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

Diabetes Mellitus, Type 2 Clinical Trial

— PIONEER 2  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02863328
• Other study ID #: NN9924-4223
• Secondary ID: 2015-005209-36U1
• Status: Completed
• Phase: Phase 3
• Start date: August 10, 2016
• Est. completion date: March 8, 2018

Study information

• Verified date: July 2022
• Source: Novo Nordisk A/S
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This trial is conducted globally. The aim of this trial is to investigate Efficacy and Safety of Oral Semaglutide versus Empagliflozin in Subjects with Type 2 Diabetes Mellitus.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 822
• Est. completion date: March 8, 2018
• Est. primary completion date: August 1, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

• Diagnosed with type 2 diabetes mellitus at least 90 days prior to day of screening

• HbA1c (glycosylated haemoglobin) of 7.0-10.5 % (53-91 mmol/mol) (both inclusive)

• Stable daily dose of metformin (at least 1500 mg or maximum tolerated dose as documented in the subject medical record) at least 90 days prior to the 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 certain specific countries: Additional specific requirements apply

• Any disorder, which in the investigator's opinion might jeopardise subject's safety or compliance with the protocol

• Family or personal history of Multiple Endocrine Neoplasia Type 2 or Medullary Thyroid Carcinoma

• 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

• Subjects presently classified as being in New York Heart Association Class IV

• Planned coronary, carotid or peripheral artery revascularisation known on the day of screening

• Subjects with ALT (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 (CKD-EPI)

• Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria in a period of 90 days before the day of screening. An exception is short-term insulin treatment for acute illness for a total of below or equal to 14 days

• Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus photography or dilated fundoscopy performed within 90 days prior to randomisation

• History or presence of malignant neoplasms within the last 5 years (except basal and squamous cell skin cancer and carcinoma in situ)

• History of diabetic ketoacidosis

Related Conditions & MeSH terms

• Diabetes
• Diabetes Mellitus
• Diabetes Mellitus, Type 2

Intervention

Drug:
• semaglutide
Oral administration once-daily.
• empagliflozin
Oral administration once-daily.

