 mmol/Mol) Without Hypoglycaemia (Severe or BG-confirmed Symptomatic Hypoglycaemia) and Without Body Weight Gain (Yes/no)
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	167	160	160	168
Yes	62 35.4%	91 52%	110 62.9%	39 21.9%
No	105 60%	69 39.4%	50 28.6%	129 72.5%

24. Secondary Outcome

Title	Participants Who Achieve HbA1c Reduction ≥ 1.0% (10.9 mmol/Mol) and Weight Loss ≥ 3% (Yes/no)
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	167	160	160	168
Yes	30 17.1%	59 33.7%	81 46.3%	18 10.1%
No	137 78.3%	101 57.7%	79 45.1%	150 84.3%

25. Secondary Outcome

Title	Time to Additional Anti-diabetic Medication
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = FAS which comprised all randomised participants.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	175	175	175	178
Count of Participants [Participants]	16 9.1%	8 4.6%	7 4%	35 19.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide 3 mg, Placebo
	Comments	Time to initiation of additional anti-diabetic medication was analysed using a Cox proportional hazards model with treatment and region as categorical fixed effects and baseline HbA1c as covariate. Withdrawal for any reason or lost to follow-up contributed to the analysis as events (initiation of additional anti-diabetic medication). Censoring time was one day before planned end of treatment.
	Type of Statistical Test	Superiority
	Comments	This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis	p-Value	0.0043
	Comments	Unadjusted two-sided p-value for test of no difference from 1
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.45
	Confidence Interval	(2-Sided) 95%; 0.26 to 0.78
	Parameter Dispersion	Type: Value:
	Estimation Comments	Oral Semaglutide 3 mg / Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide 7 mg, Placebo
	Comments	Time to initiation of additional anti-diabetic medication was analysed using a Cox proportional hazards model with treatment and region as categorical fixed effects and baseline HbA1c as covariate. Withdrawal for any reason or lost to follow-up contributed to the analysis as events (initiation of additional anti-diabetic medication). Censoring time was one day before planned end of treatment.
	Type of Statistical Test	Superiority
	Comments	This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	Unadjusted two-sided p-value for test of no difference from 1
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.33
	Confidence Interval	(2-Sided) 95%; 0.18 to 0.59
	Parameter Dispersion	Type: Value:
	Estimation Comments	Oral Semaglutide 7 mg / Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide 14 mg, Placebo
	Comments	Time to initiation of additional anti-diabetic medication was analysed using a Cox proportional hazards model with treatment and region as categorical fixed effects and baseline HbA1c as covariate. Withdrawal for any reason or lost to follow-up contributed to the analysis as events (initiation of additional anti-diabetic medication). Censoring time was one day before planned end of treatment.
	Type of Statistical Test	Superiority
	Comments	This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	Unadjusted two-sided p-value for test of no difference from 1
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.33
	Confidence Interval	(2-Sided) 95%; 0.19 to 0.60
	Parameter Dispersion	Type: Value:
	Estimation Comments	Oral Semaglutide 14 mg / Placebo

26. Secondary Outcome

Title	Time to Rescue Medication
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = FAS which comprised all randomised participants.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	175	175	175	178
Count of Participants [Participants]	13 7.4%	4 2.3%	2 1.1%	27 15.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide 3 mg, Placebo
	Comments	Time to initiation of rescue medication was analysed using a Cox proportional hazards model with treatment and region as categorical fixed effects and baseline HbA1c as covariate. Censoring time was one day before last day on trial product.
	Type of Statistical Test	Superiority
	Comments	This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis	p-Value	0.0300
	Comments	Unadjusted two-sided p-value for test of no difference from 1.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.48
	Confidence Interval	(2-Sided) 95%; 0.25 to 0.93
	Parameter Dispersion	Type: Value:
	Estimation Comments	Oral Semaglutide 3 mg / Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide 7 mg, Placebo
	Comments	Time to initiation of rescue medication was analysed using a Cox proportional hazards model with treatment and region as categorical fixed effects and baseline HbA1c as covariate. Censoring time was one day before last day on trial product.
	Type of Statistical Test	Superiority
	Comments	This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	Unadjusted two-sided p-value for test of no difference from 1.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.13
	Confidence Interval	(2-Sided) 95%; 0.04 to 0.36
	Parameter Dispersion	Type: Value:
	Estimation Comments	Oral Semaglutide 7 mg / Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Oral Semaglutide 14 mg, Placebo
	Comments	Time to initiation of rescue medication was analysed using a Cox proportional hazards model with treatment and region as categorical fixed effects and baseline HbA1c as covariate. Censoring time was one day before last day on trial product.
	Type of Statistical Test	Superiority
	Comments	This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	Unadjusted two-sided p-value for test of no difference from 1.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; 0.01 to 0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	Oral Semaglutide 14 mg /Placebo

