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

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

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2; Diabetes
• Intervention / Treatment: Drug: semaglutide; Drug: placebo

• Study Type: Interventional
• Enrollment (Actual): 703
• Phase: Phase 3

Contacts and Locations

Study Locations

• Algeria
  • Algiers, Algeria, 16000
    • Novo Nordisk Investigational Site
  • Algiers, Algeria
    • Novo Nordisk Investigational Site
  • Algiers, Algeria, 16003
    • Novo Nordisk Investigational Site
  • Algiers, Algeria, 16049
    • Novo Nordisk Investigational Site
• Bulgaria
  • Sofia, Bulgaria, 1431
    • Novo Nordisk Investigational Site
  • Sofia, Bulgaria, 1233
    • Novo Nordisk Investigational Site
• Czechia
  • Broumov, Czechia, 550 01
    • Novo Nordisk Investigational Site
  • Chrudim, Czechia, 537 01
    • Novo Nordisk Investigational Site
  • Mlada Boleslav, Czechia, 293 50
    • Novo Nordisk Investigational Site
  • Olomouc, Czechia, 77900
    • Novo Nordisk Investigational Site
  • Prague 1, Czechia, 11694
    • Novo Nordisk Investigational Site
• Italy
  • Como, Italy, 22042
    • Novo Nordisk Investigational Site
  • Palermo, Italy, 90129
    • Novo Nordisk Investigational Site
  • Pisa, Italy, 56124
    • Novo Nordisk Investigational Site
  • Rome, Italy, 00168
    • Novo Nordisk Investigational Site
  • Siena, Italy, 53100
    • Novo Nordisk Investigational Site
• Japan
  • Suita-shi, Osaka, Japan, 565-0853
    • Novo Nordisk Investigational Site
  • Tokyo, Japan, 103-0027
    • Novo Nordisk Investigational Site
  • Tokyo, Japan, 103-0028
    • Novo Nordisk Investigational Site
  • Tokyo, Japan, 104-0031
    • Novo Nordisk Investigational Site
  • Tokyo, Japan, 160-0008
    • Novo Nordisk Investigational Site
  • Yokohama-shi, Kanagawa, Japan, 236-0004
    • Novo Nordisk Investigational Site
• Mexico
  • Aguascalientes, Mexico, 20230
    • Novo Nordisk Investigational Site
  • Tamaulipas
    • Ciudad Madero, Tamaulipas, Mexico, 89440
      • Novo Nordisk Investigational Site
• Romania
  • Bucharest, Romania, 010825
    • Novo Nordisk Investigational Site
  • Bucharest, Romania, 011234
    • Novo Nordisk Investigational Site
  • Dambovita
    • Targoviste, Dambovita, Romania, 130086
      • Novo Nordisk Investigational Site
    • Targoviste, Dambovita, Romania, 130095
      • Novo Nordisk Investigational Site
  • Prahova
    • Ploiesti, Prahova, Romania, 100018
      • Novo Nordisk Investigational Site
• Russian Federation
  • Dzerzhinskiy, Russian Federation, 140091
    • Novo Nordisk Investigational Site
  • Kazan, Russian Federation, 420073
    • Novo Nordisk Investigational Site
  • Novosibirsk, Russian Federation, 630099
    • Novo Nordisk Investigational Site
  • Saint-Petersburg, Russian Federation, 194358
    • Novo Nordisk Investigational Site
  • Saint-Petersburg, Russian Federation, 199226
    • Novo Nordisk Investigational Site
  • Tomsk, Russian Federation, 634050
    • Novo Nordisk Investigational Site
  • Voronezh, Russian Federation, 394018
    • Novo Nordisk Investigational Site
  • Yaroslavl, Russian Federation, 150003
    • Novo Nordisk Investigational Site
  • Yoshkar-Ola, Russian Federation, 424004
    • Novo Nordisk Investigational Site
• Serbia
  • Belgrade, Serbia, 11000
    • Novo Nordisk Investigational Site
• Turkey
  • Adana, Turkey, 01250
    • Novo Nordisk Investigational Site
  • Istanbul, Turkey, 34096
    • Novo Nordisk Investigational Site
  • Istanbul, Turkey, 34722
    • Novo Nordisk Investigational Site
  • Istanbul, Turkey, 34303
    • Novo Nordisk Investigational Site
  • Istanbul, Turkey, 34718
    • Novo Nordisk Investigational Site
  • Istanbul, Turkey, 34752
    • Novo Nordisk Investigational Site
  • Istanbul, Turkey, 34371
    • Novo Nordisk Investigational Site
  • Istanbul, Turkey, 34400
    • Novo Nordisk Investigational Site
  • Istanbul, Turkey
    • Novo Nordisk Investigational Site
  • Istanbul, Turkey, 34147
    • Novo Nordisk Investigational Site
• United States
  • California
    • Lancaster, California, United States, 93534
      • Novo Nordisk Investigational Site
    • Los Angeles, California, United States, 90057
      • Novo Nordisk Investigational Site
    • Montclair, California, United States, 91763