Locations

Country	Name	City	State
Argentina	Novo Nordisk Investigational Site	Caba
Argentina	Novo Nordisk Investigational Site	Capital Federal
Argentina	Novo Nordisk Investigational Site	Córdoba
Argentina	Novo Nordisk Investigational Site	Córdoba
Brazil	Novo Nordisk Investigational Site	Porto Alegre
Brazil	Novo Nordisk Investigational Site	Sao Paulo
Brazil	Novo Nordisk Investigational Site	São Paulo	Sao Paulo
Croatia	Novo Nordisk Investigational Site	Karlovac
Croatia	Novo Nordisk Investigational Site	Krapinske Toplice
Croatia	Novo Nordisk Investigational Site	Pula
Croatia	Novo Nordisk Investigational Site	Virovitica
Croatia	Novo Nordisk Investigational Site	Zagreb
Croatia	Novo Nordisk Investigational Site	Zagreb
Greece	Novo Nordisk Investigational Site	Athens
Greece	Novo Nordisk Investigational Site	Athens
Greece	Novo Nordisk Investigational Site	Thessaloniki
Greece	Novo Nordisk Investigational Site	Thessaloniki
Greece	Novo Nordisk Investigational Site	Thessaloniki
Greece	Novo Nordisk Investigational Site	Thessaloniki
Greece	Novo Nordisk Investigational Site	Thessaloniki
Hungary	Novo Nordisk Investigational Site	Budapest
Hungary	Novo Nordisk Investigational Site	Budapest
Hungary	Novo Nordisk Investigational Site	Cegléd
Hungary	Novo Nordisk Investigational Site	Nyíregyhaza
Hungary	Novo Nordisk Investigational Site	Salgótarján
Hungary	Novo Nordisk Investigational Site	Szekszárd
Italy	Novo Nordisk Investigational Site	Bologna
Italy	Novo Nordisk Investigational Site	Lucca
Italy	Novo Nordisk Investigational Site	Palermo
Italy	Novo Nordisk Investigational Site	Roma
Italy	Novo Nordisk Investigational Site	Roma
Italy	Novo Nordisk Investigational Site	Siena
Poland	Novo Nordisk Investigational Site	Bialystok
Poland	Novo Nordisk Investigational Site	Lublin
Poland	Novo Nordisk Investigational Site	Pulawy
Poland	Novo Nordisk Investigational Site	Warszawa
Poland	Novo Nordisk Investigational Site	Wroclaw
Poland	Novo Nordisk Investigational Site	Zabrze
Russian Federation	Novo Nordisk Investigational Site	Kazan
Russian Federation	Novo Nordisk Investigational Site	Moscow
Russian Federation	Novo Nordisk Investigational Site	Saint Petersburg
Russian Federation	Novo Nordisk Investigational Site	Saint-Petersburg
Russian Federation	Novo Nordisk Investigational Site	Saratov
Russian Federation	Novo Nordisk Investigational Site	Tumen
Serbia	Novo Nordisk Investigational Site	Kragujevac
Serbia	Novo Nordisk Investigational Site	Nis
Serbia	Novo Nordisk Investigational Site	Novi Sad
Spain	Novo Nordisk Investigational Site	Almería
Spain	Novo Nordisk Investigational Site	Centelles (Barcelona)
Spain	Novo Nordisk Investigational Site	Hospitalet de Llobregat
Spain	Novo Nordisk Investigational Site	La Roca del Vallés
Spain	Novo Nordisk Investigational Site	Pozuelo de Alarcon
Spain	Novo Nordisk Investigational Site	Sevilla
Spain	Novo Nordisk Investigational Site	Sevilla
Spain	Novo Nordisk Investigational Site	Valencia
Spain	Novo Nordisk Investigational Site	Vic (Barcelona)
Thailand	Novo Nordisk Investigational Site	Bangkok
Thailand	Novo Nordisk Investigational Site	Bangkoknoi, Bangkok
United States	Novo Nordisk Investigational Site	Albany	New York
United States	Novo Nordisk Investigational Site	Arlington	Texas
United States	Novo Nordisk Investigational Site	Atlanta	Georgia
United States	Novo Nordisk Investigational Site	Baton Rouge	Louisiana
United States	Novo Nordisk Investigational Site	Boston	Massachusetts
United States	Novo Nordisk Investigational Site	Bradenton	Florida
United States	Novo Nordisk Investigational Site	Buckley	Michigan
United States	Novo Nordisk Investigational Site	Butte	Montana
United States	Novo Nordisk Investigational Site	Cincinnati	Ohio
United States	Novo Nordisk Investigational Site	Dallas	Texas
United States	Novo Nordisk Investigational Site	Encino	California
United States	Novo Nordisk Investigational Site	Evansville	Indiana
United States	Novo Nordisk Investigational Site	Greer	South Carolina
United States	Novo Nordisk Investigational Site	Houston	Texas
United States	Novo Nordisk Investigational Site	Houston	Texas
United States	Novo Nordisk Investigational Site	Humboldt	Tennessee
United States	Novo Nordisk Investigational Site	Indianapolis	Indiana
United States	Novo Nordisk Investigational Site	Jacksonville	Florida
United States	Novo Nordisk Investigational Site	Jacksonville	Florida
United States	Novo Nordisk Investigational Site	Jacksonville	Florida
United States	Novo Nordisk Investigational Site	Kalamazoo	Michigan
United States	Novo Nordisk Investigational Site	Katy	Texas
United States	Novo Nordisk Investigational Site	Kingsport	Tennessee
United States	Novo Nordisk Investigational Site	La Mesa	California
United States	Novo Nordisk Investigational Site	Lexington	Kentucky
United States	Novo Nordisk Investigational Site	Lexington	Kentucky
United States	Novo Nordisk Investigational Site	Mason	Ohio
United States	Novo Nordisk Investigational Site	Meridian	Idaho
United States	Novo Nordisk Investigational Site	Miami	Florida
United States	Novo Nordisk Investigational Site	Miami Lakes	Florida
United States	Novo Nordisk Investigational Site	Northport	New York
United States	Novo Nordisk Investigational Site	Northridge	California
United States	Novo Nordisk Investigational Site	Orlando	Florida
United States	Novo Nordisk Investigational Site	Oviedo	Florida
United States	Novo Nordisk Investigational Site	Palm Springs	California
United States	Novo Nordisk Investigational Site	Peoria	Illinois
United States	Novo Nordisk Investigational Site	Perry	Georgia
United States	Novo Nordisk Investigational Site	Philadelphia	Pennsylvania
United States	Novo Nordisk Investigational Site	Poway	California
United States	Novo Nordisk Investigational Site	Richmond	Virginia
United States	Novo Nordisk Investigational Site	Riverside	California
United States	Novo Nordisk Investigational Site	Rockville	Maryland
United States	Novo Nordisk Investigational Site	San Antonio	Texas
United States	Novo Nordisk Investigational Site	San Antonio	Texas
United States	Novo Nordisk Investigational Site	San Antonio	Texas
United States	Novo Nordisk Investigational Site	Spring Valley	California
United States	Novo Nordisk Investigational Site	Tuscumbia	Alabama
United States	Novo Nordisk Investigational Site	Wilmington	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Novo Nordisk A/S