27. Secondary Outcome

Title	Number of Treatment-emergent Adverse Events (TEAEs)
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = safety analysis set (SAS) which comprised all randomised participants who received at least one dose of trial product.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	175	175	175	178
Number [Events]	290	258	304	263

28. Secondary Outcome

Title	Change in Amylase - Ratio to Baseline
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	159	152	149	154
Geometric Mean (Geometric Coefficient of Variation) [Ratio]	1.05 (21.1)	1.09 (21.4)	1.12 (20.2)	0.99 (25.5)

29. Secondary Outcome

Title	Change in Lipase - Ratio to Baseline
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	159	152	149	154
Geometric Mean (Geometric Coefficient of Variation) [Ratio]	1.14 (43.8)	1.27 (51.1)	1.33 (45.1)	0.99 (54.2)

30. Secondary Outcome

Title	Change in Pulse Rate
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	161	154	151	158
Mean (Standard Deviation) [beats/min]	0 (9)	1 (9)	3 (9)	1 (9)

31. Secondary Outcome

Title	Change in Systolic Blood Pressure (SBP)
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	161	154	151	158
Mean (Standard Deviation) [mmHg]	-3 (14)	-5 (13)	-5 (14)	-3 (14)

32. Secondary Outcome

Title	Change in Diastolic Blood Pressure (DBP)
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	161	154	151	158
Mean (Standard Deviation) [mmHg]	-1 (9)	-2 (8)	-1 (9)	-1 (9)

33. Secondary Outcome

Title	Change in Electrocardiogram (ECG) Evaluation
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = SAS which comprised all randomised participants who received at least one dose of trial product. Number Analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	175	175	175	178
Normal (week 0) to normal (week 26)	102 58.3%	88 50.3%	96 54.9%	97 54.5%
Normal (week 0) to abnormal NCS (week 26)	11 6.3%	13 7.4%	4 2.3%	13 7.3%
Normal (week 0) to abnormal CS (week 26)	1 0.6%	1 0.6%	0 0%	0 0%
Abnormal NCS (week 0) to normal (week 26)	12 6.9%	12 6.9%	20 11.4%	14 7.9%
Abnormal NCS (week 0) to abnormal NCS (week 26)	40 22.9%	39 22.3%	39 22.3%	40 22.5%
Abnormal NCS (week 0) to abnormal CS (week 26)	0 0%	1 0.6%	0 0%	0 0%
Abnormal CS (week 0) to normal (week 26)	0 0%	1 0.6%	0 0%	0 0%
Abnormal CS (week 0) to abnormal NCS (week 26)	1 0.6%	3 1.7%	0 0%	2 1.1%
Abnormal CS (week 0) to abnormal CS (week 26)	0 0%	1 0.6%	0 0%	0 0%