      • Novo Nordisk Investigational Site
    • North Hollywood, California, United States, 91606
      • Novo Nordisk Investigational Site
    • Riverside, California, United States, 92506
      • Novo Nordisk Investigational Site
    • San Diego, California, United States, 92111
      • Novo Nordisk Investigational Site
    • San Jose, California, United States, 95148
      • Novo Nordisk Investigational Site
    • San Mateo, California, United States, 94401
      • Novo Nordisk Investigational Site
  • Florida
    • Doral, Florida, United States, 33166
      • Novo Nordisk Investigational Site
    • Hialeah, Florida, United States, 33012
      • Novo Nordisk Investigational Site
    • Miami, Florida, United States, 33143
      • Novo Nordisk Investigational Site
    • Miami, Florida, United States, 33173
      • Novo Nordisk Investigational Site
    • Miami, Florida, United States, 33186
      • Novo Nordisk Investigational Site
    • Palm Harbor, Florida, United States, 34684-3609
      • Novo Nordisk Investigational Site
    • Pembroke Pines, Florida, United States, 33026
      • Novo Nordisk Investigational Site
    • Port Charlotte, Florida, United States, 33952
      • Novo Nordisk Investigational Site
    • Spring Hill, Florida, United States, 34609
      • Novo Nordisk Investigational Site
    • Tampa, Florida, United States, 33607
      • Novo Nordisk Investigational Site
  • Georgia
    • Woodstock, Georgia, United States, 30189-4255
      • Novo Nordisk Investigational Site
  • Hawaii
    • Honolulu, Hawaii, United States, 96814
      • Novo Nordisk Investigational Site
  • Idaho
    • Blackfoot, Idaho, United States, 83221
      • Novo Nordisk Investigational Site
    • Nampa, Idaho, United States, 83686-6011
      • Novo Nordisk Investigational Site
  • Illinois
    • Skokie, Illinois, United States, 60077
      • Novo Nordisk Investigational Site
  • Indiana
    • Muncie, Indiana, United States, 47304
      • Novo Nordisk Investigational Site
  • Kentucky
    • Louisville, Kentucky, United States, 40213
      • Novo Nordisk Investigational Site
  • Louisiana
    • Metairie, Louisiana, United States, 70002
      • Novo Nordisk Investigational Site
  • Maryland
    • Hyattsville, Maryland, United States, 20782
      • Novo Nordisk Investigational Site
  • Michigan
    • Kalamazoo, Michigan, United States, 49009
      • Novo Nordisk Investigational Site
    • Rochester, Michigan, United States, 48307
      • Novo Nordisk Investigational Site
    • Troy, Michigan, United States, 48098
      • Novo Nordisk Investigational Site
  • Nebraska
    • Elkhorn, Nebraska, United States, 68022
      • Novo Nordisk Investigational Site
  • New York
    • Brooklyn, New York, United States, 11215
      • Novo Nordisk Investigational Site
    • West Seneca, New York, United States, 14224
      • Novo Nordisk Investigational Site
  • North Carolina
    • Asheboro, North Carolina, United States, 27203
      • Novo Nordisk Investigational Site
    • Charlotte, North Carolina, United States, 28277
      • Novo Nordisk Investigational Site
    • Greensboro, North Carolina, United States, 27408
      • Novo Nordisk Investigational Site
  • North Dakota
    • Fargo, North Dakota, United States, 58104
      • Novo Nordisk Investigational Site
  • Ohio
    • Cincinnati, Ohio, United States, 45255
      • Novo Nordisk Investigational Site
    • Willoughby Hills, Ohio, United States, 44094
      • Novo Nordisk Investigational Site
  • Oklahoma
    • Norman, Oklahoma, United States, 73069
      • Novo Nordisk Investigational Site
    • Oklahoma City, Oklahoma, United States, 73112
      • Novo Nordisk Investigational Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Novo Nordisk Investigational Site
  • South Carolina
    • Spartanburg, South Carolina, United States, 29303
      • Novo Nordisk Investigational Site
  • Texas
    • Dallas, Texas, United States, 75230
      • Novo Nordisk Investigational Site
    • Houston, Texas, United States, 77058
      • Novo Nordisk Investigational Site
    • Mesquite, Texas, United States, 75149
      • Novo Nordisk Investigational Site
    • San Antonio, Texas, United States, 78215
      • Novo Nordisk Investigational Site
    • San Antonio, Texas, United States, 78224
