Efficacy and Safety of Oral Semaglutide Versus Placebo in Subjects With Type 2 Diabetes and Moderate Renal Impairment (PIONEER 5)

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 and moderate renal impairment.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 324
• Phase: Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Aalborg, Denmark, 9000
    • Novo Nordisk Investigational Site
  • Gentofte, Denmark, 2820
    • Novo Nordisk Investigational Site
  • Hvidovre, Denmark, 2650
    • Novo Nordisk Investigational Site
  • København S, Denmark, 2300
    • Novo Nordisk Investigational Site
  • Køge, Denmark, 4600
    • Novo Nordisk Investigational Site
  • Svendborg, Denmark, 5700
    • Novo Nordisk Investigational Site
  • Århus C, Denmark, 8000
    • Novo Nordisk Investigational Site
• Finland
  • Espoo, Finland, 02230
    • Novo Nordisk Investigational Site
  • Helsinki, Finland, 00250
    • Novo Nordisk Investigational Site
  • Kerava, Finland, FI-04200
    • Novo Nordisk Investigational Site
  • Kuopio, Finland, 70100
    • Novo Nordisk Investigational Site
  • Oulu, Finland, 90100
    • Novo Nordisk Investigational Site
  • Turku, Finland, 20520
    • Novo Nordisk Investigational Site
  • Ähtäri, Finland, 63700
    • Novo Nordisk Investigational Site
• Israel
  • Haifa, Israel, 31096
    • Novo Nordisk Investigational Site
  • Haifa, Israel
    • Novo Nordisk Investigational Site
  • Jerusalem, Israel, 91120
    • Novo Nordisk Investigational Site
  • Kfar Saba, Israel, 44281
    • Novo Nordisk Investigational Site
  • Rehovot, Israel, 76100
    • Novo Nordisk Investigational Site
  • Tel Hashomer, Israel, 52621
    • Novo Nordisk Investigational Site
  • Tel-Aviv, Israel, 62038
    • Novo Nordisk Investigational Site
• Poland
  • Poznan, Poland, 60-589
    • Novo Nordisk Investigational Site
  • Zabrze, Poland, 41-800
    • Novo Nordisk Investigational Site
• Russian Federation
  • Barnaul, Russian Federation, 656024
    • Novo Nordisk Investigational Site
  • Barnaul, Russian Federation, 656045
    • Novo Nordisk Investigational Site
  • Belgorod, Russian Federation, 308007
    • Novo Nordisk Investigational Site
  • Chelyabinsk, Russian Federation, 454000
    • Novo Nordisk Investigational Site
  • Dzerzhinskiy, Russian Federation, 140091
    • Novo Nordisk Investigational Site
  • Kazan, Russian Federation, 420061
    • Novo Nordisk Investigational Site
  • Moscow, Russian Federation, 117036
    • Novo Nordisk Investigational Site
  • Penza, Russian Federation, 440026
    • Novo Nordisk Investigational Site
  • Saint-Petersburg, Russian Federation, 194358
    • Novo Nordisk Investigational Site
  • Saint-Petersburg, Russian Federation, 190068
    • Novo Nordisk Investigational Site
  • Saint-Petersburg, Russian Federation, 199226
    • Novo Nordisk Investigational Site
  • Saratov, Russian Federation, 410039
    • Novo Nordisk Investigational Site
  • Saratov, Russian Federation, 410053
    • Novo Nordisk Investigational Site
  • Tomsk, Russian Federation, 634050
    • Novo Nordisk Investigational Site
  • Ulianovsk, Russian Federation, 432063
    • Novo Nordisk Investigational Site
  • Volgograd, Russian Federation, 400138
    • Novo Nordisk Investigational Site
  • Voronezh, Russian Federation, 394018
    • Novo Nordisk Investigational Site
  • Yaroslavl, Russian Federation, 150062
    • Novo Nordisk Investigational Site
  • Yoshkar-Ola, Russian Federation, 424004
    • Novo Nordisk Investigational Site
• Sweden
  • Göteborg, Sweden, 42144
    • Novo Nordisk Investigational Site
  • Lund, Sweden, 222 22
    • Novo Nordisk Investigational Site
  • Skövde, Sweden, 54150
    • Novo Nordisk Investigational Site
  • Uppsala, Sweden, 75185
    • Novo Nordisk Investigational Site
  • Vindeln, Sweden, 922 31
    • Novo Nordisk Investigational Site
  • Örebro, Sweden, 701 85
    • Novo Nordisk Investigational Site
• United Kingdom
  • Bexhill-on-Sea, United Kingdom, TN39 4SP
    • Novo Nordisk Investigational Site
  • Doncaster, United Kingdom, DN5 0AT
    • Novo Nordisk Investigational Site
  • Edinburgh, United Kingdom, EH4 2XU
    • Novo Nordisk Investigational Site
  • Glasgow, United Kingdom, G31 2ER
    • Novo Nordisk Investigational Site
  • Hull, United Kingdom, HU3 2RW
    • Novo Nordisk Investigational Site
  • Milton Keynes, United Kingdom, MK6 5LD
    • Novo Nordisk Investigational Site
  • Rothwell, United Kingdom, NN14 6JQ
    • Novo Nordisk Investigational Site
  • Sheffield, United Kingdom, S5 7AU
    • Novo Nordisk Investigational Site
  • Wellingborough, United Kingdom, NN8 4RW
    • Novo Nordisk Investigational Site
• United States
  • Alabama
    • Tuscumbia, Alabama, United States, 35674
      • Novo Nordisk Investigational Site
  • California
    • Bermuda Dunes, California, United States, 92203
      • Novo Nordisk Investigational Site
    • Concord, California, United States, 94520
      • Novo Nordisk Investigational Site
    • Costa Mesa, California, United States, 92627
      • Novo Nordisk Investigational Site
    • Fresno, California, United States, 93720
      • Novo Nordisk Investigational Site
    • La Jolla, California, United States, 92161-0002
      • Novo Nordisk Investigational Site
    • San Ramon, California, United States, 94583
      • Novo Nordisk Investigational Site
  • Connecticut
    • Danbury, Connecticut, United States, 06810
      • Novo Nordisk Investigational Site
    • Norwalk, Connecticut, United States, 06851
      • Novo Nordisk Investigational Site
    • Waterbury, Connecticut, United States, 06708
      • Novo Nordisk Investigational Site
  • Florida
    • Clearwater, Florida, United States, 33756
      • Novo Nordisk Investigational Site
    • Cooper City, Florida, United States, 33024
      • Novo Nordisk Investigational Site
    • Jacksonville, Florida, United States, 32258
      • Novo Nordisk Investigational Site
    • Miami Lakes, Florida, United States, 33014
      • Novo Nordisk Investigational Site
    • New Port Richey, Florida, United States, 34652
      • Novo Nordisk Investigational Site
    • Orlando, Florida, United States, 32804
      • Novo Nordisk Investigational Site
    • Palm Harbor, Florida, United States, 34684
      • Novo Nordisk Investigational Site
    • Pembroke Pines, Florida, United States, 33027
      • Novo Nordisk Investigational Site
  • Georgia
    • Atlanta, Georgia, United States, 30339
      • Novo Nordisk Investigational Site
    • Atlanta, Georgia, United States, 30342
      • Novo Nordisk Investigational Site
    • Lawrenceville, Georgia, United States, 30046
      • Novo Nordisk Investigational Site
    • Marietta, Georgia, United States, 30060
      • Novo Nordisk Investigational Site
    • Roswell, Georgia, United States, 30076
      • Novo Nordisk Investigational Site
  • Illinois
    • Gurnee, Illinois, United States, 60031
      • Novo Nordisk Investigational Site
  • Indiana
    • Avon, Indiana, United States, 46123
      • Novo Nordisk Investigational Site
    • Franklin, Indiana, United States, 46131
      • Novo Nordisk Investigational Site
  • Louisiana
    • Slidell, Louisiana, United States, 70461-4231
      • Novo Nordisk Investigational Site
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Novo Nordisk Investigational Site
    • Baltimore, Maryland, United States, 21204
      • Novo Nordisk Investigational Site
  • Michigan
    • Buckley, Michigan, United States, 49620
      • Novo Nordisk Investigational Site
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • Novo Nordisk Investigational Site