34. Secondary Outcome

Title	Change in Physical Examination
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = SAS which comprised all randomised participants who received at least one dose of trial product. Number Analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	175	175	175	178
Normal	163 93.1%	167 95.4%	167 95.4%	172 96.6%
Abnormal NCS	12 6.9%	8 4.6%	8 4.6%	6 3.4%
Abnormal CS	0 0%	0 0%	0 0%	0 0%
Normal	157 89.7%	149 85.1%	155 88.6%	162 91%
Abnormal NCS	10 5.7%	9 5.1%	4 2.3%	4 2.2%
Abnormal CS	0 0%	1 0.6%	0 0%	1 0.6%
Normal	165 94.3%	171 97.7%	168 96%	169 94.9%
Abnormal NCS	10 5.7%	4 2.3%	7 4%	9 5.1%
Abnormal CS	0 0%	0 0%	0 0%	0 0%
Normal	157 89.7%	157 89.7%	153 87.4%	159 89.3%
Abnormal NCS	10 5.7%	2 1.1%	6 3.4%	8 4.5%
Abnormal CS	0 0%	0 0%	0 0%	0 0%
Normal	164 93.7%	169 96.6%	159 90.9%	168 94.4%
Abnormal NCS	11 6.3%	6 3.4%	16 9.1%	10 5.6%
Abnormal CS	0 0%	0 0%	0 0%	0 0%
Normal	153 87.4%	154 88%	148 84.6%	157 88.2%
Abnormal NCS	13 7.4%	5 2.9%	11 6.3%	10 5.6%
Abnormal CS	1 0.6%	0 0%	0 0%	0 0%
Normal	143 81.7%	152 86.9%	153 87.4%	157 88.2%
Abnormal NCS	32 18.3%	23 13.1%	20 11.4%	21 11.8%
Abnormal CS	0 0%	0 0%	2 1.1%	0 0%
Normal	138 78.9%	141 80.6%	141 80.6%	148 83.1%
Abnormal NCS	29 16.6%	17 9.7%	17 9.7%	19 10.7%
Abnormal CS	0 0%	1 0.6%	1 0.6%	0 0%
Normal	163 93.1%	165 94.3%	165 94.3%	168 94.4%
Abnormal NCS	12 6.9%	10 5.7%	10 5.7%	9 5.1%
Abnormal CS	0 0%	0 0%	0 0%	1 0.6%
Normal	155 88.6%	149 85.1%	149 85.1%	155 87.1%
Abnormal NCS	12 6.9%	10 5.7%	10 5.7%	11 6.2%
Abnormal CS	0 0%	0 0%	0 0%	1 0.6%
Normal	175 100%	175 100%	175 100%	178 100%
Abnormal NCS	0 0%	0 0%	0 0%	0 0%
Abnormal CS	0 0%	0 0%	0 0%	0 0%
Normal	167 95.4%	159 90.9%	159 90.9%	167 93.8%
Abnormal NCS	0 0%	0 0%	0 0%	0 0%
Abnormal CS	0 0%	0 0%	0 0%	0 0%
Normal	164 93.7%	169 96.6%	167 95.4%	167 93.8%
Abnormal NCS	11 6.3%	6 3.4%	8 4.6%	11 6.2%
Abnormal CS	0 0%	0 0%	0 0%	0 0%
Normal	155 88.6%	154 88%	152 86.9%	157 88.2%
Abnormal NCS	11 6.3%	5 2.9%	6 3.4%	10 5.6%
Abnormal CS	1 0.6%	0 0%	1 0.6%	0 0%
Normal	173 98.9%	172 98.3%	173 98.9%	174 97.8%
Abnormal NCS	2 1.1%	3 1.7%	2 1.1%	4 2.2%
Abnormal CS	0 0%	0 0%	0 0%	0 0%
Normal	163 93.1%	157 89.7%	159 90.9%	166 93.3%
Abnormal NCS	4 2.3%	2 1.1%	0 0%	1 0.6%
Abnormal CS	0 0%	0 0%	0 0%	0 0%
Normal	137 78.3%	156 89.1%	150 85.7%	150 84.3%
Abnormal NCS	36 20.6%	18 10.3%	24 13.7%	27 15.2%
Abnormal CS	2 1.1%	1 0.6%	1 0.6%	1 0.6%
Normal	136 77.7%	145 82.9%	140 80%	140 78.7%
Abnormal NCS	30 17.1%	13 7.4%	18 10.3%	24 13.5%
Abnormal CS	1 0.6%	1 0.6%	1 0.6%	3 1.7%
Normal	173 98.9%	170 97.1%	169 96.6%	176 98.9%
Abnormal NCS	1 0.6%	4 2.3%	6 3.4%	2 1.1%
Abnormal CS	1 0.6%	1 0.6%	0 0%	0 0%
Normal	165 94.3%	155 88.6%	156 89.1%	165 92.7%
Abnormal NCS	1 0.6%	4 2.3%	3 1.7%	2 1.1%
Abnormal CS	1 0.6%	0 0%	0 0%	0 0%

