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

• ClinicalTrials.gov Identifier: NCT03021187
• Recruitment Status: Completed
• First Posted: January 13, 2017
• Results First Posted: November 7, 2019
• Last Update Posted: March 2, 2020
• Sponsor: Novo Nordisk A/S
• Information provided by (Responsible Party): Novo Nordisk A/S

Study Description

Brief Summary:

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.

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 731 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Oral Semaglutide Versus Placebo in Subjects With Type 2 Diabetes Mellitus Treated With Insulin. A 52-week, Randomised, Double-blind, Placebo-controlled Trial (PIONEER 8 - Insulin add-on)
• Actual Study Start Date: February 2, 2017
• Actual Primary Completion Date: January 18, 2018
• Actual Study Completion Date: August 22, 2018

Arms and Interventions

Arm	Intervention/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
Experimental: Semaglutide 3 mg + 7 mg	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
Experimental: Semaglutide 3 mg + 7 mg + 14 mg	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
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

Outcome Measures

Primary Outcome Measures :

1. Change in HbA1c (Week 26) [ Time Frame: Week 0, 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.

Secondary Outcome Measures :

1. Change in Body Weight (Week 26) [ Time Frame: Week 0, 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.
2. Change in HbA1c (Week 52) [ Time Frame: Week 0, 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.
3. Change in Body Weight (kg) (Week 52) [ Time Frame: Week 0, 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.
4. Change in Fasting Plasma Glucose (FPG) [ Time Frame: Week 0, week 26, week 52 ]
   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.
5. Change in Self-measured Plasma Glucose (SMPG) Mean 7-point Profile [ Time Frame: Week 0, week 26, week 52 ]
   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.
6. Change in SMPG Mean Postprandial Increment Over All Meals [ Time Frame: Week 0, week 26, week 52 ]
   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.
7. Change in Body Weight (Percentage) [ Time Frame: Week 0, week 26, week 52 ]
   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.
8. Change in Body Mass Index [ Time Frame: Week 0, week 26, week 52 ]
   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.
9. Change in Waist Circumference [ Time Frame: Week 0, week 26, week 52 ]
   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.
10. Change in Total Cholesterol - Ratio to Baseline [ Time Frame: Week 0, week 26, week 52 ]
    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.
11. Change in LDL Cholesterol - Ratio to Baseline [ Time Frame: Week 0, week 26, week 52 ]
    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.
12. Change in HDL Cholesterol - Ratio to Baseline [ Time Frame: Week 0, week 26, week 52 ]
    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.
13. Change in Triglycerides - Ratio to Baseline [ Time Frame: Week 0, week 26, week 52 ]
    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.
14. Change in Total Daily Insulin Dose [ Time Frame: Week 0, week 26, week 52 ]
    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.
15. Participants Who Achieve: HbA1c < 7.0% (53 mmol/Mol) (American Diabetes Association (ADA) Target) (Yes/no) [ Time Frame: Week 26, week 52 ]
    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.
16. Participants Who Achieve: HbA1c ≤ 6.5% (48 mmol/Mol) (AACE Target) (Yes/no) [ Time Frame: Week 26, week 52 ]
    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.
17. Participants Who Achieve Body Weight Loss ≥5% (Yes/no) [ Time Frame: Week 26, week 52 ]
    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.
18. Participants Who Achieve Body Weight Loss ≥10% (Yes/no) [ Time Frame: Week 26, week 52 ]
    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.
19. Participants Who Achieve HbA1c <7.0 % (53 mmol/Mol) Without Hypoglycaemia (Severe or BG Confirmed Symptomatic Hypoglycaemia) and no Weight Gain (Yes/no) [ Time Frame: Week 26, week 52 ]
    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.
20. Participants Who Achieve HbA1c Reduction ≥1% (10.9 mmol/Mol) and Weight Loss ≥3% (Yes/no) [ Time Frame: Week 26, week 52 ]
    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.
21. Time to Additional Anti-diabetic Medication [ Time Frame: Weeks 0-52 ]
    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.
22. Time to Rescue Medication [ Time Frame: Weeks 0-52 ]
    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.
23. Number of Treatment-emergent Adverse Events (TEAEs) During Exposure to Trial Product [ Time Frame: Weeks 0-57 ]
    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.
24. Number of Treatment-emergent Severe or BG-confirmed Symptomatic Hypoglycaemic Episodes [ Time Frame: Weeks 0-57 ]
    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.
25. Participants With Treatment-emergent Severe or BG-confirmed Symptomatic Hypoglycaemic Episodes [ Time Frame: Weeks 0-57 ]
    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.
26. Change in Amylase - Ratio to Baseline [ Time Frame: Week 0, week 26, week 52 ]
    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.
27. Change in Lipase - Ratio to Baseline [ Time Frame: Week 0, week 26, week 52 ]
    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
28. Change in Pulse Rate [ Time Frame: Week 0, week 26, week 52 ]
    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.
29. Change in SBP and DBP [ Time Frame: Week 0, week 26, week 52 ]
    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.
30. Change in ECG Evaluation [ Time Frame: Week 0, week 26, week 52 ]
    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.
31. Change in Physical Examination [ Time Frame: Week -2, week 52 ]
    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.
32. Change in Eye Examination Category [ Time Frame: Week -2, week 52 ]
    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.
33. Semaglutide Plasma Concentrations for Population PK Analyses [ Time Frame: Weeks 0-52 ]
    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.
34. Change in SF-36v2 (Acute Version) Health Survey: Scores From the 8 Domains, the Physical Component Summary (PCS) and the Mental Component Summary (MCS) [ Time Frame: Week 0, week 26, week 52 ]
    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.
35. Change in IWQoL-Lite-CT: Total Score and Scores From the 4 Domains [ Time Frame: Week 0, week 26, week 52 ]
    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.
36. Change in DTSQs: Individual Items and Treatment Satisfaction Score (6 of the 8 Items Summed) [ Time Frame: Week 0, week 26, week 52 ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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).