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  Croatia,  Greece,  Hungary,  Italy,  Poland,  Russian Federation,  Serbia,  Spain,  Thailand, 

References & Publications (3)

Aroda VR, Bauer R, Christiansen E, Haluzík M, Kallenbach K, Montanya E, Rosenstock J, Meier JJ. Efficacy and safety of oral semaglutide by subgroups of patient characteristics in the PIONEER phase 3 programme. Diabetes Obes Metab. 2022 Jul;24(7):1338-1350 — View Citation

Eliasson B, Ericsson Å, Fridhammar A, Nilsson A, Persson S, Chubb B. Long-Term Cost Effectiveness of Oral Semaglutide Versus Empagliflozin and Sitagliptin for the Treatment of Type 2 Diabetes in the Swedish Setting. Pharmacoecon Open. 2022 May;6(3):343-35 — View Citation

Rodbard HW, Rosenstock J, Canani LH, Deerochanawong C, Gumprecht J, Lindberg SØ, Lingvay I, Søndergaard AL, Treppendahl MB, Montanya E; PIONEER 2 Investigators. Oral Semaglutide Versus Empagliflozin in Patients With Type 2 Diabetes Uncontrolled on Metform — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in HbA1c	Change from baseline (week 0) in glycosylated haemoglobin (HbA1c) was evaluated at week 26. The endpoint was evaluated based on 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. The endpoint was also evaluated based on the data from the on-treatment without rescue medication observation period which was the time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.	Week 0, week 26
Secondary	Change in Body Weight (Kg)	Change from baseline (week 0) in body weight was evaluated at week 26. The endpoint was evaluated based on 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. The endpoint was also evaluated based on the data from the on-treatment without rescue medication observation period which was the time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.	Week 0, week 26
Secondary	Change in HbA1c (%)	Change from baseline (week 0) in HbA1c was evaluated at week 52. 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.	Week 0, week 52
Secondary	Change in Body Weight (kg)	Change from baseline (week 0) in body weight was evaluated at week 52. 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.	Week 0, week 52
Secondary	Change in Fasting Plasma Glucose	Change from baseline (week 0) in fasting plasma glucose was evaluated at week 26 and week 52. 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.	Week 0, week 26, week 52
Secondary	Change in SMPG : Mean of the 7-point Profile	Change from baseline (week 0) in mean of the 7-point self-measured plasma glucose (SMPG) (i.e. before and after breakfast, lunch and dinner, and at bedtime) profile was evaluated at week 26 and week 52. 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.	Week 0, week 26 and week 52
Secondary	Change in SMPG : Mean Postprandial Increment Over All Meals	Change from baseline (week 0) in mean postprandial glucose increment was evaluated at week 26 and week 52. 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.	Week 0, week 26 and week 52
Secondary	Change in Fasting C-peptide (Ratio to Baseline)	Change from baseline (week 0) in fasting C-peptide (Nanomoles per liter [nmol/L]) at week 26 and week 52 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.	Week 0, week 26 and week 52
Secondary	Change in Fasting Insulin (Ratio to Baseline)	Change from baseline (week 0) in fasting insulin (picomoles per liter [pmol/L]) at week 26 and week 52 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.	Week 0, week 26 and week 52
Secondary	Change in Fasting Pro-insulin (Ratio to Baseline)	Change from baseline (week 0) in fasting pro-insulin (pmol/L) at week 26 and week 52 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.	Week 0, week 26 and week 52
Secondary	Change in Fasting Glucagon (Ratio to Baseline)	Change from baseline (week 0) in fasting glucagon (picograms per milliliter [pg/mL]) at week 26 and week 52 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.	Week 0, week 26 and week 52
Secondary	Change in HOMA-IR (Ratio to Baseline)	Change from baseline (week 0) in homeostatic model assessment index of insulin resistance (HOMA-IR) (%) at week 26 and week 52 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.	Week 0, week 26 and week 52
Secondary	Change in HOMA-B (Ratio to Baseline)	Change from baseline (week 0) in homeostatic model assessment index of beta-cell function (HOMA-B) (%) at week 26 and week 52 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.	Week 0, week 26 and week 52
Secondary	Change in C-reactive Protein (Ratio to Baseline)	Change from baseline (week 0) in C-reactive protein (milligrams per liter [mg/L]) at week 26 and week 52 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.	Week 0, week 26 and week 52
Secondary	Change in Body Weight (%)	Relative change from baseline (week 0) in body weight (kg) was evaluated at week 26 and week 52. 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.	Week 0, week 26, week 52
Secondary	Change in Body Mass Index	Change from baseline (week 0) in body mass index (BMI) was evaluated at week 26 and week 52. 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.	Week 0, week 26, week 52
Secondary	Change in Waist Circumference	Change from baseline (week 0) in waist circumference was evaluated at week 26 and week 52. 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.	Week 0, week 26, week 52
Secondary	Change in Fasting Total Cholesterol (Ratio to Baseline)	Change from baseline (week 0) in fasting total cholesterol (mmol/L) at week 26 and week 52 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.	Week 0, week 26 and week 52
Secondary	Change in Fasting LDL Cholesterol (Ratio to Baseline)	Change from baseline (week 0) in fasting low density lipoprotein (LDL) cholesterol (mmol/L) at week 26 and week 52 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.	Week 0, week 26 and week 52
Secondary	Change in Fasting HDL Cholesterol (Ratio to Baseline)	Change from baseline (week 0) in fasting high density lipoprotein (HDL) cholesterol (mmol/L) at week 26 and week 52 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.	Week 0, week 26 and week 52
Secondary	Change in Fasting VLDL Cholesterol (Ratio to Baseline)	Change from baseline (week 0) in fasting very low density lipoprotein (VLDL) cholesterol (mmol/L) at week 26 and week 52 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.	Week 0, week 26 and week 52
Secondary	Change in Fasting Free Fatty Acids (Ratio to Baseline)	Change from baseline (week 0) in fasting free fatty acids (FFA) (mmol/L) at week 26 and week 52 is presented as ratio to baseline. The results are based on the data from the in-trial observation period. Because of an issue with the handling of the blood samples for FFA, all FFA data are considered invalid for this trial; thus, no conclusion with regards to FFA levels can be made based on the FFA data. 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.	Week 0, week 26 and week 52
Secondary	Change in Fasting Triglycerides (Ratio to Baseline)	Change from baseline (week 0) in fasting triglycerides (mmol/L) at week 26 and week 52 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.	Week 0, week 26 and week 52
Secondary	Participants Who Achieve HbA1c <7.0 % (53 mmol/Mol) ADA Target (Yes/no)	Participants who achieved HbA1c <7.0% (53 mmol/mol) (American Diabetes Association (ADA) target) at week 26 and week 52. 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.	Week 26 and week 52
Secondary	Participants Who Achieve HbA1c =6.5% (48 mmol/Mol), AACE Target (Yes/no)	Participants who achieved HbA1c =6.5% (48 mmol/mol) (American Association of Clinical Endocrinologists (AACE) target) at week 26 and week 52. 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.	Week 26 and week 52
Secondary	Participants Who Achieve Weight Loss =5% (Yes/no)	Participants who achieved weight loss of =5% at week 26 and week 52. 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.	Week 26 and week 52
Secondary	Participants Who Achieve Weight Loss =10% (Yes/no)	Participants who achieved weight loss of =10% at week 26 and week 52. 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.	Week 26 and week 52
Secondary	Participants Who Achieve HbA1c <7.0 % (53 mmol/Mol) Without Hypoglycaemia (Severe or BG Confirmed Symptomatic Hypoglycaemia) and no Weight Gain (Yes/no)	Participants who achieved HbA1c <7.0% (53 mmol/mol) without severe or blood glucose (BG) confirmed symptomatic hypoglycaemia and without weight gain at week 26 and week 52. Severe or BG-confirmed symptomatic hypoglycaemia: an episode, that is severe according to the ADA classification or BG-confirmed by a plasma glucose value <3.1 mmol/L with symptoms consistent with hypoglycaemia. 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.	Week 26 and week 52
Secondary	Participants Who Achieve HbA1c Reduction =1% (10.9 mmol/Mol) and Weight Loss =3% (Yes/no)	Participants who achieved HbA1c reduction =1%-point and weight loss of =3% at week 26 and week 52. 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.	Week 26 and week 52
Secondary	Time to Additional Anti-diabetic Medication	Presented results are the number of participants who had taken additional anti-diabetic medication anytime during the periods, from week 0 to week 26 and week 0 to week 52. Additional anti-diabetic medication: use of new anti-diabetic medication for more than 21 days with the initiation at or after randomisation (week 0) and before (planned) end-of-treatment (week 26/week 52), and/or intensification of anti-diabetic medication (a more than 20% increase in dose relative to baseline) for more than 21 days with the intensification at or after randomisation and before (planned) end-of-treatment. 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.	Weeks 0-52