      • Novo Nordisk Investigational Site
    • San Antonio, Texas, United States, 78230
      • Novo Nordisk Investigational Site
    • San Antonio, Texas, United States, 78228-3419
      • Novo Nordisk Investigational Site
    • Sugar Land, Texas, United States, 77479
      • Novo Nordisk Investigational Site
    • Waco, Texas, United States, 76710
      • Novo Nordisk Investigational Site
  • Utah
    • Bountiful, Utah, United States, 84010
      • Novo Nordisk Investigational Site
  • Virginia
    • Norfolk, Virginia, United States, 23510-2015
      • Novo Nordisk Investigational Site
    • Richmond, Virginia, United States, 23219
      • Novo Nordisk Investigational Site
    • Salem, Virginia, United States, 24153-6404
      • Novo Nordisk Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 IV. - 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: placebo; Oral administration once daily.
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HbA1c	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.	Week 0, week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Pulse Rate	Change from baseline (week 0) in pulse rate was evaluated at week 26. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Week 0, week 26
Change in Body Weight (kg)	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.	Week 0, week 26
Change in Fasting Plasma Glucose	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.	Week 0, week 26
Change in Mean 7-point SMPG Profile	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.	Week 0, week 26
Change in Mean Postprandial Increment Over All Meals in SMPG	Change from baseline (week 0) to week 26 in the average of the post-prandial increments over all meals. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26
Change in Fasting Insulin - Ratio to Baseline	Change from baseline (week 0) to week 26 in fasting insulin (pmol/L) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product	Week 0, week 26
Change in Fasting Pro-insulin - Ratio to Baseline	Change from baseline (week 0) to week 26 in fasting pro-insulin (pmol/L) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product	Week 0, week 26
Change in Fasting Glucagon - Ratio to Baseline	Change from baseline (week 0) to week 26 in fasting glucagon (pg/mL) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product	Week 0, week 26
Change in HOMA-IR (Insulin Resistance) - Ratio to Baseline	Change from baseline (week 0) to week 26 in homeostatic model assessment index of insulin resistance (HOMA-IR) (%) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26
Change in HOMA-B (Beta-cell Function) - Ratio to Baseline	Change from baseline (week 0) to week 26 in homeostatic model assessment index of beta-cell function (HOMA-B) (%) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26
Change in CRP - Ratio to Baseline	Change from baseline (week 0) to week 26 in C-reactive protein (CRP) (mg/L) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26
Change in Body Weight (%)	Change from baseline (week 0) to week 26 in body weight. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26
Change in BMI	Change from baseline (week 0) to week 26 in body mass index (BMI). Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26
Change in Waist Circumference	Change from baseline (week 0) to week 26 in waist circumference. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26
Change in Fasting Total Cholesterol - Ratio to Baseline	Change from baseline (week 0) to week 26 in fasting total cholesterol (mmol/L) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26
Change in Fasting LDL Cholesterol - Ratio to Baseline	Change from baseline (week 0) to week 26 in fasting low-density lipoprotein (LDL) cholesterol (mmol/L) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26
Change in Fasting HDL Cholesterol - Ratio to Baseline	Change from baseline (week 0) to week 26 in fasting high-density lipoprotein (HDL) cholesterol (mmol/L) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26
Change in Fasting Triglycerides - Ratio to Baseline	Change from baseline (week 0) to week 26 in triglycerides (mmol/L) is presented as ratio to baseline. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26