Contacts and Locations

Locations

United States, Alabama

Novo Nordisk Investigational Site

Anniston, Alabama, United States, 36207

Novo Nordisk Investigational Site

Birmingham, Alabama, United States, 35211

United States, Arizona

Novo Nordisk Investigational Site

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, 85723-0001

Novo Nordisk Investigational Site

Tucson, Arizona, United States, 85741

United States, California

Novo Nordisk Investigational Site

Anaheim, California, United States, 92801

Novo Nordisk Investigational Site

Fresno, California, United States, 93720

Novo Nordisk Investigational Site

Los Angeles, California, United States, 90017

Novo Nordisk Investigational Site

Los Angeles, California, United States, 90057

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

United States, Colorado

Novo Nordisk Investigational Site

Colorado Springs, Colorado, United States, 80904

Novo Nordisk Investigational Site

Denver, Colorado, United States, 80246

United States, Florida

Novo Nordisk Investigational Site

Hialeah, Florida, United States, 33016

United States, Georgia

Novo Nordisk Investigational Site

Atlanta, Georgia, United States, 30342

United States, Illinois

Novo Nordisk Investigational Site

Chicago, Illinois, United States, 60607

United States, Indiana

Novo Nordisk Investigational Site

Franklin, Indiana, United States, 46131

United States, Kentucky

Novo Nordisk Investigational Site

Lexington, Kentucky, United States, 40503

Novo Nordisk Investigational Site

Paducah, Kentucky, United States, 42003

United States, Louisiana

Novo Nordisk Investigational Site

Metairie, Louisiana, United States, 70002

Novo Nordisk Investigational Site

Natchitoches, Louisiana, United States, 71457-5881

United States, Maryland

Novo Nordisk Investigational Site

Hyattsville, Maryland, United States, 20782

Novo Nordisk Investigational Site

Rockville, Maryland, United States, 20852

United States, Massachusetts

Novo Nordisk Investigational Site

Boston, Massachusetts, United States, 02215

United States, Michigan

Novo Nordisk Investigational Site

Troy, Michigan, United States, 48098

United States, Nevada

Novo Nordisk Investigational Site

Henderson, Nevada, United States, 89052-2649

Novo Nordisk Investigational Site

Las Vegas, Nevada, United States, 89148

United States, New York

Novo Nordisk Investigational Site

West Seneca, New York, United States, 14224

United States, North Carolina

Novo Nordisk Investigational Site

Asheville, North Carolina, United States, 28803

Novo Nordisk Investigational Site

Chapel Hill, North Carolina, United States, 27517

United States, Ohio

Novo Nordisk Investigational Site

Cincinnati, Ohio, United States, 45245

Novo Nordisk Investigational Site

Dayton, Ohio, United States, 45439

United States, Pennsylvania

Novo Nordisk Investigational Site

Beaver, Pennsylvania, United States, 15009

Novo Nordisk Investigational Site

Lansdale, Pennsylvania, United States, 19446-1002

United States, South Carolina

Novo Nordisk Investigational Site

Summerville, South Carolina, United States, 29485

United States, Tennessee

Novo Nordisk Investigational Site

Chattanooga, Tennessee, United States, 37411

Novo Nordisk Investigational Site

Kingsport, Tennessee, United States, 37660-4652

United States, Texas

Novo Nordisk Investigational Site

Austin, Texas, United States, 78731

Novo Nordisk Investigational Site