35. Secondary Outcome

Title	Change in Eye Examination Category
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = SAS which comprised all randomised participants who received at least one dose of trial product. Number Analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	175	175	175	178
Normal	109 62.3%	112 64%	109 62.3%	122 68.5%
Abnormal NCS	59 33.7%	59 33.7%	63 36%	54 30.3%
Abnormal CS	5 2.9%	4 2.3%	3 1.7%	2 1.1%
Normal	101 57.7%	94 53.7%	99 56.6%	105 59%
Abnormal NCS	55 31.4%	55 31.4%	54 30.9%	54 30.3%
Abnormal CS	2 1.1%	4 2.3%	3 1.7%	3 1.7%
Normal	111 63.4%	116 66.3%	108 61.7%	120 67.4%
Abnormal NCS	58 33.1%	55 31.4%	63 36%	55 30.9%
Abnormal CS	5 2.9%	4 2.3%	4 2.3%	3 1.7%
Normal	103 58.9%	93 53.1%	98 56%	106 59.6%
Abnormal NCS	52 29.7%	56 32%	55 31.4%	53 29.8%
Abnormal CS	2 1.1%	4 2.3%	3 1.7%	3 1.7%

36. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.
Measure Participants	173	171	172
Count of Participants [Participants]	2 1.1%	1 0.6%	0 0%

37. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.
Measure Participants	173	171	172
Count of Participants [Participants]	1 0.6%	0 0%	0 0%

38. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.
Measure Participants	173	171	172
Count of Participants [Participants]	2 1.1%	1 0.6%	0 0%

39. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.
Measure Participants	173	171	172
Count of Participants [Participants]	0 0%	0 0%	0 0%

40. Secondary Outcome

Title	Anti-semaglutide Binding Antibody Levels
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analysed = participants who were found positive for anti-semaglutide antibodies.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.
Measure Participants	2	1	0
Week 4	15 (13)	2 (0)
Week 8	7 (4)
Week 14	3 (0)
Week 31	3 (0)

41. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = SAS which comprised all randomised participants who received at least one dose of trial product.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	175	175	175	178
Number [Episodes]	5	2	1	1

42. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = SAS which comprised all randomised participants who received at least one dose of trial product.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	175	175	175	178
Number [Participants]	5 2.9%	2 1.1%	1 0.6%	1 0.6%

43. Secondary Outcome

Title	SNAC Plasma Concentrations
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = FAS which comprised all randomised participants. Number Analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.
Measure Participants	175	175	175
Week 4: 25 minutes post-dose	443.5 (378.4)	446.0 (329.4)	449.4 (330.5)
Week 4: 40 minutes post-dose	381.7 (227.5)	367.3 (238.5)	387.7 (186.3)
Week 14: 25 minutes post-dose	384.6 (415.4)	380.6 (427.0)	338.2 (339.5)
Week 14: 40 minutes post-dose	361.0 (259.2)	326.4 (350.1)	262.2 (377.4)
Week 26: 25 minutes post-dose	412.4 (533.3)	479.6 (334.3)	330.9 (578.4)
Week 26: 40 minutes post-dose	299.1 (411.1)	401.0 (271.6)	300.9 (372.5)

44. Secondary Outcome

Title	Semaglutide Plasma Concentrations for Population PK Analysis
Description	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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = FAS which comprised all randomised participants. Number Analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.
Measure Participants	175	175	175
Week 4	3.120 (130.2)	2.765 (118.7)	2.829 (127.6)
Week 8	3.073 (132.0)	6.216 (158.5)	6.461 (164.3)
Week 14	2.716 (145.7)	6.375 (177.3)	12.69 (235.2)
Week 26	2.466 (158.7)	5.016 (195.3)	11.07 (252.6)

45. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	165	158	158	167
1) Physical Functioning	0.14 (6.25)	1.18 (6.36)	1.05 (5.75)	0.66 (6.18)
2) Role-Physical	-0.41 (6.62)	-0.08 (7.04)	0.79 (6.86)	-0.25 (6.73)
3) Bodily Pain	1.17 (9.02)	-0.67 (9.37)	-0.14 (9.61)	0.40 (8.77)
4) General Health	0.97 (8.08)	0.92 (7.51)	2.07 (6.88)	0.18 (7.53)
5) Vitality	-0.08 (8.10)	0.77 (7.83)	0.40 (8.21)	-0.47 (8.02)
6) Social Functioning	0.21 (9.15)	1.00 (7.64)	0.88 (7.94)	0.18 (8.37)
7) Role-Emotional	-0.05 (9.89)	-0.63 (9.27)	0.85 (9.49)	-1.28 (10.02)
8) Mental Health	0.04 (7.62)	0.06 (8.51)	0.67 (8.74)	-0.25 (9.64)
Physical component summary	0.52 (6.04)	0.61 (5.86)	0.89 (5.66)	0.65 (5.44)
Mental component summary	-0.07 (8.08)	-0.00 (8.00)	0.67 (8.40)	-0.90 (9.08)

46. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = FAS which comprised all randomised participants. Number Analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	175	175	175	178
1) Trouble bending over	-0.17 (1.09)	-0.12 (1.07)	-0.13 (0.96)	-0.08 (1.06)
2) Tired/winded walking up stairs	-0.13 (1.03)	-0.16 (1.04)	-0.23 (1.02)	-0.11 (0.96)
3) Difficulty standing	-0.12 (1.34)	-0.22 (1.40)	-0.08 (1.18)	-0.01 (1.28)
4) Uncomfortable in small seats	-0.09 (1.08)	-0.05 (1.20)	-0.09 (1.04)	0.03 (1.33)
5) Bodily pain	-0.27 (1.10)	-0.08 (1.11)	-0.06 (1.05)	-0.14 (1.07)
6) Self-conscious eating in social settings	0.00 (0.97)	0.01 (1.15)	-0.11 (0.96)	-0.10 (1.08)
7) Less confident	-0.22 (1.05)	-0.29 (0.98)	-0.35 (1.00)	-0.20 (1.07)
8) Feel judged by others	-0.01 (1.00)	-0.23 (0.92)	-0.20 (0.93)	-0.13 (0.90)
9) Less important/worthy of respect	-0.05 (0.83)	-0.04 (0.79)	-0.11 (0.74)	-0.15 (0.77)
10) Frustrated shopping for clothes	-0.08 (0.95)	-0.10 (0.96)	-0.19 (0.92)	-0.14 (1.09)
11) Feel bad or upset in pictures	-0.16 (1.07)	-0.20 (0.91)	-0.23 (0.99)	-0.14 (1.07)
12) Feel down or depressed	-0.22 (1.07)	-0.18 (0.88)	-0.24 (0.86)	-0.16 (1.01)
13) Less interested in sex	-0.14 (1.24)	0.04 (1.07)	-0.03 (1.11)	-0.06 (1.16)
14) Avoid social gatherings	0.05 (0.76)	-0.07 (0.69)	-0.04 (0.63)	-0.02 (0.58)
15) Less productive	-0.09 (1.00)	-0.13 (0.97)	-0.10 (0.97)	-0.07 (0.80)
16) Lack energy to do things I would like to do	-0.14 (1.06)	-0.20 (1.11)	-0.14 (1.01)	-0.03 (1.01)
17) Not as physically active	-0.09 (1.06)	-0.41 (1.26)	-0.04 (1.11)	-0.08 (1.22)
18) Unable to walk far/quickly	-0.08 (1.09)	-0.29 (1.26)	0.02 (0.99)	-0.19 (1.21)
19) Worried about health	-0.32 (1.35)	-0.49 (1.39)	-0.42 (1.27)	-0.30 (1.39)
20) Limited self-esteem	-0.03 (1.04)	-0.09 (1.10)	-0.07 (1.02)	-0.09 (0.89)
21) Self-conscious about weight	-0.10 (0.92)	-0.12 (1.06)	0.01 (1.08)	-0.05 (0.91)
22) Frustrated/upset with self	-0.12 (0.91)	-0.25 (1.02)	-0.14 (1.08)	0.02 (0.91)

47. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = FAS which comprised all randomised participants. Number Analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	175	175	175	178
Poor	6 3.4%	11 6.3%	11 6.3%	7 3.9%
Fair	50 28.6%	51 29.1%	45 25.7%	59 33.1%
Good	67 38.3%	53 30.3%	56 32%	71 39.9%
Very good	30 17.1%	38 21.7%	32 18.3%	23 12.9%
Excellent	14 8%	4 2.3%	15 8.6%	7 3.9%
Poor	10 5.7%	7 4%	9 5.1%	9 5.1%
Fair	41 23.4%	41 23.4%	38 21.7%	42 23.6%
Good	62 35.4%	51 29.1%	55 31.4%	59 33.1%
Very good	32 18.3%	48 27.4%	33 18.9%	41 23%
Excellent	22 12.6%	11 6.3%	24 13.7%	15 8.4%

48. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Overall number of participants analyzed = number of participants with available data.

Arm/Group Title	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.	Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.	Participants were to take placebo tablets once daily for a period of 26 weeks.
Measure Participants	167	158	159	167
Much worse	0 0%	0 0%	1 0.6%	1 0.6%
Moderately worse	1 0.6%	2 1.1%	0 0%	1 0.6%
A little worse	6 3.4%	2 1.1%	3 1.7%	3 1.7%
No difference	56 32%	44 25.1%	29 16.6%	66 37.1%
A little better	45 25.7%	42 24%	48 27.4%	36 20.2%
Moderately better	23 13.1%	28 16%	31 17.7%	31 17.4%
Much better	36 20.6%	40 22.9%	47 26.9%	29 16.3%
Much worse	1 0.6%	0 0%	1 0.6%	0 0%
Moderately worse	0 0%	0 0%	0 0%	1 0.6%
A little worse	5 2.9%	2 1.1%	3 1.7%	2 1.1%
No difference	60 34.3%	53 30.3%	36 20.6%	63 35.4%
A little better	38 21.7%	32 18.3%	37 21.1%	39 21.9%
Moderately better	18 10.3%	27 15.4%	32 18.3%	32 18%
Much better	45 25.7%	44 25.1%	50 28.6%	30 16.9%