Participants Who Achieve HbA1c < 7.0 % (53 mmol/Mol) ADA Target (Yes/no)	Participants who achieved HbA1c <7.0% (53 mmol/mol) (American Diabetes Association (ADA) target), at week 26 are presented. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 26
Participants Who Achieve HbA1c ≤ 6.5 % (48 mmol/Mol) AACE Target (Yes/no)	Participants who achieved HbA1c ≤6.5% (48 mmol/mol) (American Association of Clinical Endocrinologists (AACE) target), at week 26 are presented. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 26
Participants Who Achieve Body Weight Loss ≥ 5 % (Yes/no)	Participants who achieved body weight loss more than or equal to 5% of their baseline body weight (yes/no) at week 26 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 26
Participants Who Achieve Body Weight Loss ≥ 10 % (Yes/no)	Participants who achieved body weight loss more than or equal to 10% of their baseline body weight (yes/no) at week 26 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 26
Participants Who Achieve HbA1c < 7.0 % (53 mmol/Mol) Without Hypoglycaemia (Severe or BG-confirmed Symptomatic Hypoglycaemia) and Without Body Weight Gain (Yes/no)	Participants who achieved HbA1c less than 7.0 % without severe or blood glucose (BG) confirmed symptomatic hypoglycaemia and without weight gain (yes/no) at week 26 are presented. Severe hypoglycaemia was defined as an episode requiring assistance of another person to actively administer carbohydrate or glucagon, or take other corrective actions. BG-confirmed symptomatic hypoglycaemia was defined as an episode with plasma glucose value <3.1 mmol/L with symptoms consistent with hypoglycaemia. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product	Week 26
Participants Who Achieve HbA1c Reduction ≥ 1.0% (10.9 mmol/Mol) and Weight Loss ≥ 3% (Yes/no)	Participants who achieved HbA1c reduction more than or equal to 1% of their baseline HbA1c and weight loss of more than or equal to 3% of their baseline body weight (yes/no) at week 26 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 26
Time to Additional Anti-diabetic Medication	Presented results are the number of participants who had taken additional anti-diabetic medication anytime during the period from week 0 to week 26. Additional anti-diabetic medication was defined as any new anti-diabetic medication used for more than 21 days with the initiation at or after randomisation (week 0) and before (planned) end-of-treatment (week 26), and/or intensification of anti-diabetic medication (a more than 20% increase in dose relative to baseline) for more than 21 days with the intensification at or after randomisation and before (planned) end-of-treatment. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Weeks 0-26
Time to Rescue Medication	Presented results are the number of participants who had taken rescue medication anytime during the period from week 0 to week 26. Rescue medication was defined as any new anti-diabetic medication used as add-on to trial product and used for more than 21 days with the initiation at or after randomisation (week 0) and before last day on trial product, and/or intensification of anti-diabetic medication (a more than 20% increase in dose relative to baseline) for more than 21 days with the intensification at or after randomisation and before last day on trial product. Results are based on the data from the on-treatment without rescue medication observation period, which was the time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication or premature trial product discontinuation.	Weeks 0-26
Number of Treatment-emergent Adverse Events (TEAEs)	Treatment emergent adverse events (TEAEs) were recorded from week 0 to week 31 (26-week treatment period + 5-week follow-up period). Adverse events (AEs) with onset during the on-treatment observation period were considered treatment-emergent. On-treatment observation period: Time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Approximately upto week 31
Change in Amylase - Ratio to Baseline	Change from baseline (week 0) to week 26 in amylase (units/litre (U/L)) is presented as ratio to baseline. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Week 0, week 26
Change in Lipase - Ratio to Baseline	Change from baseline (week 0) to week 26 in lipase (U/L) is presented as ratio to baseline. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Week 0, week 26
