Efficacy and Safety of Oral Semaglutide Versus Placebo in Subjects With Type 2 Diabetes Mellitus Treated With Insulin (PIONEER 8)

Efficacy and Safety of Oral Semaglutide Versus Placebo in Subjects With Type 2 Diabetes Mellitus Treated With Insulin. A 52-week, Randomised, Double-blind, Placebo-controlled Trial (PIONEER 8 - Insulin add-on)

This trial is conducted globally. The aim of the trial is to investigate the efficacy and safety of oral semaglutide versus placebo in subjects with Type 2 Diabetes Mellitus treated with insulin. All subjects should continue their pre-trial insulin therapy (basal, basal-bolus or premixed regimen including combinations of soluble insulins) throughout the trial. Subjects treated with metformin in addition to insulin treatment must continue their metformin treatment throughout the entire trial.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 731
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 3P4
      • Novo Nordisk Investigational Site
  • New Brunswick
    • Moncton, New Brunswick, Canada, E1G 1A7
      • Novo Nordisk Investigational Site
  • Ontario
    • Brampton, Ontario, Canada, L6S 0C6
      • Novo Nordisk Investigational Site
    • Etobicoke, Ontario, Canada, M9W 1P1
      • Novo Nordisk Investigational Site
    • London, Ontario, Canada, N6G 2M1
      • Novo Nordisk Investigational Site
    • Toronto, Ontario, Canada, M5T 3L9
      • Novo Nordisk Investigational Site
    • Waterloo, Ontario, Canada, N2J 1C4
      • Novo Nordisk Investigational Site
• France
  • Besançon cedex, France, 25030
    • Novo Nordisk Investigational Site
  • Bourgoin-jallieu, France, 38302
    • Novo Nordisk Investigational Site
  • Brest, France, 29200
    • Novo Nordisk Investigational Site
  • LA ROCHE-sur-YON cedex 9, France, 85295
    • Novo Nordisk Investigational Site
  • LA ROCHELLE cedex, France, 17019
    • Novo Nordisk Investigational Site
  • Le Coudray, France, 28630
    • Novo Nordisk Investigational Site
  • Le Creusot, France, 71200
    • Novo Nordisk Investigational Site
  • Narbonne, France, 11108
    • Novo Nordisk Investigational Site
  • Paris, France, 75014
    • Novo Nordisk Investigational Site
  • Saint Herblain, France, 44800
    • Novo Nordisk Investigational Site
  • TOULOUSE cedex, France, 31054
    • Novo Nordisk Investigational Site
  • Venissieux, France, 69200
    • Novo Nordisk Investigational Site
• Greece
  • Athens, Greece, GR-17562
    • Novo Nordisk Investigational Site
  • Athens, Greece, GR-11527
    • Novo Nordisk Investigational Site
  • Ioannina, Greece, 45500
    • Novo Nordisk Investigational Site
  • Larissa, Greece, GR-41110
    • Novo Nordisk Investigational Site
  • Piraeus, Greece, GR-18536
    • Novo Nordisk Investigational Site
  • Thessaloniki, Greece, GR-54649
    • Novo Nordisk Investigational Site
• India
  • Kolkata, India, 700020
    • Novo Nordisk Investigational Site
  • Gujarat
    • Ahmedabad, Gujarat, India, 380007
      • Novo Nordisk Investigational Site
  • Karnataka
    • Bangalore, Karnataka, India, 560 017
      • Novo Nordisk Investigational Site
  • Kerala
    • Kozhikode, Kerala, India, 673017
      • Novo Nordisk Investigational Site
  • Madhya Pradesh
    • Indore, Madhya Pradesh, India, 452010
      • Novo Nordisk Investigational Site
  • Maharashtra
    • Mumbai, Maharashtra, India, 400008
      • Novo Nordisk Investigational Site
    • Mumbai, Maharashtra, India, 400010
      • Novo Nordisk Investigational Site
    • Pune, Maharashtra, India, 411001
      • Novo Nordisk Investigational Site
  • New Delhi
    • New Dehli, New Delhi, India, 110029
      • Novo Nordisk Investigational Site
  • Rajasthan
    • Jaipur, Rajasthan, India, 302004
      • Novo Nordisk Investigational Site
  • Tamil Nadu
    • Chennai, Tamil Nadu, India, 600086
      • Novo Nordisk Investigational Site
  • West Bengal
    • Kolkata, West Bengal, India, 700054
      • Novo Nordisk Investigational Site
• Japan
  • Amagasaki-shi, Hyogo, Japan, 661-0002
    • Novo Nordisk Investigational Site
  • Chuo-ku, Tokyo, Japan, 103-0002
    • Novo Nordisk Investigational Site
  • Ebina-shi, Kanagawa, Japan, 243-0432
    • Novo Nordisk Investigational Site
  • Iruma-shi, Saitama, Japan, 358-0011
    • Novo Nordisk Investigational Site
  • Kanagawa, Japan, 247-0055
    • Novo Nordisk Investigational Site
  • Kumamoto, Japan, 862-0976
    • Novo Nordisk Investigational Site