Secondary	Time to Rescue Medication	Presented results are the number of participants who had taken rescue medication anytime during the periods, from week 0 to week 26 and week 0 to week 52. Rescue medication: use of new antidiabetic medication 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. On-treatment without rescue medication observation period: the time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication.	Weeks 0-52
Secondary	Number of Treatment-emergent Adverse Events (TEAE)	A treatment-emergent adverse event (TEAE) is defined as an adverse event (AE) with onset in the on-treatment observation period (the time period where participants are considered treated with trial product) and was assessed up to approximately 57 weeks (52-week treatment period plus the 5-week follow-up period).	Weeks 0-57
Secondary	Change in Amylase (Ratio to Baseline)	Change from baseline (week 0) in amylase (units per liter [U/L]) at week 26 and week 52 is presented as ratio to baseline. Results are based on the data from the on-treatment observation period. On-treatment observation period: the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Week 0, week 26, week 52
Secondary	Change in Lipase (Ratio to Baseline)	Change from baseline (week 0) in lipase (U/L) at week 26 and week 52 is presented as ratio to baseline. Results are based on the data from the on-treatment observation period. On-treatment observation period: the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Week 0, week 26, week 52
Secondary	Change in Pulse Rate	Change from baseline (week 0) in pulse rate was evaluated at week 26 and week 52. Results are based on the data from the on-treatment observation period. On-treatment observation period: the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Week 0, week 26, week 52
Secondary	Change in Blood Pressure (Systolic and Diastolic Blood Pressure)	Change from baseline (week 0) in systolic blood pressure (SBP) and diastolic blood pressure (DBP) was evaluated at week 26 and week 52. Results are based on the data from the on-treatment observation period. On-treatment observation period: the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Week 0, week 26, week 52
Secondary	Change in ECG	Change from baseline (week 0) in electrocardiogram (ECG) was evaluated at week 26 and week 52. Change from baseline results are presented as shift in findings (normal, abnormal and not clinically significant (NCS), and abnormal and clinically significant (CS)) from week 0 to week 26 and week 52. 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.	Week 0, week 26, week 52
Secondary	Change in Physical Examination	The physical examination findings (normal, abnormal NCS and abnormal CS) of the participants at week -2 and week 52 are presented for the following examinations: Cardiovascular system, Nervous system (central and peripheral); Gastrointestinal system, incl. mouth; General appearance; Head (ears, eyes, nose), throat, neck; Lymph node palpation; Musculoskeletal system; Respiratory system; Skin; Thyroid gland. 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.	Week -2, week 52
Secondary	Change in Eye Examination	The eye examination findings (normal, abnormal NCS and abnormal CS) of the participants at baseline (week -2) and week 52 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.	Week -2, week 52
Secondary	Occurrence of Anti-semaglutide Binding Antibodies (Yes/no)	This outcome measure is only applicable for the oral semaglutide 14 mg treatment arm. Number of participants who measured with anti-semaglutide binding antibodies anytime during post-baseline visits (week 0 to week 57) 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.	Weeks 0-57
Secondary	Occurrence of Anti-semaglutide Neutralising Antibodies (Yes/no)	This outcome measure is only applicable for the oral semaglutide 14 mg treatment arm. Number of participants who measured with anti-semaglutide neutralising antibodies anytime during post-baseline visits (week 0 to week 57) 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.	Weeks 0-57
Secondary	Occurrence of Anti-semaglutide Binding Antibodies Cross Reacting With Native GLP-1 (Yes/no)	This outcome measure is only applicable for the oral semaglutide 14 mg treatment arm. Number of participants who measured with anti-semaglutide binding antibodies cross reacting with native glucagon-like peptide-1 (GLP-1) anytime during post-baseline visits (week 0 to week 57) 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.	Weeks 0-57
Secondary	Occurrence of Anti-semaglutide Neutralising Antibodies Cross Reacting With Native GLP-1 (Yes/no)	This outcome measure is only applicable for the oral semaglutide 14 mg treatment arm. Number of participants who measured with anti-semaglutide neutralising antibodies cross reacting with native GLP-1 anytime during post-baseline visits (week 0 to week 57) 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.	Weeks 0-57