Change in Systolic Blood Pressure (SBP)	Change from baseline (week 0) in SBP was evaluated at week 26. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Week 0, week 26
Change in Diastolic Blood Pressure (DBP)	Change from baseline (week 0) in DBP was evaluated at week 26. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Week 0, week 26
Change in Electrocardiogram (ECG) Evaluation	Change from baseline (week 0) in ECG was evaluated at week 26. Change from baseline results are presented as shift in findings (normal, abnormal and not clinically significant (NCS) and abnormal and clinically significant (CS)) from week 0 to week 26. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26
Change in Physical Examination	Participants with physical examination findings, normal, abnormal NCS and abnormal CS at baseline (week -2) and week 26 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product. Results are presented for the following examinations: 1) Cardiovascular system; 2) Nervous system (central and peripheral); 3) Gastrointestinal system, incl. mouth; 4) General appearance; 5) Head (ears, eyes, nose), throat, neck; 6) Lymph node palpation; 7) Musculoskeletal system; 8) Respiratory system; 9) Skin; 10) Thyroid gland.	Week 0, week 26
Change in Eye Examination Category	Participants with eye examination (fundoscopy) findings, normal, abnormal NCS and abnormal CS at baseline (week -2), and week 26 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26
Occurrence of Anti-semaglutide Binding Antibodies (Yes/no)	This outcome measure is only applicable for the oral semaglutide treatment arms (3 mg, 7 mg and 14 mg). Number of participants who measured with anti-semaglutide binding antibodies anytime during post-baseline visits (week 0 to week 31) are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Weeks 0-31
Occurrence of Anti-semaglutide Neutralising Antibodies (Yes/no)	This outcome measure is only applicable for the oral semaglutide treatment arms (3 mg, 7 mg and 14 mg). Number of participants who measured with anti-semaglutide neutralising antibodies anytime during post-baseline visits (week 0 to week 31) are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Weeks 0-31
Occurrence of Anti-semaglutide Binding Antibodies Cross Reacting With Native GLP-1 (Yes/no)	This outcome measure is only applicable for the oral semaglutide treatment arms (3 mg, 7 mg and 14 mg). Number of participants who measured with anti-semaglutide binding antibodies cross reacting with native glucagon-like peptide-1 (GLP-1) anytime during post-baseline visits (week 0 to week 31) are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Weeks 0-31
Occurrence of Anti-semaglutide Neutralising Antibodies Cross Reacting With Native GLP-1 (Yes/no)	This outcome measure is only applicable for the oral semaglutide treatment arms (3 mg, 7 mg and 14 mg). Number of participants who measured with anti-semaglutide neutralising antibodies cross reacting with native GLP-1 anytime during post-baseline visits (week 0 to week 31) are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Weeks 0-31
Anti-semaglutide Binding Antibody Levels	This outcome measure is only applicable for the oral semaglutide treatment arms (3 mg, 7 mg and 14 mg). It is based on the data from participants who were measured with anti-semaglutide antibodies anytime during post-baseline visits (week 0 to week 31). Results are presented as percentage of bound radioactivity-labelled semaglutide /total added radioactivity-labelled semaglutide (%B/T). Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Weeks 0-31
Number of Treatment-emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemic Episodes During Exposure to Trial Product	Treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes were recorded during week 0 to week 31 (26-weeks treatment period + 5-weeks follow-up period). Hypoglycaemic episodes with onset during the on-treatment observation period were considered treatment-emergent. On-treatment observation period was defined as the time period when a subject was on treatment with trial product, including any period after initiation of rescue medication. Severe hypoglycaemia was defined as an episode requiring assistance of another person to actively administer carbohydrate or glucagon, or take other corrective actions. BG-confirmed symptomatic hypoglycaemia: Confirmed by a glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.	Weeks 0-31
Participants With Treatment-emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemic Episodes During Exposure to Trial Product	Treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes were recorded from week 0 to week 31 (26-week treatment period + 5-week follow-up period). Hypoglycaemic episodes with onset during the on-treatment observation period were considered treatment-emergent. On-treatment observation period was defined as the time period when a subject was on treatment with trial product, including any period after initiation of rescue medication. Severe hypoglycaemia was defined as an episode requiring assistance of another person to actively administer carbohydrate or glucagon, or take other corrective actions. BG-confirmed symptomatic hypoglycaemia: Confirmed by a glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.	Weeks 0-31
SNAC Plasma Concentrations	This outcome measure is only applicable for the oral semaglutide 3 mg, 7 mg and 14 mg treatment arms. Sodium N-[8-(2-hydroxybenzoyl) amino]caprylate (SNAC) plasma concentrations were measured after 25 and 40 minutes post-dose at weeks 4, 14 and 26. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Weeks 0-26
Semaglutide Plasma Concentrations for Population PK Analysis	This outcome measure is only applicable for the oral semaglutide 3 mg, 7 mg and 14 mg treatment arms. Semaglutide plasma concentrations were measured at weeks 4, 8, 14 and 26. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Weeks 0 - 26
Change in SF-36v2 (Acute Version) Health Survey: Scores From the 8 Domains, the Physical Component Summary (PCS) and the Mental Component Summary (MCS)	SF-36 is a 36-item patient-reported survey of patient health that measures the participant's overall health-related quality of life (HRQoL). SF-36v2™ (acute version) questionnaire measured eight domains of functional health and well-being as well as two component summary scores (physical component summary (PCS) and mental component summary (MCS)). The 0-100 scale scores (where higher scores indicated a better HRQoL) from the SF-36 were converted to norm-based scores to enable a direct interpretation in relation to the distribution of the scores in the 2009 U.S. general population. In the metric of norm-based scores, 50 and 10 corresponds to the mean and standard deviation respectively of the 2009 U.S. general population. Change from baseline (week 0) in the sub-domain scores and component summary (PCS and MCS) scores were evaluated at week 26. A positive change score indicates an improvement since baseline. Results are based on the data from the in-trial observation period.	Week 0, week 26
IWQOL-Lite Clinical Trial Version: Total Score of the 22 Items (Used for Validation of the Questionnaire)	The Impact of Weight on Quality of Life Clinical Trials Version (IWQOL-Lite-CT) is designed to assess the impact of changes in weight on patients' quality of life within the context of clinical trials. IWQOL-Lite-CT is a 22-item questionnaire-based instrument used to assess the impact of body weight changes on participant's overall health-related quality of life (HRQoL). All IWQOL-Lite-CT composite scores range from 0 to 100, with higher scores reflecting better levels of functioning. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 0, week 26
PGI-S Item: Scores of the Two Individual Items (Used for Validation of the IWQOL Questionnaire)	Patient global impression of status (PGI-S) is a 2-item questionnaire used to assess the participant's impression of physical functioning and mental health status during the clinical trial. The PGI-S contains two items evaluated on a 5-point graded response scale. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 26
PGI-C Item: Scores of the Two Individual Items (Used for Validation of the IWQOL Questionnaire)	Patient global impression of change (PGI-C) is a 2-item questionnaire used to assess the participant's impression of change from baseline in physical functioning and mental health status. The PGI-C contains two items evaluated on a 7-point graded response scale. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.	Week 26