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Novo Nordisk Investigational Site
    • Nashua, New Hampshire, United States, 03063
      • Novo Nordisk Investigational Site
  • New Jersey
    • Teaneck, New Jersey, United States, 07666
      • Novo Nordisk Investigational Site
  • New York
    • Albany, New York, United States, 12206
      • Novo Nordisk Investigational Site
    • New Hyde Park, New York, United States, 11042
      • Novo Nordisk Investigational Site
    • Northport, New York, United States, 11768
      • 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
    • Whiteville, North Carolina, United States, 28472
      • Novo Nordisk Investigational Site
    • Wilmington, North Carolina, United States, 28401
      • Novo Nordisk Investigational Site
  • North Dakota
    • Fargo, North Dakota, United States, 58103
      • Novo Nordisk Investigational Site
  • Ohio
    • Dayton, Ohio, United States, 45439
      • Novo Nordisk Investigational Site
    • Delaware, Ohio, United States, 43015
      • Novo Nordisk Investigational Site
    • Franklin, Ohio, United States, 45005
      • Novo Nordisk Investigational Site
  • Oklahoma
    • Norman, Oklahoma, United States, 73069
      • Novo Nordisk Investigational Site
  • South Carolina
    • Murrells Inlet, South Carolina, United States, 29576
      • Novo Nordisk Investigational Site
    • Myrtle Beach, South Carolina, United States, 29572
      • Novo Nordisk Investigational Site
  • Tennessee
    • Kingsport, Tennessee, United States, 37660
      • Novo Nordisk Investigational Site
  • Texas
    • Amarillo, Texas, United States, 79106
      • Novo Nordisk Investigational Site
    • Dallas, Texas, United States, 75231
      • Novo Nordisk Investigational Site
    • Houston, Texas, United States, 77058
      • Novo Nordisk Investigational Site
    • Houston, Texas, United States, 77061
      • Novo Nordisk Investigational Site
    • Houston, Texas, United States, 77081
      • Novo Nordisk Investigational Site
    • Midland, Texas, United States, 79707
      • Novo Nordisk Investigational Site
    • San Antonio, Texas, United States, 78212
      • Novo Nordisk Investigational Site
  • Virginia
    • Richmond, Virginia, United States, 23219
      • Novo Nordisk Investigational Site
    • Winchester, Virginia, United States, 22601
      • Novo Nordisk Investigational Site
    • Winchester, Virginia, United States, 22601-3834
      • Novo Nordisk Investigational Site
  • Washington
    • Olympia, Washington, United States, 98502
      • 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
• Diagnosed with type 2 diabetes mellitus for at least 90 days prior to day of screening
• HbA1c (glycosylated haemoglobin) of 7.0-9.5% (53-80 mmol/mol) (both inclusive)
• Moderate renal impairment defined as estimated glomerular filtration rate of 30-59 mL/min/1.73 m^2 as per Chronic Kidney Disease Epidemiology Collaboration formula
• Stable daily dose(s) within 90 days prior to the day of screening of any of the following treatment regimens:
• 1-2 of the following oral anti-diabetic drugs:
• Metformin equal or above 1500 mg or maximum tolerated dose documented in the subject medical record),
• Sulfonylurea (equal or above half of the maximum approved dose according to local label or maximum tolerated dose as documented in subject medical record)
• Basal insulin alone (20% change in total daily dose of insulin glargine, insulin detemir, insulin degludec or NPH insulin) or
• Metformin (equal or above 1500 mg or maximum tolerated dose documented in the subject medical record) in combination with basal insulin (20% change in total daily dose of insulin glargine, insulin detemir, insulin degludec or NPH insulin)

Exclusion Criteria:

• Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using an adequate contraceptive method (adequate contraceptive measure as required by local regulation or practice). For certain specific countries: Additional specific requirements apply
• Any disorder, which in the investigator's opinion might jeopardise subject's safety or compliance with the protocol
• Family or personal history of Multiple Endocrine Neoplasia Type 2 or Medullary Thyroid Carcinoma
• History of pancreatitis (acute or chronic)
• History of major surgical procedures involving the stomach potentially affecting absorption of trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery)
• Any of the following: myocardial infarction, stroke or hospitalisation for unstable angina or transient ischaemic attack within the past 180 days prior to the day of screening 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
• Rapidly progressing renal disease (e.g. such as acute glomerulonephritis) as judged by the investigator or known nephrotic albuminuria (above 2200 mg/24 hours or above 2200 mg/g)
• Use of systemic immunosuppressive treatment within 90 days prior to screening
• Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria in a period of 90 days before the day of screening. An exception is short-term insulin treatment for acute illness for a total of below or equal to 14 days
• Known hypoglycaemic unawareness and/or recurrent severe hypoglycaemic episodes as judged by the investigator
• 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)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: placebo; Oral administration once daily.
Experimental: 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) in glycosylated haemoglobin (HbA1c) was evaluated at week 26. The endpoint was evaluated 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. The endpoint was also evaluated based on the data from the on-treatment without rescue medication observation period, which was the time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication and/or premature trial product discontinuation.	Week 0, week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Body Weight (kg)	Change from baseline (week 0) in body weight was evaluated at week 26. The endpoint was evaluated 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. The endpoint was also evaluated based on the data from the on-treatment without rescue medication observation period, which was the time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication and/or premature trial product discontinuation.	Week 0, week 26
Change in FPG	Change from baseline (week 0) in fasting plasma glucose (FPG) was evaluated at 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 and/or premature discontinuation of trial product.	Week 0, week 26
Change in Body Weight (%)	Relative change from baseline (week 0) in body weight (kg) was evaluated at 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 and/or premature discontinuation of trial product.	Week 0, week 26
Change in BMI	Change from baseline (week 0) in body mass index (BMI) was evaluated at 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 and/or premature discontinuation of trial product.	Week 0, week 26
Change in Waist Circumference	Change from baseline (week 0) in waist circumference was evaluated at 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 and/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% (American Diabetes Association (ADA) target) (yes/no), was evaluated at 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 and/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% (American Association of Clinical Endocrinologists (AACE) target) (yes/no), was evaluated at 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 and/or premature discontinuation of trial product.	Week 26
Participants Who Achieve Weight Loss ≥5% (Yes/no)	Participants who achieved weight loss ≥5% of their baseline body weight (yes/no) was evaluated at 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 and/or premature discontinuation of trial product.	Week 26
Participants Who Achieve Weight Loss ≥10% (Yes/no)	Participants who achieved weight loss of ≥10% of their baseline body weight (yes/no) was evaluated at 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 and/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 no Weight Gain (Yes/no)	Participants who achieved HbA1c <7.0 % without severe or blood glucose (BG) confirmed symptomatic hypoglycaemia and without weight gain (yes/no) was evaluated at week 26. 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
Participants Who Achieve HbA1c Reduction ≥1% (10.9 mmol/Mol) and Weight Loss ≥3% (Yes/no)	Participants who achieved HbA1c reduction ≥1% and weight loss of ≥3% (yes/no) was evaluated at 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 and/or premature discontinuation of trial product.	Week 26
Change in Total Cholesterol (Ratio to Baseline)	Change from baseline (week 0) in total cholesterol (mmol/L) at week 26 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 and/or premature discontinuation of trial product.	Week 0, week 26
Change in LDL Cholesterol (Ratio to Baseline)	Change from baseline (week 0) in low-density lipoprotein (LDL) cholesterol (mmol/L) at week 26 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 and/or premature discontinuation of trial product.	Week 0, week 26
Change in HDL Cholesterol (Ratio to Baseline)	Change from baseline (week 0) in high-density lipoprotein (HDL) cholesterol (mmol/L) at week 26 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 and/or premature discontinuation of trial product.	Week 0, week 26
Change in Triglycerides (Ratio to Baseline)	Change from baseline (week 0) in triglycerides (mmol/L) at week 26 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 and/or premature discontinuation of trial product.	Week 0, week 26
Change in CRP (Ratio to Baseline)	Change from baseline (week 0) in C-reactive protein (CRP) (mg/L) at week 26 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 and/or premature discontinuation of trial product.	Week 0, 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 and/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 and/or premature trial product discontinuation.	Weeks 0-26
Number of TEAEs	Treatment emergent adverse events (TEAEs) were recorded from week 0 to week 31 (26 weeks treatment period + 5 weeks 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 0-31
Number of Treatment-emergent Severe or BG-confirmed Symptomatic Hypoglycaemic Episodes	Treatment emergent severe or BG-confirmed symptomatic hypoglycaemic episodes were recorded from week 0 to week 31 (26 weeks treatment period + 5 weeks follow-up period). Hypoglycaemic episodes with onset during the first dose of trial product until last dose of trial product were considered treatment -emergent. Severe or BG-confirmed symptomatic hypoglycaemia was defined as an episode, that is severe according to the ADA classification or BG-confirmed by a plasma glucose value <3.1 mmol/L with symptoms consistent with hypoglycaemia. 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 0-31
Participants With Treatment-emergent Severe or BG-confirmed Symptomatic Hypoglycaemic Episodes (Yes/no)	Number of participants with treatment emergent severe or BG-confirmed symptomatic hypoglycaemic episodes was recorded from week 0 to week 31 (26 weeks treatment period + 5 weeks follow-up period). Hypoglycaemic episodes with onset during the first dose of trial product until last dose of trial product were considered treatment -emergent. Severe or BG-confirmed symptomatic hypoglycaemia was defined as an episode, that is severe according to the ADA classification or BG-confirmed by a plasma glucose value <3.1 mmol/L with symptoms consistent with hypoglycaemia. 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 0-31
Change in Amylase (Ratio to Baseline)	Change from baseline (week 0) in amylase (units/litre (U/L)) at week 26 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) in lipase (U/L) at week 26 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 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 Blood Pressure (Systolic and Diastolic Blood Pressure)	Change from baseline (week 0) in systolic and diastolic blood pressure 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 Urinary Albumin to Creatinine Ratio (Ratio to Baseline)	Change from baseline (week 0) in urinary albumin to creatinine ratio (mg/mmol) at week 26 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 ECG	Change from baseline (week 0) in electrocardiogram (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 and/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 [wk] -2) and wk 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 and/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 -2, week 26
Change in Eye Examination	Participants with eye 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 and/or premature discontinuation of trial product.	Week -2, week 26
Occurrence of Anti-semaglutide Binding Antibodies (Yes/no)	This outcome measure is only applicable for the oral semaglutide 14 mg treatment arm. Number of participants who measured with anti-semaglutide binding antibodies anytime during post-baseline visits (weeks 0-31) 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 and/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 14 mg treatment arm. Number of participants who measured with anti-semaglutide neutralising antibodies anytime during post-baseline visits (weeks 0-31) 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 and/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 14 mg treatment arm. Number of participants who measured with anti-semaglutide binding antibodies cross reacting with native glucagon-like peptide-1 (GLP-1) anytime during post-baseline visits (weeks 0-31) 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 and/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 14 mg treatment arm. Number of participants who measured with anti-semaglutide neutralising antibodies cross reacting with native GLP-1 anytime during post-baseline visits (weeks 0-31) 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 and/or premature discontinuation of trial product.	Weeks 0-31
Anti-semaglutide Binding Antibody Levels	This outcome measure is only applicable for the oral semaglutide 14 mg treatment arm. It is based on the data from participants who were measured with anti-semaglutide antibodies anytime during post-baseline visits (weeks 0-31). 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 and/or premature discontinuation of trial product.	Weeks 0-31
Semaglutide Plasma Concentrations for Population PK Analyses	This outcome measure is only applicable for the oral semaglutide 14 mg treatment arm. 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
SNAC Plasma Concentrations	This outcome measure is only applicable for the oral semaglutide 14 mg treatment arm. Sodium N-[8-(2-hydroxybenzoyl) amino]caprylate (SNAC) plasma concentrations were measured after 25 and 40 minutes post-dose at 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
Change in Short Form Health Survey Version 2.0 (SF-36v2™, Acute Version) Health Survey: Scores From the 8 Domains and Summaries of the Physical Component Score (PCS) and the Mental Component Score (MCS)	SF-36 is a 36-item patient-reported survey of patient health that measures the participant's overall health-related quality of life (HRQoL). SF-36v2™ (acute version) questionnaire measured eight domains of functional health and well-being as well as two component summary scores (physical component summary (PCS) and mental component summary (MCS)). The 0-100 scale scores (where higher scores indicated a better HRQoL) from the SF-36 were converted to norm-based scores to enable a direct interpretation in relation to the distribution of the scores in the 2009 U.S. general population. In the metric of norm-based scores, 50 and 10 corresponds to the mean and standard deviation respectively of the 2009 U.S. general population. Change from baseline (week 0) in the domain scores and component summary (PCS and MCS) scores were evaluated at 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
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. 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
Change in Urinalysis	Participants with urinalysis, "leukocytes and erythrocytes" findings, negative, trace, small, moderate or large at baseline (week [wk] 0) and wk 26 are presented. Participants with urinalysis, "nitrit" findings, negative or positive at baseline (wk 0) and wk 26 are presented. 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 -2, 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, Blicher TM, Rosenlund S, Eriksson JW, Heller S, Hels OH, Pratley R, Sathyapalan T, Desouza C; PIONEER 5 Investigators. Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial. Lancet Diabetes Endocrinol. 2019 Jul;7(7):515-527. doi: 10.1016/S2213-8587(19)30192-5. Epub 2019 Jun 9. Erratum In: Lancet Diabetes Endocrinol. 2019 Sep;7(9):e21.
• 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.
• 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.
• 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, 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.

Helpful Links

• Clinical Trials at Novo Nordisk

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2016
• Primary Completion (Actual): April 10, 2018
• Study Completion (Actual): May 15, 2018

Study Registration Dates

• First Submitted: July 6, 2016
• First Submitted That Met QC Criteria: July 6, 2016
• First Posted (Estimate): July 11, 2016

Study Record Updates

• Last Update Posted (Actual): February 17, 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: NN9924-4234; 2015-005326-19 (EudraCT Number); U1111-1176-9230 (Other Identifier: WHO)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: According to 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