  • Kumamoto-shi, Kumamoto, Japan, 860-0811
    • Novo Nordisk Investigational Site
  • Miyazaki, Japan, 880-0034
    • Novo Nordisk Investigational Site
  • Naka-shi, Japan, 311 0113
    • Novo Nordisk Investigational Site
  • Osaka, Japan, 569-1045
    • Novo Nordisk Investigational Site
  • Saga-shi, Saga, Japan, 849-0937
    • Novo Nordisk Investigational Site
  • Sapporo-shi, Japan, 062 0007
    • Novo Nordisk Investigational Site
  • Shimotsuke-shi, Tochigi, Japan, 329-0433
    • Novo Nordisk Investigational Site
  • Shizuoka-shi, Shizuoka, Japan, 424-0853
    • Novo Nordisk Investigational Site
  • 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, 105-8471
    • Novo Nordisk Investigational Site
  • Ube-shi, Yamaguchi, Japan, 755-0046
    • Novo Nordisk Investigational Site
• Mexico
  • Durango, Mexico, 34000
    • Novo Nordisk Investigational Site
  • San Luis Potosi, Mexico, 78200
    • Novo Nordisk Investigational Site
• Poland
  • Bialystok, Poland, 15-404
    • Novo Nordisk Investigational Site
  • Lublin, Poland, 20-044
    • Novo Nordisk Investigational Site
  • Poznan, Poland, 60-589
    • Novo Nordisk Investigational Site
  • Pulawy, Poland, 24-100
    • Novo Nordisk Investigational Site
• Puerto Rico
  • Manati, Puerto Rico, 00674
    • Novo Nordisk Investigational Site
• Russian Federation
  • Kazan, Russian Federation, 420073
    • Novo Nordisk Investigational Site
  • Moscow, Russian Federation, 115478
    • Novo Nordisk Investigational Site
  • Penza, Russian Federation, 440026
    • Novo Nordisk Investigational Site
  • Saint-Petersburg, Russian Federation, 191119
    • Novo Nordisk Investigational Site
  • Saint-Petersburg, Russian Federation, 194354
    • Novo Nordisk Investigational Site
  • St. Petersburg, Russian Federation, 194354
    • Novo Nordisk Investigational Site
• United States
  • Alabama
    • Anniston, Alabama, United States, 36207
      • Novo Nordisk Investigational Site
    • Birmingham, Alabama, United States, 35211
      • Novo Nordisk Investigational Site
  • Arizona
    • Fountain Hills, Arizona, United States, 85268
      • Novo Nordisk Investigational Site
    • Glendale, Arizona, United States, 85308
      • Novo Nordisk Investigational Site
    • Mesa, Arizona, United States, 85213
      • Novo Nordisk Investigational Site
    • Phoenix, Arizona, United States, 85037
      • Novo Nordisk Investigational Site
    • Tucson, Arizona, United States, 85741
      • Novo Nordisk Investigational Site
    • Tucson, Arizona, United States, 85723-0001
      • Novo Nordisk Investigational Site
  • California
    • Anaheim, California, United States, 92801
      • Novo Nordisk Investigational Site
    • Fresno, California, United States, 93720
      • Novo Nordisk Investigational Site
    • Los Angeles, California, United States, 90057
      • Novo Nordisk Investigational Site
    • Los Angeles, California, United States, 90017
      • Novo Nordisk Investigational Site
    • Riverside, California, United States, 92506
      • Novo Nordisk Investigational Site
    • Van Nuys, California, United States, 91405
      • Novo Nordisk Investigational Site
    • Vista, California, United States, 92083
      • Novo Nordisk Investigational Site
  • Colorado
    • Colorado Springs, Colorado, United States, 80904
      • Novo Nordisk Investigational Site
    • Denver, Colorado, United States, 80246
      • Novo Nordisk Investigational Site
  • Florida
    • Hialeah, Florida, United States, 33016
      • Novo Nordisk Investigational Site
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Novo Nordisk Investigational Site
  • Illinois
    • Chicago, Illinois, United States, 60607
      • Novo Nordisk Investigational Site
  • Indiana
    • Franklin, Indiana, United States, 46131
      • Novo Nordisk Investigational Site
  • Kentucky
    • Lexington, Kentucky, United States, 40503
      • Novo Nordisk Investigational Site
    • Paducah, Kentucky, United States, 42003
      • Novo Nordisk Investigational Site
  • Louisiana
    • Metairie, Louisiana, United States, 70002
      • Novo Nordisk Investigational Site
    • Natchitoches, Louisiana, United States, 71457-5881
      • Novo Nordisk Investigational Site
  • Maryland
    • Hyattsville, Maryland, United States, 20782
      • Novo Nordisk Investigational Site
    • Rockville, Maryland, United States, 20852
      • Novo Nordisk Investigational Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Novo Nordisk Investigational Site
  • Michigan
    • Troy, Michigan, United States, 48098
      • Novo Nordisk Investigational Site
  • Nevada
    • Henderson, Nevada, United States, 89052-2649
      • Novo Nordisk Investigational Site
    • Las Vegas, Nevada, United States, 89148
      • Novo Nordisk Investigational Site
  • New York
    • West Seneca, New York, United States, 14224
      • Novo Nordisk Investigational Site
  • North Carolina
    • Asheville, North Carolina, United States, 28803
      • Novo Nordisk Investigational Site
    • Chapel Hill, North Carolina, United States, 27517
      • Novo Nordisk Investigational Site
  • Ohio
    • Cincinnati, Ohio, United States, 45245
      • Novo Nordisk Investigational Site
    • Dayton, Ohio, United States, 45439
      • Novo Nordisk Investigational Site
  • Pennsylvania
    • Beaver, Pennsylvania, United States, 15009
      • Novo Nordisk Investigational Site
    • Lansdale, Pennsylvania, United States, 19446-1002
      • Novo Nordisk Investigational Site
  • South Carolina
    • Summerville, South Carolina, United States, 29485
      • Novo Nordisk Investigational Site
  • Tennessee
    • Chattanooga, Tennessee, United States, 37411
      • Novo Nordisk Investigational Site
    • Kingsport, Tennessee, United States, 37660-4652
      • Novo Nordisk Investigational Site
  • Texas
    • Austin, Texas, United States, 78731
      • Novo Nordisk Investigational Site
    • Dallas, Texas, United States, 75390-9302
      • Novo Nordisk Investigational Site
    • Dallas, Texas, United States, 75251
      • Novo Nordisk Investigational Site
    • Houston, Texas, United States, 77090
      • Novo Nordisk Investigational Site
    • Mesquite, Texas, United States, 75149
      • Novo Nordisk Investigational Site
    • Midland, Texas, United States, 79707
      • Novo Nordisk Investigational Site
    • Round Rock, Texas, United States, 78681
      • Novo Nordisk Investigational Site
  • Utah
    • Murray, Utah, United States, 84123
      • Novo Nordisk Investigational Site
  • Virginia
    • Winchester, Virginia, United States, 22601
      • Novo Nordisk Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 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. - Diagnosed with type 2 diabetes mellitus 90 days or more prior to the day of screening. - HbA1c (glycosylated haemoglobin) of 7.0-9.5% (53-80 mmol/mol) (both inclusive). - Stable treatment with one of the following insulin regimens (minimum 10 IU/day) 90 or more days prior to the day of screening. Maximum 20% change in total daily dose is acceptable: (1) Basal insulin alone or (2) Basal and bolus insulin in any combination or (3) Premixed insulin including combinations of soluble insulins 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 Greece only: adequate contraceptive measures are defined as combined hormonal contraception (containing oestrogen and progesterone), which suppress ovulation (oral, intravaginal, percutaneous), progesterone-only hormonal contraception which suppress ovulation (oral, injectable, implantable), intrauterine device, hormone-releasing intrauterine system, bilateral tubal occlusion, partner with vasectomy, sexual abstinence. For Japan only: Adequate contraceptive measures are abstinence (not having sex), diaphragm, condom (by the partner), intrauterine device, sponge, spermicide or oral contraceptives. For Canada only: adequate contraceptive measures are defined as combined hormonal contraception (containing oestrogen and progesterone), which suppress ovulation (oral, intravaginal, percutaneous), progesterone-only hormonal contraception which suppress ovulation (oral, injectable, implantable), intrauterine device, hormone-releasing intrauterine system, bilateral tubal occlusion, partner with vasectomy, sexual abstinence - Any disorder, which in the investigator's opinion might jeopardise subject's safety or compliance with the protocol. - Family or personal history of Multiple Endocrine Neoplasia Type 2 (MEN 2) or Medullary Thyroid Carcinoma (MTC). - History of pancreatitis (acute or chronic). - History of major surgical procedures involving the stomach and potentially affecting absorption of trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery). - Any of the following: myocardial infarction (MI), stroke or hospitalisation for unstable angina or transient ischaemic attack within the past 180 days prior to the day of screening and randomisation. - Classified as being in New York Heart Association (NYHA) Class IV. - Planned coronary, carotid or peripheral artery revascularisation known on the day of screening. - Renal impairment defined as estimated Glomerular Filtration Rate (eGFR) less than 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 change of insulin treatment for acute illness for a total of 14 days or less. - Known hypoglycaemic unawareness according to Clarke's questionnaire. - 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). - Subjects with alanine aminotransferase (ALT) more than 2.5 x upper normal limit (UNL).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: placebo; Oral semaglutide placebo administered once-daily for 52 weeks as an add-on to the subjects' pre-trial insulin treatment
Experimental: Semaglutide 3 mg	Drug: semaglutide; Oral semaglutide administered once-daily for 52 weeks as an add-on to the subjects' pre-trial insulin treatment; Drug: semaglutide; Oral semaglutide (3 mg followed by 7 mg) administered once-daily for 52 weeks as an add-on to the subjects' pre-trial insulin treatment; Drug: semaglutide; Oral semaglutide (3 mg followed by 7 mg and finally 14 mg) administered once-daily for 52 weeks as an add-on to the subjects' pre-trial insulin treatment
Experimental: Semaglutide 3 mg + 7 mg	Drug: semaglutide; Oral semaglutide administered once-daily for 52 weeks as an add-on to the subjects' pre-trial insulin treatment; Drug: semaglutide; Oral semaglutide (3 mg followed by 7 mg) administered once-daily for 52 weeks as an add-on to the subjects' pre-trial insulin treatment; Drug: semaglutide; Oral semaglutide (3 mg followed by 7 mg and finally 14 mg) administered once-daily for 52 weeks as an add-on to the subjects' pre-trial insulin treatment
Experimental: Semaglutide 3 mg + 7 mg + 14 mg	Drug: semaglutide; Oral semaglutide administered once-daily for 52 weeks as an add-on to the subjects' pre-trial insulin treatment; Drug: semaglutide; Oral semaglutide (3 mg followed by 7 mg) administered once-daily for 52 weeks as an add-on to the subjects' pre-trial insulin treatment; Drug: semaglutide; Oral semaglutide (3 mg followed by 7 mg and finally 14 mg) administered once-daily for 52 weeks as an add-on to the subjects' pre-trial insulin treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HbA1c (Week 26)	Change from baseline (week 0) in glycosylated haemoglobin (HbA1c) was evaluated at week 26. The endpoint was evaluated based on data from the in-trial observation period. In-trial observation period started at the date of randomisation and included the period after initiation of rescue medication and/or premature trial product discontinuation, if any. The endpoint was also analysed based on data from the on-treatment without rescue medication observation period. On-treatment without rescue medication observation period started at the date of the first dose of trial product and includes the period after initiation of rescue medication, if any, and excludes the period after premature trial discontinuation, if any.	Week 0, week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Eye Examination Category	Participants with eye examination (fundoscopy) findings, normal, abnormal NCS and abnormal CS at baseline (week -2) and week 52 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product.	Week -2, week 52
Change in Body Weight (Week 26)	Change from baseline (week 0) in body weight was evaluated at week 26. The endpoint was evaluated based on data from the in-trial observation period. In-trial observation period started at the date of randomisation and included the period after initiation of rescue medication and/or premature trial product discontinuation, if any. The endpoint was also evaluated based on data from the on-treatment without rescue medication observation period. It started at the date of first dose of trial product and excluded the period after initiation of rescue medication and/or premature trial product discontinuation, if any.	Week 0, week 26
Change in HbA1c (Week 52)	Change from baseline (week 0) in HbA1c to week 52. The endpoint was evaluated based on data from the in-trial observation period. In trial observation period started at the date of randomisation and included the period after initiation of rescue medication and/or premature trial product discontinuation, if any.	Week 0, week 52
Change in Body Weight (kg) (Week 52)	Change from baseline (week 0) in body weight to week 52. The endpoint was evaluated based on data from the in-trial observation period. In trial observation period started at the date of randomisation and included the period after initiation of rescue medication and/or premature trial product discontinuation, if any.	Week 0, week 52
Change in Fasting Plasma Glucose (FPG)	Change from baseline (week 0) in FPG to week 26 and week 52. The endpoint was evaluated based on data from the in-trial observation period. In trial observation period started at the date of randomisation and included the period after initiation of rescue medication and/or premature trial product discontinuation, if any.	Week 0, week 26, week 52
Change in Self-measured Plasma Glucose (SMPG) Mean 7-point Profile	Change from baseline (week 0) in self-measured plasma glucose (SMPG) mean 7-point profile to week 26 and week 52. 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 endpoint was evaluated based on data from the in-trial observation period. In trial observation period started at the date of randomisation and included the period after initiation of rescue medication and/or premature trial product discontinuation, if any.	Week 0, week 26, week 52
Change in SMPG Mean Postprandial Increment Over All Meals	Change from baseline (week 0) in SMPG mean postprandial increment over all meals to week 26 and week 52. The endpoint was evaluated based on data from the in-trial observation period. In trial observation period started at the date of randomisation and included the period after initiation of rescue medication and/or premature trial product discontinuation, if any.	Week 0, week 26, week 52
Change in Body Weight (Percentage)	Relative change from baseline (week 0) in body weight (%) was evaluated at weeks 26 and 52.The endpoint was evaluated based on data from the in-trial observation period. In trial observation period started at the date of randomisation and included the period after initiation of rescue medication and/or premature trial product discontinuation, if any.	Week 0, week 26, week 52
Change in Body Mass Index	Change from baseline (week 0) in body mass index (BMI) was evaluated at weeks 26 and 52. BMI was calculated based on body weight and height based on the formula: BMI kg/m^2 = body weight (kg)/(Height (m) x Height (m)). Data based on in-trial observation period is presented. In trial observation period started at the date of randomisation and included the period after initiation of rescue medication and/or premature trial product discontinuation, if any.	Week 0, week 26, week 52
Change in Waist Circumference	Change from baseline (week 0) in waist circumference was evaluated at weeks 26 and 52.The endpoint was evaluated based on data from the in-trial observation period. In trial observation period started at the date of randomisation and included the period after initiation of rescue medication and/or premature trial product discontinuation, if any.	Week 0, week 26, week 52
Change in Total Cholesterol - Ratio to Baseline	Change from baseline in total cholesterol (mmol/L) is presented as ratio to baseline at week 26 and week 52. Results are based on the data from the in-trial observation period. In trial observation period started at the date of randomisation and included the period after initiation of rescue medication and/or premature trial product discontinuation, if any.	Week 0, week 26, week 52
Change in LDL Cholesterol - Ratio to Baseline	Change from baseline in LDL cholesterol (mmol/L) is presented as ratio to baseline at week 26 and week 52. Results are based on the data from the in-trial observation period. In trial observation period started at the date of randomisation and included the period after initiation of rescue medication and/or premature trial product discontinuation, if any.	Week 0, week 26, week 52
Change in HDL Cholesterol - Ratio to Baseline	Change from baseline (week 0) in HDL cholesterol (mmol/L) at weeks 26 and 52 is presented as ratio to baseline. Results are based on the data from the in-trial observation period. In trial observation period started at the date of randomisation and included the period after initiation of rescue medication and/or premature trial product discontinuation, if any.	Week 0, week 26, week 52
Change in Triglycerides - Ratio to Baseline	Change from baseline (week 0) in triglycerides (mmol/L) at weeks 26 and 52 is presented as ratio to baseline. Results are based on the data from the in-trial observation period. In trial observation period started at the date of randomisation and included the period after initiation of rescue medication and/or premature trial product discontinuation, if any.	Week 0, week 26, week 52
Change in Total Daily Insulin Dose	Change from baseline in total daily insulin dose to week 26 and week 52 is presented. Results are based on the data from the in-trial observation period. In trial observation period started at the date of randomisation and included the period after initiation of rescue medication and/or premature trial product discontinuation, if any.	Week 0, week 26, week 52
Participants Who Achieve: HbA1c < 7.0% (53 mmol/Mol) (American Diabetes Association (ADA) Target) (Yes/no)	Number of particpants achieving HbA1c < 7.0 % (53 mmol/mol) according to American Diabetes Association (ADA) target, at week 26 and week 52. The endpoint was evaluated based on data from the in-trial observation period. In trial observation period started at the date of randomisation and included the period after initiation of rescue medication and/or premature trial product discontinuation, if any.	Week 26, week 52
Participants Who Achieve: HbA1c ≤ 6.5% (48 mmol/Mol) (AACE Target) (Yes/no)	Number of participants achieving HbA1c ≤ 6.5% (48 mmol/mol) according to American Association of Clinical Endocrinologists (AACE) target, at week 26 and week 52. The endpoint was evaluated based on data from the in-trial observation period. In trial observation period started at the date of randomisation and included the period after initiation of rescue medication and/or premature trial product discontinuation, if any.	Week 26, week 52
Participants Who Achieve Body Weight Loss ≥5% (Yes/no)	Participants who achieved weight loss more than or equal to 5% of their baseline body weight (yes/no) at weeks 26 and 52 are presented. The endpoint was evaluated based on data from the in-trial observation period. In trial observation period started at the date of randomisation and included the period after initiation of rescue medication and/or premature trial product discontinuation, if any.	Week 26, week 52
Participants Who Achieve Body Weight Loss ≥10% (Yes/no)	Participants who achieved weight loss more than or equal to 10% of their baseline body weight (yes/no) at weeks 26 and 52 are presented. The endpoint was evaluated based on data from the in-trial observation period. In trial observation period started at the date of randomisation and included the period after initiation of rescue medication and/or premature trial product discontinuation, if any. Results are based on the data from the in-trial observation period, which started at the date of randomisation and included the period after initiatiion of of rescue medication and/or premature trial product discontinuation, if any.	Week 26, week 52
Participants Who Achieve HbA1c <7.0 % (53 mmol/Mol) Without Hypoglycaemia (Severe or BG Confirmed Symptomatic Hypoglycaemia) and no Weight Gain (Yes/no)	Participants who achieved HbA1c less than 7.0 % without severe or blood glucose (BG) confirmed symptomatic hypoglycaemia and without weight gain (yes/no) at weeks 26 and 52 are presented. Severe hypoglycaemia was defined as an episode requiring assistance of another person to actively administer carbohydrate or glucagon, or take other corrective actions. BG-confirmed symptomatic hypoglycaemia was defined as an episode with plasma glucose value <3.1 mmol/L with symptoms consistent with hypoglycaemia. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product.	Week 26, week 52
Participants Who Achieve HbA1c Reduction ≥1% (10.9 mmol/Mol) and Weight Loss ≥3% (Yes/no)	Participants who achieved HbA1c reduction more than or equal to 1% of their baseline HbA1c and weight loss of more than or equal to 3% of their baseline body weight (yes/no) at weeks 26 and 52 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product.	Week 26, week 52
Time to Additional Anti-diabetic Medication	Presented results are the number of participants who had taken additional anti-diabetic medication anytime during the periods, from week 0 to week 26 and week 0 to week 52. Additional anti-diabetic medication was defined as 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 52), and/or intensification of anti-diabetic medication (a more than 20% increase in dose relative to baseline) for more than 21 days with the intensification at or after randomisation and before (planned) end-of-treatment. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product.	Weeks 0-52
Time to Rescue Medication	Presented results are the number of participants who had taken rescue medication anytime during the periods, from week 0 to week 26 and week 0 to week 52. Rescue medication was defined as use of new anti-diabetic medication as add-on to trial product and used for more than 21 days with the initiation at or after randomisation (week 1) and before last day on trial product, and/or intensification of anti-diabetic medication (a more than 20% increase in dose relative to baseline) for more than 21 days with the intensification at or after randomisation and before last day on trial product. Results are based on the data from the on-treatment without rescue medication observation period, which was the time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication and/or premature trial product discontinuation.	Weeks 0-52
Number of Treatment-emergent Adverse Events (TEAEs) During Exposure to Trial Product	Treatment emergent adverse events (TEAEs) were recorded from week 0 to week 57 (52-week treatment period plus the 5-week follow-up period). Adverse events (AEs) with onset during the on-treatment observation period were considered treatment-emergent. On-treatment observation period was defined as the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Weeks 0-57
Number of Treatment-emergent Severe or BG-confirmed Symptomatic Hypoglycaemic Episodes	Treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes were recorded during week 0 to week 57 (52-week treatment period plus the 5-week follow-up period). Hypoglycaemic episodes with onset during the on-treatment observation period were considered treatment-emergent. On-treatment observation period was defined as the time period when a subject was on treatment with trial product, including any period after initiation of rescue medication. Severe hypoglycaemia was defined as an episode requiring assistance of another person to actively administer carbohydrate or glucagon, or take other corrective actions. BG-confirmed symptomatic hypoglycaemia: Confirmed by a glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.	Weeks 0-57
Participants With Treatment-emergent Severe or BG-confirmed Symptomatic Hypoglycaemic Episodes	Treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes were recorded during week 0 to week 57 (52-week treatment period plus the 5-week follow-up period). Hypoglycaemic episodes with onset during the on-treatment observation period were considered treatment-emergent. On-treatment observation period was defined as the time period when a subject was on treatment with trial product, including any period after initiation of rescue medication. Severe hypoglycaemia was defined as an episode requiring assistance of another person to actively administer carbohydrate or glucagon, or take other corrective actions. BG-confirmed symptomatic hypoglycaemia: Confirmed by a glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.	Weeks 0-57
Change in Amylase - Ratio to Baseline	Change from baseline (week 0) in amylase (units/litre (U/L)) at weeks 26 and 52 is presented as ratio to baseline. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Week 0, week 26, week 52
Change in Lipase - Ratio to Baseline	Change from baseline (week 0) in lipase (units/litre (U/L)) at weeks 26 and 52 is presented as ratio to baseline. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication	Week 0, week 26, week 52
Change in Pulse Rate	Change from baseline (week 0) in pulse rate was evaluated at weeks 26 and 52 Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Week 0, week 26, week 52
Change in SBP and DBP	Change from baseline (week 0) in systolic blood pressure (SBP) and diastolic blood pressure (DBP) was evaluated at weeks 26 and 52 Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Week 0, week 26, week 52
Change in ECG Evaluation	Change from baseline (week 0) in electrocardiogram (ECG) was evaluated at weeks 26 and 52. Change from baseline results are presented as shift in findings (normal; abnormal and not clinically significant (NCS); abnormal and clinically significant (CS)) from week 0 to week 26 and 52. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product.	Week 0, week 26, week 52
Change in Physical Examination	Participants with physical examination findings, normal, abnormal NCS and abnormal CS at baseline (weeks -2) and weeks 52 presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. Results are presented for the following examinations: 1) Cardiovascular system; 2) Central and peripheral nervous system; 3) Gastrointestinal system, incl. mouth; 4) General appearance; 5) Head, ears, eyes, nose, throat, neck; 6) Lymph node palpation; 7) Musculoskeletal system; 8) Respiratory system; 9) Skin; 10) Thyroid gland.	Week -2, week 52
Semaglutide Plasma Concentrations for Population PK Analyses	This outcome measure is only applicable for the oral semaglutide treatment arms (3 mg, 7 mg and 14 mg). Semaglutide plasma concentrations were measured at week 4, 14, 26, 38 and 52. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.	Weeks 0-52
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 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
Change in IWQoL-Lite-CT: Total Score and Scores From the 4 Domains	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. The items of the IWQOL-Lite-CT pertain to physical functioning (physical, physical function and pain/discomfort) and psychosocial domains and all items employ a 5-point graded response scale (never, rarely, sometimes, usually, always; or not at all true, a little true, moderately true, mostly true, completely true). 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 started at the date of randomisation and included the period after initiation of rescue medication and/or premature trial product discontinuation, if any.	Week 0, week 26, week 52
Change in DTSQs: Individual Items and Treatment Satisfaction Score (6 of the 8 Items Summed)	Change from baseline (week 0) in Diabetes Treatment Satisfaction Questionnaire - status version (DTSQs) was evaluated at week 26 and week 52. The DTSQs items are scored on a 7-point graded response scale ranging from 6 to 0. Higher scores indicate higher levels of treatment satisfaction for DTSQs items 1, 4 -8. For items 2 and 3 a higher score indicates a higher patient perceived experience of hyperglycaemia and hypoglycaemia, respectively. Thus, lower scores indicate a perception of blood glucose levels being "none of the time" unacceptably high (item 2) or low (item 3). The domain score of total treatment satisfaction (total treatment satisfaction score) was computed by adding the six items scores 1, 4-8. The score has a minimum of 0 and a maximum of 36. A higher treatment satisfaction score indicates a higher level of treatment satisfaction.	Week 0, week 26, week 52

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.
• 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.
• Pratley RE, Crowley MJ, Gislum M, Hertz CL, Jensen TB, Khunti K, Mosenzon O, Buse JB. Oral Semaglutide Reduces HbA1c and Body Weight in Patients with Type 2 Diabetes Regardless of Background Glucose-Lowering Medication: PIONEER Subgroup Analyses. Diabetes Ther. 2021 Apr;12(4):1099-1116. doi: 10.1007/s13300-020-00994-9. Epub 2021 Mar 4.
• Zinman B, Aroda VR, Buse JB, Cariou B, Harris SB, Hoff ST, Pedersen KB, Tarp-Johansen MJ, Araki E; PIONEER 8 Investigators. Efficacy, Safety, and Tolerability of Oral Semaglutide Versus Placebo Added to Insulin With or Without Metformin in Patients With Type 2 Diabetes: The PIONEER 8 Trial. Diabetes Care. 2019 Dec;42(12):2262-2271. doi: 10.2337/dc19-0898. Epub 2019 Sep 17.

Study record dates

Study Major Dates

• Study Start (Actual): February 2, 2017
• Primary Completion (Actual): January 18, 2018
• Study Completion (Actual): August 22, 2018

Study Registration Dates

• First Submitted: January 12, 2017
• First Submitted That Met QC Criteria: January 12, 2017
• First Posted (Estimate): January 13, 2017

Study Record Updates

• Last Update Posted (Actual): March 2, 2020
• Last Update Submitted That Met QC Criteria: February 14, 2020
• Last Verified: February 1, 2020

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: NN9924-4280; 2016-000988-16 (EudraCT Number); U1111-1180-3637 (Other Identifier: World Health Organization (WHO)); JapicCTI-173508 (Other Identifier: JAPIC)

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