Dallas, Texas, United States, 75251

Novo Nordisk Investigational Site

Dallas, Texas, United States, 75390-9302

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

United States, Utah

Novo Nordisk Investigational Site

Murray, Utah, United States, 84123

United States, Virginia

Novo Nordisk Investigational Site

Winchester, Virginia, United States, 22601

Canada, Manitoba

Novo Nordisk Investigational Site

Winnipeg, Manitoba, Canada, R3E 3P4

Canada, New Brunswick

Novo Nordisk Investigational Site

Moncton, New Brunswick, Canada, E1G 1A7

Canada, Ontario

Novo Nordisk Investigational Site

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

France

Novo Nordisk Investigational Site

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

Greece

Novo Nordisk Investigational Site

Athens, Greece, GR-11527

Novo Nordisk Investigational Site

Athens, Greece, GR-17562

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

India

Novo Nordisk Investigational Site

Ahmedabad, Gujarat, India, 380007

Novo Nordisk Investigational Site

Bangalore, Karnataka, India, 560 017

Novo Nordisk Investigational Site

Kozhikode, Kerala, India, 673017

Novo Nordisk Investigational Site

Indore, Madhya Pradesh, India, 452010

Novo Nordisk Investigational Site

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 Dehli, New Delhi, India, 110029

Novo Nordisk Investigational Site

Jaipur, Rajasthan, India, 302004

Novo Nordisk Investigational Site

Chennai, Tamil Nadu, India, 600086

Novo Nordisk Investigational Site

Kolkata, West Bengal, India, 700054

Novo Nordisk Investigational Site

Kolkata, India, 700020

Japan

Novo Nordisk Investigational Site

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-shi, Kumamoto, Japan, 860-0811

Novo Nordisk Investigational Site

Kumamoto, Japan, 862-0976

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

Mexico

Novo Nordisk Investigational Site

Durango, Mexico, 34000

Novo Nordisk Investigational Site

San Luis Potosi, Mexico, 78200

Poland

Novo Nordisk Investigational Site

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

Puerto Rico

Novo Nordisk Investigational Site

Manati, Puerto Rico, 00674

Russian Federation

Novo Nordisk Investigational Site

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

Sponsors and Collaborators

Novo Nordisk A/S

  Study Documents (Full-Text)

Documents provided by Novo Nordisk A/S:

Study Protocol  [PDF] February 8, 2019

Statistical Analysis Plan  [PDF] February 8, 2019

More Information

Publications of Results:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Pratley RE, Crowley MJ, Gislum M, Hertz CL, Jensen TB, Khunti K, Mosenzon O, Buse JB. Oral Semaglutide Reduces HbA(1c) 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.

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. Review.

Husain M, Bain SC, Jeppesen OK, Lingvay I, Sørrig R, Treppendahl MB, Vilsbøll 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.

• Responsible Party: Novo Nordisk A/S
• ClinicalTrials.gov Identifier: NCT03021187
• 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 )
• First Posted: January 13, 2017
• Results First Posted: November 7, 2019
• Last Update Posted: March 2, 2020
• Last Verified: February 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: According to the Novo Nordisk disclosure commitment on novonordisk-trials.com

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases