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

• ClinicalTrials.gov Identifier: NCT02906930
• Recruitment Status: Completed
• First Posted: September 20, 2016
• Results First Posted: February 17, 2020
• Last Update Posted: July 20, 2022
• 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 this trial is to investigate efficacy and safety of oral semaglutide versus placebo in subjects with type 2 diabetes mellitus treated with diet and exercise only.

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: 703 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 Diet and Exercise Only.
• Actual Study Start Date: September 20, 2016
• Actual Primary Completion Date: October 30, 2017
• Actual Study Completion Date: December 8, 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: 3 mg oral semaglutide	Drug: semaglutide; Oral administration once daily.
Experimental: 7 mg oral semaglutide	Drug: semaglutide; Oral administration once daily.
Experimental: 14 mg oral semaglutide	Drug: semaglutide; Oral administration once daily.
Placebo Comparator: Placebo	Drug: placebo; Oral administration once daily.

Outcome Measures

Primary Outcome Measures :

1. Change in HbA1c [ Time Frame: Week 0, week 26 ]
   Change from baseline (week 0) to week 26 in glycosylated haemoglobin (HbA1c). The endpoint was evaluated based on data from the in-trial observation period. The in-trial observation period - time period from when a subject was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product. The primary endpoint was also analysed based on data from the on-treatment without rescue medication observation period. The on-treatment without rescue medication observation period - time period when a subject was on treatment with trial product, excluding any period after initiation of rescue medication.

Secondary Outcome Measures :

1. Change in Body Weight (kg) [ Time Frame: Week 0, week 26 ]
   Change from baseline (week 0) to week 26 in body weight. The endpoint was evaluated based on data from the in-trial observation period. The in-trial observation period - time period from when a subject was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product. The primary endpoint was also analysed based on data from the on-treatment without rescue medication observation period. The on-treatment without rescue medication observation period - time period when a subject was on treatment with trial product, excluding any period after initiation of rescue medication.
2. Change in Fasting Plasma Glucose [ Time Frame: Week 0, week 26 ]
   Change from baseline (week 0) to week 26 in fasting plasma glucose. The endpoint was evaluated based on data from the in-trial observation period. The in-trial observation period - time period from when a subject was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
3. Change in Mean 7-point SMPG Profile [ Time Frame: Week 0, week 26 ]
   Change from baseline (week 0) to week 26 in mean 7-point self-measured plasma glucose (SMPG) profile. SMPG was recorded at the following 7 time points: before breakfast, 90 minutes after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 minutes after dinner and at bedtime. Mean 7-point profile was defined as the area under the profile, calculated using the trapezoidal method, divided by the measurement time. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
4. Change in Mean Postprandial Increment Over All Meals in SMPG [ Time Frame: Week 0, week 26 ]
   Change from baseline (week 0) to week 26 in the average of the post-prandial increments over all meals. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
5. Change in Fasting Insulin - Ratio to Baseline [ Time Frame: Week 0, week 26 ]
   Change from baseline (week 0) to week 26 in fasting insulin (pmol/L) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product
6. Change in Fasting Pro-insulin - Ratio to Baseline [ Time Frame: Week 0, week 26 ]
   Change from baseline (week 0) to week 26 in fasting pro-insulin (pmol/L) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product
7. Change in Fasting Glucagon - Ratio to Baseline [ Time Frame: Week 0, week 26 ]
   Change from baseline (week 0) to week 26 in fasting glucagon (pg/mL) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product
8. Change in HOMA-IR (Insulin Resistance) - Ratio to Baseline [ Time Frame: Week 0, week 26 ]
   Change from baseline (week 0) to week 26 in homeostatic model assessment index of insulin resistance (HOMA-IR) (%) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
9. Change in HOMA-B (Beta-cell Function) - Ratio to Baseline [ Time Frame: Week 0, week 26 ]
   Change from baseline (week 0) to week 26 in homeostatic model assessment index of beta-cell function (HOMA-B) (%) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
10. Change in CRP - Ratio to Baseline [ Time Frame: Week 0, week 26 ]
    Change from baseline (week 0) to week 26 in C-reactive protein (CRP) (mg/L) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
11. Change in Body Weight (%) [ Time Frame: Week 0, week 26 ]
    Change from baseline (week 0) to week 26 in body weight. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
12. Change in BMI [ Time Frame: Week 0, week 26 ]
    Change from baseline (week 0) to week 26 in body mass index (BMI). Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
13. Change in Waist Circumference [ Time Frame: Week 0, week 26 ]
    Change from baseline (week 0) to week 26 in waist circumference. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
14. Change in Fasting Total Cholesterol - Ratio to Baseline [ Time Frame: Week 0, week 26 ]
    Change from baseline (week 0) to week 26 in fasting total cholesterol (mmol/L) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
15. Change in Fasting LDL Cholesterol - Ratio to Baseline [ Time Frame: Week 0, week 26 ]
    Change from baseline (week 0) to week 26 in fasting low-density lipoprotein (LDL) cholesterol (mmol/L) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
16. Change in Fasting HDL Cholesterol - Ratio to Baseline [ Time Frame: Week 0, week 26 ]
    Change from baseline (week 0) to week 26 in fasting high-density lipoprotein (HDL) cholesterol (mmol/L) is presented as ratio to baseline. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
17. Change in Fasting Triglycerides - Ratio to Baseline [ Time Frame: Week 0, week 26 ]
    Change from baseline (week 0) to week 26 in triglycerides (mmol/L) is presented as ratio to baseline. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
18. Participants Who Achieve HbA1c < 7.0 % (53 mmol/Mol) ADA Target (Yes/no) [ Time Frame: Week 26 ]
    Participants who achieved HbA1c <7.0% (53 mmol/mol) (American Diabetes Association (ADA) target), at week 26 are presented. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
19. Participants Who Achieve HbA1c ≤ 6.5 % (48 mmol/Mol) AACE Target (Yes/no) [ Time Frame: Week 26 ]
    Participants who achieved HbA1c ≤6.5% (48 mmol/mol) (American Association of Clinical Endocrinologists (AACE) target), at week 26 are presented. The results are based on the data from the in-trial observation period. In trial observation period: the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
20. Participants Who Achieve Body Weight Loss ≥ 5 % (Yes/no) [ Time Frame: Week 26 ]
    Participants who achieved body weight loss more than or equal to 5% of their baseline body weight (yes/no) at week 26 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
21. Participants Who Achieve Body Weight Loss ≥ 10 % (Yes/no) [ Time Frame: Week 26 ]
    Participants who achieved body weight loss more than or equal to 10% of their baseline body weight (yes/no) at week 26 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
22. Participants Who Achieve HbA1c < 7.0 % (53 mmol/Mol) Without Hypoglycaemia (Severe or BG-confirmed Symptomatic Hypoglycaemia) and Without Body Weight Gain (Yes/no) [ Time Frame: Week 26 ]
    Participants who achieved HbA1c less than 7.0 % without severe or blood glucose (BG) confirmed symptomatic hypoglycaemia and without weight gain (yes/no) at week 26 are presented. Severe hypoglycaemia was defined as an episode requiring assistance of another person to actively administer carbohydrate or glucagon, or take other corrective actions. BG-confirmed symptomatic hypoglycaemia was defined as an episode with plasma glucose value <3.1 mmol/L with symptoms consistent with hypoglycaemia. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product
23. Participants Who Achieve HbA1c Reduction ≥ 1.0% (10.9 mmol/Mol) and Weight Loss ≥ 3% (Yes/no) [ Time Frame: Week 26 ]
    Participants who achieved HbA1c reduction more than or equal to 1% of their baseline HbA1c and weight loss of more than or equal to 3% of their baseline body weight (yes/no) at week 26 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
24. Time to Additional Anti-diabetic Medication [ Time Frame: Weeks 0-26 ]
    Presented results are the number of participants who had taken additional anti-diabetic medication anytime during the period from week 0 to week 26. Additional anti-diabetic medication was defined as any new anti-diabetic medication used for more than 21 days with the initiation at or after randomisation (week 0) and before (planned) end-of-treatment (week 26), and/or intensification of anti-diabetic medication (a more than 20% increase in dose relative to baseline) for more than 21 days with the intensification at or after randomisation and before (planned) end-of-treatment. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
25. Time to Rescue Medication [ Time Frame: Weeks 0-26 ]
    Presented results are the number of participants who had taken rescue medication anytime during the period from week 0 to week 26. Rescue medication was defined as any new anti-diabetic medication used as add-on to trial product and used for more than 21 days with the initiation at or after randomisation (week 0) and before last day on trial product, and/or intensification of anti-diabetic medication (a more than 20% increase in dose relative to baseline) for more than 21 days with the intensification at or after randomisation and before last day on trial product. Results are based on the data from the on-treatment without rescue medication observation period, which was the time period when a participant was on treatment with trial product, excluding any period after initiation of rescue medication or premature trial product discontinuation.
26. Number of Treatment-emergent Adverse Events (TEAEs) [ Time Frame: Approximately upto week 31 ]
    Treatment emergent adverse events (TEAEs) were recorded from week 0 to week 31 (26-week treatment period + 5-week follow-up period). Adverse events (AEs) with onset during the on-treatment observation period were considered treatment-emergent. On-treatment observation period: Time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.
27. Change in Amylase - Ratio to Baseline [ Time Frame: Week 0, week 26 ]
    Change from baseline (week 0) to week 26 in amylase (units/litre (U/L)) is presented as ratio to baseline. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.
28. Change in Lipase - Ratio to Baseline [ Time Frame: Week 0, week 26 ]
    Change from baseline (week 0) to week 26 in lipase (U/L) is presented as ratio to baseline. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.
29. Change in Pulse Rate [ Time Frame: Week 0, week 26 ]
    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.
30. Change in Systolic Blood Pressure (SBP) [ Time Frame: Week 0, week 26 ]
    Change from baseline (week 0) in SBP was evaluated at week 26. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.
31. Change in Diastolic Blood Pressure (DBP) [ Time Frame: Week 0, week 26 ]
    Change from baseline (week 0) in DBP was evaluated at week 26. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.
32. Change in Electrocardiogram (ECG) Evaluation [ Time Frame: Week 0, week 26 ]
    Change from baseline (week 0) in ECG was evaluated at week 26. Change from baseline results are presented as shift in findings (normal, abnormal and not clinically significant (NCS) and abnormal and clinically significant (CS)) from week 0 to week 26. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
33. Change in Physical Examination [ Time Frame: Week 0, week 26 ]
    Participants with physical examination findings, normal, abnormal NCS and abnormal CS at baseline (week -2) and week 26 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product. Results are presented for the following examinations: 1) Cardiovascular system; 2) Nervous system (central and peripheral); 3) Gastrointestinal system, incl. mouth; 4) General appearance; 5) Head (ears, eyes, nose), throat, neck; 6) Lymph node palpation; 7) Musculoskeletal system; 8) Respiratory system; 9) Skin; 10) Thyroid gland.
34. Change in Eye Examination Category [ Time Frame: Week 0, week 26 ]
    Participants with eye examination (fundoscopy) findings, normal, abnormal NCS and abnormal CS at baseline (week -2), and week 26 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
35. Occurrence of Anti-semaglutide Binding Antibodies (Yes/no) [ Time Frame: Weeks 0-31 ]
    This outcome measure is only applicable for the oral semaglutide treatment arms (3 mg, 7 mg and 14 mg). Number of participants who measured with anti-semaglutide binding antibodies anytime during post-baseline visits (week 0 to week 31) are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
36. Occurrence of Anti-semaglutide Neutralising Antibodies (Yes/no) [ Time Frame: Weeks 0-31 ]
    This outcome measure is only applicable for the oral semaglutide treatment arms (3 mg, 7 mg and 14 mg). Number of participants who measured with anti-semaglutide neutralising antibodies anytime during post-baseline visits (week 0 to week 31) are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
37. Occurrence of Anti-semaglutide Binding Antibodies Cross Reacting With Native GLP-1 (Yes/no) [ Time Frame: Weeks 0-31 ]
    This outcome measure is only applicable for the oral semaglutide treatment arms (3 mg, 7 mg and 14 mg). Number of participants who measured with anti-semaglutide binding antibodies cross reacting with native glucagon-like peptide-1 (GLP-1) anytime during post-baseline visits (week 0 to week 31) are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
38. Occurrence of Anti-semaglutide Neutralising Antibodies Cross Reacting With Native GLP-1 (Yes/no) [ Time Frame: Weeks 0-31 ]
    This outcome measure is only applicable for the oral semaglutide treatment arms (3 mg, 7 mg and 14 mg). Number of participants who measured with anti-semaglutide neutralising antibodies cross reacting with native GLP-1 anytime during post-baseline visits (week 0 to week 31) are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
39. Anti-semaglutide Binding Antibody Levels [ Time Frame: Weeks 0-31 ]
    This outcome measure is only applicable for the oral semaglutide treatment arms (3 mg, 7 mg and 14 mg). It is based on the data from participants who were measured with anti-semaglutide antibodies anytime during post-baseline visits (week 0 to week 31). Results are presented as percentage of bound radioactivity-labelled semaglutide /total added radioactivity-labelled semaglutide (%B/T). Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
40. Number of Treatment-emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemic Episodes During Exposure to Trial Product [ Time Frame: Weeks 0-31 ]
    Treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes were recorded during week 0 to week 31 (26-weeks treatment period + 5-weeks follow-up period). Hypoglycaemic episodes with onset during the on-treatment observation period were considered treatment-emergent. On-treatment observation period was defined as the time period when a subject was on treatment with trial product, including any period after initiation of rescue medication. Severe hypoglycaemia was defined as an episode requiring assistance of another person to actively administer carbohydrate or glucagon, or take other corrective actions. BG-confirmed symptomatic hypoglycaemia: Confirmed by a glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.
41. Participants With Treatment-emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemic Episodes During Exposure to Trial Product [ Time Frame: Weeks 0-31 ]
    Treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes were recorded from week 0 to week 31 (26-week treatment period + 5-week follow-up period). Hypoglycaemic episodes with onset during the on-treatment observation period were considered treatment-emergent. On-treatment observation period was defined as the time period when a subject was on treatment with trial product, including any period after initiation of rescue medication. Severe hypoglycaemia was defined as an episode requiring assistance of another person to actively administer carbohydrate or glucagon, or take other corrective actions. BG-confirmed symptomatic hypoglycaemia: Confirmed by a glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.
42. SNAC Plasma Concentrations [ Time Frame: Weeks 0-26 ]
    This outcome measure is only applicable for the oral semaglutide 3 mg, 7 mg and 14 mg treatment arms. Sodium N-[8-(2-hydroxybenzoyl) amino]caprylate (SNAC) plasma concentrations were measured after 25 and 40 minutes post-dose at weeks 4, 14 and 26. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.
43. Semaglutide Plasma Concentrations for Population PK Analysis [ Time Frame: Weeks 0 - 26 ]
    This outcome measure is only applicable for the oral semaglutide 3 mg, 7 mg and 14 mg treatment arms. Semaglutide plasma concentrations were measured at weeks 4, 8, 14 and 26. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.
44. 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 ]
    SF-36 is a 36-item patient-reported survey of patient health that measures the participant's overall health-related quality of life (HRQoL). SF-36v2™ (acute version) questionnaire measured eight domains of functional health and well-being as well as two component summary scores (physical component summary (PCS) and mental component summary (MCS)). The 0-100 scale scores (where higher scores indicated a better HRQoL) from the SF-36 were converted to norm-based scores to enable a direct interpretation in relation to the distribution of the scores in the 2009 U.S. general population. In the metric of norm-based scores, 50 and 10 corresponds to the mean and standard deviation respectively of the 2009 U.S. general population. Change from baseline (week 0) in the sub-domain scores and component summary (PCS and MCS) scores were evaluated at week 26. A positive change score indicates an improvement since baseline. Results are based on the data from the in-trial observation period.
45. IWQOL-Lite Clinical Trial Version: Total Score of the 22 Items (Used for Validation of the Questionnaire) [ Time Frame: Week 0, week 26 ]
    The Impact of Weight on Quality of Life Clinical Trials Version (IWQOL-Lite-CT) is designed to assess the impact of changes in weight on patients' quality of life within the context of clinical trials. IWQOL-Lite-CT is a 22-item questionnaire-based instrument used to assess the impact of body weight changes on participant's overall health-related quality of life (HRQoL). All IWQOL-Lite-CT composite scores range from 0 to 100, with higher scores reflecting better levels of functioning. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
46. PGI-S Item: Scores of the Two Individual Items (Used for Validation of the IWQOL Questionnaire) [ Time Frame: Week 26 ]
    Patient global impression of status (PGI-S) is a 2-item questionnaire used to assess the participant's impression of physical functioning and mental health status during the clinical trial. The PGI-S contains two items evaluated on a 5-point graded response scale. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.
47. PGI-C Item: Scores of the Two Individual Items (Used for Validation of the IWQOL Questionnaire) [ Time Frame: Week 26 ]
    Patient global impression of change (PGI-C) is a 2-item questionnaire used to assess the participant's impression of change from baseline in physical functioning and mental health status. The PGI-C contains two items evaluated on a 7-point graded response scale. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product.

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. For Algeria only: Male or female, age above or equal to 19 years at the time of signing informed consent - Diagnosed with type 2 diabetes mellitus for at least 30 days prior to day of screening - HbA1c (glycosylated haemoglobin) between 7.0-9.5% (53-80 mmol/mol) (both inclusive) - Treatment with diet and exercise for at least 30 days prior to day of screening Exclusion Criteria: - Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using an adequate contraceptive method (adequate contraceptive measure as required by local regulation or practice) For Japan only: Adequate contraceptive measures are abstinence (not having sex), diaphragm, condom (by the partner), intrauterine device, sponge, spermicide or oral contraceptives.For Czech Republic only: Adequate contraceptive measures are always one highly reliable method (such as intrauterine device, sterilisation of one of the partners, hormonal birth control methods) plus one supplementary barrier method (such as condom, diaphragm) with a spermicide. In justified cases, this combination may be replaced with a double-barrier method with a spermicide. Total sexual abstinence may also be considered contraception. (Please note: hormonal contraception should always be discussed with a gynaecologist) - Any disorder, which in the investigator's opinion might jeopardise subject's safety or compliance with the protocol - Family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid carcinomas - History of pancreatitis (acute or chronic) - History of major surgical procedures involving the stomach potentially affecting absorption of trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery) - Any of the following: myocardial infarction, stroke or hospitalisation for unstable angina or transient ischaemic attack within the past 180 days prior to the day of screening and randomisation - Subjects presently classified as being in New York Heart Association Class IV. - Planned coronary, carotid or peripheral artery revascularisation known on the day of screening - Subjects with alanine aminotransferase above 2.5 x upper normal limit - Renal impairment defined as estimated glomerular filtration rate below 60 mL/min/1.73 m^2 as per Chronic Kidney Disease Epidemiology Collaboration formula - Treatment with any medication for the indication of diabetes or obesity in a period of 90 days before the day of screening. An exception is short-term insulin treatment for acute illness for a total of below or equal to 14 days - Proliferative retinopathy or maculopathy requiring acute treatment. Verified by fundus photography or dilated fundoscopy performed within 90 days prior to randomisation - History or presence of malignant neoplasms within the last 5 years (except basal and squamous cell skin cancer and in-situ carcinomas)

Contacts and Locations

Locations

United States, California

Novo Nordisk Investigational Site

Lancaster, California, United States, 93534

Novo Nordisk Investigational Site

Los Angeles, California, United States, 90057

Novo Nordisk Investigational Site

Montclair, California, United States, 91763

Novo Nordisk Investigational Site

North Hollywood, California, United States, 91606

Novo Nordisk Investigational Site

Riverside, California, United States, 92506

Novo Nordisk Investigational Site

San Diego, California, United States, 92111

Novo Nordisk Investigational Site

San Jose, California, United States, 95148

Novo Nordisk Investigational Site

San Mateo, California, United States, 94401

United States, Florida

Novo Nordisk Investigational Site

Doral, Florida, United States, 33166

Novo Nordisk Investigational Site

Hialeah, Florida, United States, 33012

Novo Nordisk Investigational Site

Miami, Florida, United States, 33143

Novo Nordisk Investigational Site

Miami, Florida, United States, 33173

Novo Nordisk Investigational Site

Miami, Florida, United States, 33186

Novo Nordisk Investigational Site

Palm Harbor, Florida, United States, 34684-3609

Novo Nordisk Investigational Site

Pembroke Pines, Florida, United States, 33026

Novo Nordisk Investigational Site

Port Charlotte, Florida, United States, 33952

Novo Nordisk Investigational Site

Spring Hill, Florida, United States, 34609

Novo Nordisk Investigational Site

Tampa, Florida, United States, 33607

United States, Georgia

Novo Nordisk Investigational Site

Woodstock, Georgia, United States, 30189-4255

United States, Hawaii

Novo Nordisk Investigational Site

Honolulu, Hawaii, United States, 96814

United States, Idaho

Novo Nordisk Investigational Site

Blackfoot, Idaho, United States, 83221

Novo Nordisk Investigational Site

Nampa, Idaho, United States, 83686-6011

United States, Illinois

Novo Nordisk Investigational Site

Skokie, Illinois, United States, 60077

United States, Indiana

Novo Nordisk Investigational Site

Muncie, Indiana, United States, 47304

United States, Kentucky

Novo Nordisk Investigational Site

Louisville, Kentucky, United States, 40213

United States, Louisiana

Novo Nordisk Investigational Site

Metairie, Louisiana, United States, 70002

United States, Maryland

Novo Nordisk Investigational Site

Hyattsville, Maryland, United States, 20782

United States, Michigan

Novo Nordisk Investigational Site

Kalamazoo, Michigan, United States, 49009

Novo Nordisk Investigational Site

Rochester, Michigan, United States, 48307

Novo Nordisk Investigational Site

Troy, Michigan, United States, 48098

United States, Nebraska

Novo Nordisk Investigational Site

Elkhorn, Nebraska, United States, 68022

United States, New York

Novo Nordisk Investigational Site

Brooklyn, New York, United States, 11215

Novo Nordisk Investigational Site

West Seneca, New York, United States, 14224

United States, North Carolina

Novo Nordisk Investigational Site

Asheboro, North Carolina, United States, 27203

Novo Nordisk Investigational Site

Charlotte, North Carolina, United States, 28277

Novo Nordisk Investigational Site

Greensboro, North Carolina, United States, 27408

United States, North Dakota

Novo Nordisk Investigational Site

Fargo, North Dakota, United States, 58104

United States, Ohio

Novo Nordisk Investigational Site

Cincinnati, Ohio, United States, 45255

Novo Nordisk Investigational Site

Willoughby Hills, Ohio, United States, 44094

United States, Oklahoma

Novo Nordisk Investigational Site

Norman, Oklahoma, United States, 73069

Novo Nordisk Investigational Site

Oklahoma City, Oklahoma, United States, 73112

United States, Pennsylvania

Novo Nordisk Investigational Site

Philadelphia, Pennsylvania, United States, 19140

United States, South Carolina

Novo Nordisk Investigational Site

Spartanburg, South Carolina, United States, 29303

United States, Texas

Novo Nordisk Investigational Site

Dallas, Texas, United States, 75230

Novo Nordisk Investigational Site

Houston, Texas, United States, 77058

Novo Nordisk Investigational Site

Mesquite, Texas, United States, 75149

Novo Nordisk Investigational Site

San Antonio, Texas, United States, 78215

Novo Nordisk Investigational Site

San Antonio, Texas, United States, 78224

Novo Nordisk Investigational Site

San Antonio, Texas, United States, 78228-3419

Novo Nordisk Investigational Site

San Antonio, Texas, United States, 78230

Novo Nordisk Investigational Site

Sugar Land, Texas, United States, 77479

Novo Nordisk Investigational Site

Waco, Texas, United States, 76710

United States, Utah

Novo Nordisk Investigational Site

Bountiful, Utah, United States, 84010

United States, Virginia

Novo Nordisk Investigational Site

Norfolk, Virginia, United States, 23510-2015

Novo Nordisk Investigational Site

Richmond, Virginia, United States, 23219

Novo Nordisk Investigational Site

Salem, Virginia, United States, 24153-6404

Algeria

Novo Nordisk Investigational Site

Algiers, Algeria, 16000

Novo Nordisk Investigational Site

Algiers, Algeria, 16003

Novo Nordisk Investigational Site

Algiers, Algeria, 16049

Novo Nordisk Investigational Site

Algiers, Algeria

Bulgaria

Novo Nordisk Investigational Site

Sofia, Bulgaria, 1233

Novo Nordisk Investigational Site

Sofia, Bulgaria, 1431

Czechia

Novo Nordisk Investigational Site

Broumov, Czechia, 550 01

Novo Nordisk Investigational Site

Chrudim, Czechia, 537 01

Novo Nordisk Investigational Site

Mlada Boleslav, Czechia, 293 50

Novo Nordisk Investigational Site

Olomouc, Czechia, 77900

Novo Nordisk Investigational Site

Prague 1, Czechia, 11694

Italy

Novo Nordisk Investigational Site

Como, Italy, 22042

Novo Nordisk Investigational Site

Palermo, Italy, 90129

Novo Nordisk Investigational Site

Pisa, Italy, 56124

Novo Nordisk Investigational Site

Rome, Italy, 00168

Novo Nordisk Investigational Site

Siena, Italy, 53100

Japan

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, 104-0031

Novo Nordisk Investigational Site

Tokyo, Japan, 160-0008

Novo Nordisk Investigational Site

Yokohama-shi, Kanagawa, Japan, 236-0004

Mexico

Novo Nordisk Investigational Site

Ciudad Madero, Tamaulipas, Mexico, 89440

Novo Nordisk Investigational Site

Aguascalientes, Mexico, 20230

Romania

Novo Nordisk Investigational Site

Targoviste, Dambovita, Romania, 130086

Novo Nordisk Investigational Site

Targoviste, Dambovita, Romania, 130095

Novo Nordisk Investigational Site

Ploiesti, Prahova, Romania, 100018

Novo Nordisk Investigational Site

Bucharest, Romania, 010825

Novo Nordisk Investigational Site

Bucharest, Romania, 011234

Russian Federation

Novo Nordisk Investigational Site

Dzerzhinskiy, Russian Federation, 140091

Novo Nordisk Investigational Site

Kazan, Russian Federation, 420073

Novo Nordisk Investigational Site

Novosibirsk, Russian Federation, 630099

Novo Nordisk Investigational Site

Saint-Petersburg, Russian Federation, 194358

Novo Nordisk Investigational Site

Saint-Petersburg, Russian Federation, 199226

Novo Nordisk Investigational Site

Tomsk, Russian Federation, 634050

Novo Nordisk Investigational Site

Voronezh, Russian Federation, 394018

Novo Nordisk Investigational Site

Yaroslavl, Russian Federation, 150003

Novo Nordisk Investigational Site

Yoshkar-Ola, Russian Federation, 424004

Serbia

Novo Nordisk Investigational Site

Belgrade, Serbia, 11000

Turkey

Novo Nordisk Investigational Site

Adana, Turkey, 01250

Novo Nordisk Investigational Site

Istanbul, Turkey, 34096

Novo Nordisk Investigational Site

Istanbul, Turkey, 34147

Novo Nordisk Investigational Site

Istanbul, Turkey, 34303

Novo Nordisk Investigational Site

Istanbul, Turkey, 34371

Novo Nordisk Investigational Site

Istanbul, Turkey, 34400

Novo Nordisk Investigational Site

Istanbul, Turkey, 34718

Novo Nordisk Investigational Site

Istanbul, Turkey, 34722

Novo Nordisk Investigational Site

Istanbul, Turkey, 34752

Novo Nordisk Investigational Site

Istanbul, Turkey

Sponsors and Collaborators

Novo Nordisk A/S

Investigators

• Study Director: Global Clinical Registry (GCR, 1452); Novo Nordisk A/S

  Study Documents (Full-Text)

Documents provided by Novo Nordisk A/S:

Study Protocol  [PDF] June 20, 2018

Statistical Analysis Plan  [PDF] June 20, 2018

More Information

Additional Information:

Clinical Trials at Novo Nordisk 

Publications of Results:

Aroda VR, Rosenstock J, Terauchi Y, Altuntas Y, Lalic NM, Morales Villegas EC, Jeppesen OK, Christiansen E, Hertz CL, Haluzik M; PIONEER 1 Investigators. PIONEER 1: Randomized Clinical Trial of the Efficacy and Safety of Oral Semaglutide Monotherapy in Comparison With Placebo in Patients With Type 2 Diabetes. Diabetes Care. 2019 Sep;42(9):1724-1732. doi: 10.2337/dc19-0749. Epub 2019 Jun 11.

Araki E, Terauchi Y, Watada H, Deenadayalan S, Christiansen E, Horio H, Kadowaki T. Efficacy and safety of oral semaglutide in Japanese patients with type 2 diabetes: A post hoc subgroup analysis of the PIONEER 1, 3, 4 and 8 trials. Diabetes Obes Metab. 2021 Dec;23(12):2785-2794. doi: 10.1111/dom.14536. Epub 2021 Sep 27.

Aroda VR, Bauer R, Christiansen E, Haluzik M, Kallenbach K, Montanya E, Rosenstock J, Meier JJ. Efficacy and safety of oral semaglutide by subgroups of patient characteristics in the PIONEER phase 3 programme. Diabetes Obes Metab. 2022 Jul;24(7):1338-1350. doi: 10.1111/dom.14710. Epub 2022 May 9.

Gorst-Rasmussen A, Tarp-Johansen MJ. Fast tipping point sensitivity analyses in clinical trials with missing continuous outcomes under multiple imputation. J Biopharm Stat. 2022 Nov 2;32(6):942-953. doi: 10.1080/10543406.2022.2058525. Epub 2022 Jun 2.

Other Publications:

Kolotkin RL, Williams VSL, Ervin CM, Williams N, Meincke HH, Qin S, von Huth Smith L, Fehnel SE. Validation of a new measure of quality of life in obesity trials: Impact of Weight on Quality of Life-Lite Clinical Trials Version. Clin Obes. 2019 Jun;9(3):e12310. doi: 10.1111/cob.12310. Epub 2019 Apr 16.

Aroda VR, Saugstrup T, Buse JB, Donsmark M, Zacho J, Davies MJ. Incorporating and interpreting regulatory guidance on estimands in diabetes clinical trials: The PIONEER 1 randomized clinical trial as an example. Diabetes Obes Metab. 2019 Oct;21(10):2203-2210. doi: 10.1111/dom.13804. Epub 2019 Jun 30.

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

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.

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.

• Responsible Party: Novo Nordisk A/S
• ClinicalTrials.gov Identifier: NCT02906930
• Other Study ID Numbers: NN9924-4233; 2015-005622-19 ( EudraCT Number ); U1111-1177-5112 ( Other Identifier: WHO ); JapicCTI-163384 ( Other Identifier: JapicCTI )
• First Posted: September 20, 2016
• Results First Posted: February 17, 2020
• Last Update Posted: July 20, 2022
• Last Verified: July 2022

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