Secondary	Anti-semaglutide Binding Antibody Levels	This outcome measure is only applicable for the oral semaglutide 14 mg treatment arm. It is based on the data from participants who were measured with anti-semaglutide antibodies anytime during post-baseline visits (week 0 to week 57). Results are presented as percentage of bound radioactivity-labelled semaglutide /total added radioactivity-labelled semaglutide (%B/T). 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.	Weeks 0-57
Secondary	Number of Treatment-emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemic Episodes	Treatment-emergent hypoglycaemia is an episode with onset in the on-treatment observation period (the time period where participants are considered treated with trial product) and was assessed up to approximately 57 weeks (52-week treatment period plus the 5-week follow-up period). Severe or BG-confirmed symptomatic hypoglycaemia is an episode that is severe according to the American Diabetes Association classification or blood glucose-confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Results are based on the data from the on-treatment observation period. On-treatment observation period: the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Weeks 0-57
Secondary	Participants With Treatment-emergent Severe or BG-confirmed Symptomatic Hypoglycaemic Episodes (Yes/no)	Number of participants with treatment-emergent severe or BG-confirmed symptomatic hypoglycaemic episodes was recorded during week 0-57. Results are based on the data from the on-treatment observation period. On-treatment observation period: the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Weeks 0-57
Secondary	Semaglutide Plasma Concentrations for Population PK Analyses	Semaglutide plasma concentrations were measured after 25 minutes post-dose at week 4, 26 and 52. Results are based on the data from the on-treatment observation period. On-treatment observation period: the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Weeks 0-52
Secondary	SNAC Plasma Concentrations	This outcome measure is only applicable for the oral semaglutide 14 mg treatment arm. Sodium N-[8-(2-hydroxybenzoyl) amino]caprylate (SNAC) plasma concentrations were measured after 25 and 40 minutes post-dose at week 4, 26 and 52. Results are based on the data from the on-treatment observation period. On-treatment observation period: the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Weeks 0-52
Secondary	Change in Short Form Health Survey Version 2.0 (SF-36v2™, Acute Version) Health Survey: Scores From the 8 Domains and Summaries of the Physical Component Score (PCS) and the Mental Component Score (MCS)	SF-36 is a 36-item patient-reported survey of patient health that measures the participant's overall health-related quality of life (HRQoL). SF-36v2™ (acute version) questionnaire measured eight domains of functional health and well-being as well as two component summary scores (physical component summary (PCS) and mental component summary (MCS)). The 0-100 scale scores (where higher scores indicated a better HRQoL) from the SF-36 were converted to norm-based scores to enable a direct interpretation in relation to the distribution of the scores in the 2009 U.S. general population. In the metric of norm-based scores, 50 and 10 corresponds to the mean and standard deviation respectively of the 2009 U.S. general population. Change from baseline (week 0) in the domain scores and component summary (PCS and MCS) scores were evaluated at weeks 26 and 52. A positive change score indicates an improvement since baseline. Results are based on the data from the in-trial observation period.	Week 0, week 26, week 52
Secondary	Change in CoEQ: Scores From the 4 Domains and the 19 Items	Change from baseline (week 0) in Control of Eating Questionnaire (CoEQ) was evaluated at weeks 26 and 52. The CoEQ comprised 19 items to assess the intensity and type of food cravings, as well as subjective sensation of appetite and mood, with the 4 domains: 'craving control' (items 9-12, 19), 'positive mood' (items 5-8), 'craving for savoury' (items 4, 16-18) and 'craving for sweet' (items 3, 13-15). The 19 items were scored on an 11-point graded response scale ranging from 10 to 0, with items relating to each of the 4 domains being averaged to create a final score. A low score in the domains 'craving for sweet and 'craving for savoury' represents a low level of craving; whereas a high score in the domains 'craving control' and 'positive mood' represents good control and a good mood, respectively. Results are based on the data from the in-trial observation period.	Week 0, week 26, week 52

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