Adverse Events

Time Frame	Week 0 to week 31 (26 weeks treatment period + 5 weeks follow-up period). Results are based on the safety analysis set (SAS), which comprised all randomised participants who received at least one dose of trial product.
Adverse Event Reporting Description	Serious adverse events and other AEs were based on the on-treatment observation period, i.e., the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication. All-cause mortality were based on the in-trial observation period, i.e., 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.
Arm/Group Title	Oral Semaglutide 3 mg		Oral Semaglutide 7 mg		Oral Semaglutide 14 mg		Placebo
Arm/Group Description	Participants were to take oral semaglutide 3 mg tablets once daily from week 0 to week 26.		Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4 and 7 mg from week 4 to week 26.		Participants were to take oral semaglutide tablets once daily in a dose escalation manner from week 0 to week 26: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 26.		Participants were to take placebo tablets once daily for a period of 26 weeks.
All Cause Mortality
	Oral Semaglutide 3 mg		Oral Semaglutide 7 mg		Oral Semaglutide 14 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/175 (0%)		0/175 (0%)		1/175 (0.6%)		0/178 (0%)
Serious Adverse Events
	Oral Semaglutide 3 mg		Oral Semaglutide 7 mg		Oral Semaglutide 14 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/175 (2.9%)		3/175 (1.7%)		2/175 (1.1%)		8/178 (4.5%)
Cardiac disorders
Myocardial infarction	0/175 (0%)	0	0/175 (0%)	0	1/175 (0.6%)	1	0/178 (0%)	0
Endocrine disorders
Thyroiditis subacute	0/175 (0%)	0	1/175 (0.6%)	1	0/175 (0%)	0	0/178 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/175 (0.6%)	1	0/175 (0%)	0	0/175 (0%)	0	0/178 (0%)	0
Pancreatitis acute	1/175 (0.6%)	1	0/175 (0%)	0	0/175 (0%)	0	0/178 (0%)	0
Hepatobiliary disorders
Cholecystitis acute	1/175 (0.6%)	1	0/175 (0%)	0	0/175 (0%)	0	0/178 (0%)	0
Cholelithiasis	1/175 (0.6%)	1	0/175 (0%)	0	0/175 (0%)	0	0/178 (0%)	0
Infections and infestations
Appendicitis perforated	0/175 (0%)	0	0/175 (0%)	0	0/175 (0%)	0	1/178 (0.6%)	1
Bacterial pyelonephritis	0/175 (0%)	0	0/175 (0%)	0	1/175 (0.6%)	1	0/178 (0%)	0
Pyelonephritis acute	0/175 (0%)	0	1/175 (0.6%)	1	0/175 (0%)	0	0/178 (0%)	0
Injury, poisoning and procedural complications
Rib fracture	1/175 (0.6%)	1	0/175 (0%)	0	0/175 (0%)	0	0/178 (0%)	0
Investigations
Blood calcitonin increased	0/175 (0%)	0	0/175 (0%)	0	0/175 (0%)	0	1/178 (0.6%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Invasive ductal breast carcinoma	0/175 (0%)	0	0/175 (0%)	0	0/175 (0%)	0	1/178 (0.6%)	1
Neuroendocrine tumour of the lung	0/175 (0%)	0	0/175 (0%)	0	0/175 (0%)	0	1/178 (0.6%)	1
Papillary thyroid cancer	1/175 (0.6%)	1	0/175 (0%)	0	0/175 (0%)	0	0/178 (0%)	0
Prostate cancer stage II	1/175 (0.6%)	1	0/175 (0%)	0	0/175 (0%)	0	0/178 (0%)	0
Nervous system disorders
Cerebral infarction	0/175 (0%)	0	0/175 (0%)	0	0/175 (0%)	0	1/178 (0.6%)	1
Ischaemic stroke	0/175 (0%)	0	0/175 (0%)	0	0/175 (0%)	0	1/178 (0.6%)	1
Psychiatric disorders
Hallucination, visual	1/175 (0.6%)	1	0/175 (0%)	0	0/175 (0%)	0	0/178 (0%)	0
Renal and urinary disorders
Nephrolithiasis	0/175 (0%)	0	1/175 (0.6%)	1	0/175 (0%)	0	0/178 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/175 (0%)	0	1/175 (0.6%)	1	0/175 (0%)	0	0/178 (0%)	0
Pulmonary embolism	0/175 (0%)	0	0/175 (0%)	0	0/175 (0%)	0	1/178 (0.6%)	1
Skin and subcutaneous tissue disorders
Dermatitis allergic	0/175 (0%)	0	0/175 (0%)	0	0/175 (0%)	0	1/178 (0.6%)	1
Surgical and medical procedures
Palatoplasty	0/175 (0%)	0	1/175 (0.6%)	1	0/175 (0%)	0	0/178 (0%)	0
Vascular disorders
Shock	0/175 (0%)	0	0/175 (0%)	0	0/175 (0%)	0	1/178 (0.6%)	1
Other (Not Including Serious) Adverse Events
	Oral Semaglutide 3 mg		Oral Semaglutide 7 mg		Oral Semaglutide 14 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	48/175 (27.4%)		37/175 (21.1%)		45/175 (25.7%)		26/178 (14.6%)
Gastrointestinal disorders
Diarrhoea	15/175 (8.6%)	18	9/175 (5.1%)	9	9/175 (5.1%)	10	4/178 (2.2%)	4
Nausea	14/175 (8%)	17	9/175 (5.1%)	13	28/175 (16%)	43	10/178 (5.6%)	12
Vomiting	5/175 (2.9%)	5	8/175 (4.6%)	11	12/175 (6.9%)	15	4/178 (2.2%)	4
Infections and infestations
Influenza	9/175 (5.1%)	9	5/175 (2.9%)	5	4/175 (2.3%)	4	2/178 (1.1%)	2
Nasopharyngitis	10/175 (5.7%)	11	11/175 (6.3%)	11	3/175 (1.7%)	4	6/178 (3.4%)	7
Metabolism and nutrition disorders
Decreased appetite	2/175 (1.1%)	2	3/175 (1.7%)	3	9/175 (5.1%)	9	1/178 (0.6%)	1
Nervous system disorders
Headache	6/175 (3.4%)	7	10/175 (5.7%)	16	9/175 (5.1%)	31	9/178 (5.1%)	12

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

At the end of the trial, one or more scientific publications may be prepared collaboratively by the investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or communication for up to 60 days to protect intellectual property.