Collaborators and Investigators

• Sponsor: Novo Nordisk A/S

Publications and helpful links

General Publications

• Husain M, Bain SC, Holst AG, Mark T, Rasmussen S, Lingvay I. Effects of semaglutide on risk of cardiovascular events across a continuum of cardiovascular risk: combined post hoc analysis of the SUSTAIN and PIONEER trials. Cardiovasc Diabetol. 2020 Sep 30;19(1):156. doi: 10.1186/s12933-020-01106-4.
• Mosenzon O, Capehorn MS, De Remigis A, Rasmussen S, Weimers P, Rosenstock J. Impact of semaglutide on high-sensitivity C-reactive protein: exploratory patient-level analyses of SUSTAIN and PIONEER randomized clinical trials. Cardiovasc Diabetol. 2022 Sep 2;21(1):172. doi: 10.1186/s12933-022-01585-7.
• Thethi TK, Pratley R, Meier JJ. Efficacy, safety and cardiovascular outcomes of once-daily oral semaglutide in patients with type 2 diabetes: The PIONEER programme. Diabetes Obes Metab. 2020 Aug;22(8):1263-1277. doi: 10.1111/dom.14054. Epub 2020 May 13.
• Husain M, Bain SC, Jeppesen OK, Lingvay I, Sorrig R, Treppendahl MB, Vilsboll T. Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk. Diabetes Obes Metab. 2020 Mar;22(3):442-451. doi: 10.1111/dom.13955. Epub 2020 Feb 5.
• Aroda VR, Bauer R, Christiansen E, Haluzik 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. doi: 10.1111/dom.14710. Epub 2022 May 9.
• Araki E, Terauchi Y, Watada H, Deenadayalan S, Christiansen E, Horio H, Kadowaki T. Efficacy and safety of oral semaglutide in Japanese patients with type 2 diabetes: A post hoc subgroup analysis of the PIONEER 1, 3, 4 and 8 trials. Diabetes Obes Metab. 2021 Dec;23(12):2785-2794. doi: 10.1111/dom.14536. Epub 2021 Sep 27.
• 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.
• 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.
• Aroda VR, Rosenstock J, Terauchi Y, Altuntas Y, Lalic NM, Morales Villegas EC, Jeppesen OK, Christiansen E, Hertz CL, Haluzik M; PIONEER 1 Investigators. PIONEER 1: Randomized Clinical Trial of the Efficacy and Safety of Oral Semaglutide Monotherapy in Comparison With Placebo in Patients With Type 2 Diabetes. Diabetes Care. 2019 Sep;42(9):1724-1732. doi: 10.2337/dc19-0749. Epub 2019 Jun 11.
• Gorst-Rasmussen A, Tarp-Johansen MJ. Fast tipping point sensitivity analyses in clinical trials with missing continuous outcomes under multiple imputation. J Biopharm Stat. 2022 Nov 2;32(6):942-953. doi: 10.1080/10543406.2022.2058525. Epub 2022 Jun 2.

Helpful Links

• Clinical Trials at Novo Nordisk

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2016
• Primary Completion (Actual): October 30, 2017
• Study Completion (Actual): December 8, 2017

Study Registration Dates

• First Submitted: September 15, 2016
• First Submitted That Met QC Criteria: September 15, 2016
• First Posted (Estimate): September 20, 2016

Study Record Updates

• Last Update Posted (Actual): July 20, 2022
• Last Update Submitted That Met QC Criteria: July 11, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: NN9924-4233; 2015-005622-19 (EudraCT Number); U1111-1177-5112 (Other Identifier: WHO); JapicCTI-163384 (Other Identifier: JapicCTI)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: According to the Novo Nordisk disclosure commitment on novonordisk-trials.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No