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Efficacy and Safety of Oral Semaglutide Versus Liraglutide and Versus Placebo in Subjects With Type 2 Diabetes Mellitus (PIONEER 4)

Primary Purpose

Diabetes, Diabetes Mellitus, Type 2

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

semaglutide

liraglutide

placebo

About this trial

This is an interventional treatment trial for Diabetes

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 at least 20 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 % (53-80.3 mmol/mol) (both inclusive)
Stable daily dose of metformin (above or equal to 1500 mg or maximum tolerated dose as documented in the subject medical record) alone or in combination with a stable daily dose of a SGLT-2 (sodium-glucose co-transporter-2) inhibitor for at least 90 days prior to day of screening (fixed-dose combinations are allowed)

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 (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
Subjects presently classified as being in New York Heart Association (NYHA) Class IV
Planned coronary, carotid or peripheral artery revascularisation known on the day of screening
Subjects with ALT (alanine aminotransferase) above 2.5 × upper normal limit (UNL)
Renal impairment defined as estimated Glomerular Filtration Rate (eGFR) below 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 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 carcinoma in situ)
History of diabetic ketoacidosis

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Placebo Comparator

Arm Label

Oral Semaglutide

Liraglutide

Placebo

Arm Description

Outcomes

Primary Outcome Measures

Change in HbA1c (Week 26)

Change from baseline (week 0) in glycosylated haemoglobin (HbA1c) was evaluated at week 26. The endpoint was evaluated based on 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.

Secondary Outcome Measures

Change in Body Weight (Week 26)

Change from baseline (week 0) in body weight was evaluated at week 26. The endpoint was evaluated based on 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.

Change in HbA1c (Week 52)

Change from baseline (week 0) in HbA1c was evaluated at 52 weeks. 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.

Change in Body Weight (Week 52)

Change from baseline (week 0) in body weight was evaluated at 52 weeks. 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.

Change in Body Weight (%)

Relative change from baseline (week 0) in body weight (kg) was evaluated at weeks 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.

Change in Fasting Plasma Glucose

Change from baseline (week 0) in fasting plasma glucose (FPG) was evaluated at weeks 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.

Change in Body Mass Index

Change from baseline (week 0) in body mass index (BMI) was evaluated at weeks 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.

Change in Waist Circumference

Change from baseline (week 0) in waist circumference was evaluated at weeks 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.

Change in Total Cholesterol - Ratio to Baseline

Change from baseline (week 0) in total 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, 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.

Change in Low-density Lipoprotein (LDL) Cholesterol - Ratio to Baseline

Change from baseline (week 0) in low-density lipoprotein (LDL) 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, 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.

Change in Very Low Density Lipoprotein (VLDL) Cholesterol - Ratio to Baseline

Change from baseline (week 0) in VLDL 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, 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.

Change in High-density Lipoprotein (HDL) Cholesterol - Ratio to Baseline

Change from baseline (week 0) in HDL cholesterol (mmol/L) at weeks 26 and 52 is presented as ratio to baseline. Results are based on the data from the in-trial observation period, 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.

Change in Triglycerides - Ratio to Baseline

Change from baseline (week 0) in triglycerides (mmol/L) at weeks 26 and 52 is presented as ratio to baseline. Results are based on the data from the in-trial observation period, 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.

Change in Free Fatty Acids - Ratio to Baseline

Change from baseline (week 0) in free fatty acids (FFA) (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, 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.

Change in SMPG - Mean 7-point Profile

Change from baseline (week 0) to week 26 and week 52 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. 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.

Change in SMPG - Mean Postprandial Increment Over All Meals

Change from baseline (week 0) in the average of the post-prandial increments over all meals was evaluated at weeks 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.

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 weeks 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.

Participants Who Achieve HbA1c <6.5% (48 mmol/Mol) AACE Target (Yes/no)

Participants who achieved HbA1c less than or equal to 6.5% (American Association of Clinical Endocrinologists (AACE) target) (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.

Participants Who Achieve Weight Loss ≥5% (Yes/no)

Participants who achieved weight loss more than or equal to 5% of their baseline body weight (yes/no) at weeks 26 and 52 are presented. 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.

Participants Who Achieve Weight Loss ≥ 10% (Yes/no)

Participants who achieved weight loss more than or equal to 10% of their baseline body weight (yes/no) at weeks 26 and 52 are presented. 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.

Participants Who Achieve HbA1c <7.0 % (53 mmol/Mol) Without Hypoglycaemia (Severe or BG Confirmed Symptomatic Hypoglycaemia) and no Weight Gain (Yes/no)

Participants who achieved HbA1c less than 7.0 % without severe or blood glucose (BG) confirmed symptomatic hypoglycaemia and without weight gain (yes/no) at weeks 26 and 52 are presented. Severe hypoglycaemia was defined as an episode requiring assistance of another person to actively administer carbohydrate or glucagon, or take other corrective actions. BG-confirmed symptomatic hypoglycaemia was defined as an episode with plasma glucose value <3.1 mmol/L with symptoms consistent with hypoglycaemia. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product.

Participants Who Achieve HbA1c Reduction ≥1% (10.9 mmol/Mol) and Weight Loss ≥3% (Yes/no)

Participants who achieved HbA1c reduction more than or equal to 1% of their baseline HbA1c and weight loss of more than or equal to 3% of their baseline body weight (yes/no) at weeks 26 and 52 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product.

Time to Additional Anti-diabetic Medication

Presented results are the number of participants who had taken additional anti-diabetic medication anytime during the periods, from week 0 to week 26 and week 0 to week 52. Additional anti-diabetic medication was defined as 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 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.

Time to Rescue Medication

Presented results are the number of participants who had taken rescue medication anytime during the periods, from week 0 to week 26 and week 0 to week 52. Rescue medication was defined as 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.

Number of Treatment-emergent Adverse Events (TEAEs) During Exposure to Trial Product

Treatment emergent adverse events (TEAEs) were recorded from week 0 to week 57 (52-week treatment period plus the 5-week follow-up period). Adverse events (AEs) with onset during the on-treatment observation period were considered treatment-emergent. On-treatment observation period: Time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.

Change in Amylase - Ratio to Baseline

Change from baseline (week 0) in amylase (units/litre (U/L)) at weeks 26 and 52 is presented as ratio to baseline. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.

Change in Lipase - Ratio to Baseline

Change from baseline (week 0) in lipase (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.

Change in Pulse Rate

Change from baseline (week 0) in pulse rate was evaluated at weeks 26 and 52. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.

Change in SBP and DBP

Change from baseline (week 0) in systolic blood pressure (SBP) and diastolic blood pressure (DBP) was evaluated at weeks 26 and 52. Results are based on the data from the on-treatment observation period which was the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication.

Change in ECG Evaluation

Change from baseline (week 0) in electrocardiogram (ECG) was evaluated at weeks 26 and week 52. 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 and week 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.

Change in Physical Examination

Participants with physical examination findings, normal, abnormal NCS and abnormal CS at baseline (weeks -2) and weeks 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. 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.

Change in Eye Examination Category

Participants with eye examination (fundoscopy) findings, normal, abnormal NCS and abnormal CS at baseline (week -2) and week 52 are presented. Results are based on the data from the in-trial observation period, which was the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product.

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 0-57) 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.

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 0-57) 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.

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 0-57) 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.

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 0-57) 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.

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 0-57). 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.

Number of Treatment-emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemic Episodes

Treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes were recorded during weeks 0-57 (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.

Participants With 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 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.

Change in DTSQs: Individual Items and Total 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 (wk 26) and week 52 (wk 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.

Full Information

NCT ID

NCT02863419

First Posted

August 8, 2016

Last Updated

July 11, 2022

Sponsor

Novo Nordisk A/S

1. Study Identification

Unique Protocol Identification Number

NCT02863419

Brief Title

Efficacy and Safety of Oral Semaglutide Versus Liraglutide and Versus Placebo in Subjects With Type 2 Diabetes Mellitus

Acronym

PIONEER 4

Official Title

Efficacy and Safety of Oral Semaglutide Versus Liraglutide and Versus Placebo in Subjects With Type 2 Diabetes Mellitus

Study Type

Interventional

2. Study Status

Record Verification Date

July 2022

Overall Recruitment Status

Completed

Study Start Date

August 10, 2016 (Actual)

Primary Completion Date

August 19, 2017 (Actual)

Study Completion Date

March 30, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novo Nordisk A/S

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

This trial is conducted globally. The aim of this trial is to investigate efficacy and safety of oral Semaglutide versus Liraglutide and versus Placebo in Subjects with Type 2 Diabetes Mellitus.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Diabetes, Diabetes Mellitus, Type 2

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

711 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Oral Semaglutide

Arm Type

Experimental

Arm Title

Liraglutide

Arm Type

Active Comparator

Arm Title

Placebo

Arm Type

Placebo Comparator

Intervention Type

Drug

Intervention Name(s)

semaglutide

Intervention Description

Oral semaglutide once-daily.

Intervention Type

Drug

Intervention Name(s)

liraglutide

Intervention Description

Subcutaneous (s.c.) injection once-daily.

Intervention Type

Drug

Intervention Name(s)

placebo

Intervention Description

Placebo once-daily.

Primary Outcome Measure Information:

Title

Change in HbA1c (Week 26)

Description

Time Frame

Week 0, week 26

Secondary Outcome Measure Information:

Title

Change in Body Weight (Week 26)

Description

Time Frame

Week 0, week 26

Title

Change in HbA1c (Week 52)

Description

Time Frame

Week 0, week 52

Title

Change in Body Weight (Week 52)

Description

Time Frame

Week 0, week 52

Title

Change in Body Weight (%)

Description

Time Frame

Week 0, Week 26, Week 52

Title

Change in Fasting Plasma Glucose

Description

Time Frame

Week 0, week 26, week 52

Title

Change in Body Mass Index

Description

Time Frame

Week 0, week 26, week 52

Title

Change in Waist Circumference

Description

Time Frame

Week 0, week 26, week 52

Title

Change in Total Cholesterol - Ratio to Baseline

Description

Time Frame

Week 0, week 26, week 52

Title

Change in Low-density Lipoprotein (LDL) Cholesterol - Ratio to Baseline

Description

Time Frame

Week 0, week 26, week 52

Title

Change in Very Low Density Lipoprotein (VLDL) Cholesterol - Ratio to Baseline

Description

Time Frame

Week 0, week 26, week 52

Title

Change in High-density Lipoprotein (HDL) Cholesterol - Ratio to Baseline

Description

Time Frame

Week 0, week 26, week 52

Title

Change in Triglycerides - Ratio to Baseline

Description

Time Frame

Week 0, week 26, week 52

Title

Change in Free Fatty Acids - Ratio to Baseline

Description

Time Frame

Week 0, week 26, week 52

Title

Change in SMPG - Mean 7-point Profile

Description

Time Frame

Week 0, week 26, week 52

Title

Change in SMPG - Mean Postprandial Increment Over All Meals

Description

Time Frame

Week 0, week 26, week 52

Title

Participants Who Achieve HbA1c <7.0% (53 mmol/Mol) ADA Target (Yes/no)

Description

Time Frame

Week 26, week 52

Title

Participants Who Achieve HbA1c <6.5% (48 mmol/Mol) AACE Target (Yes/no)

Description

Time Frame

Week 26, week 52

Title

Participants Who Achieve Weight Loss ≥5% (Yes/no)

Description

Time Frame

Week 26, week 52

Title

Participants Who Achieve Weight Loss ≥ 10% (Yes/no)

Description

Time Frame

Week 26, week 52

Title

Participants Who Achieve HbA1c <7.0 % (53 mmol/Mol) Without Hypoglycaemia (Severe or BG Confirmed Symptomatic Hypoglycaemia) and no Weight Gain (Yes/no)

Description

Time Frame

Week 26, week 52

Title

Participants Who Achieve HbA1c Reduction ≥1% (10.9 mmol/Mol) and Weight Loss ≥3% (Yes/no)

Description

Time Frame

Week 26, week 52

Title

Time to Additional Anti-diabetic Medication

Description

Time Frame

Weeks 0-52

Title

Time to Rescue Medication

Description

Time Frame

Weeks 0-52

Title

Number of Treatment-emergent Adverse Events (TEAEs) During Exposure to Trial Product

Description

Time Frame

Weeks 0-57

Title

Change in Amylase - Ratio to Baseline

Description

Time Frame

Week 0, week 26, week 52

Title

Change in Lipase - Ratio to Baseline

Description

Time Frame

Week 0, week 26, week 52

Title

Change in Pulse Rate

Description

Time Frame

Week 0, week 26, week 52

Title

Change in SBP and DBP

Description

Time Frame

Week 0, week 26, week 52

Title

Change in ECG Evaluation

Description

Time Frame

Week 0, week 26, week 52

Title

Change in Physical Examination

Description

Time Frame

Week -2, week 52

Title

Change in Eye Examination Category

Description

Time Frame

Week -2, Week 52

Title

Occurrence of Anti-semaglutide Binding Antibodies (Yes/no)

Description

Time Frame

Weeks 0-57

Title

Occurrence of Anti-semaglutide Neutralising Antibodies (Yes/no)

Description

Time Frame

Weeks 0-57

Title

Occurrence of Anti-semaglutide Binding Antibodies Cross Reacting With Native GLP-1 (Yes/no)

Description

Time Frame

Week 0-57

Title

Occurrence of Anti-semaglutide Neutralising Antibodies Cross Reacting With Native GLP-1 (Yes/no)

Description

Time Frame

Weeks 0-57

Title

Anti-semaglutide Binding Antibody Levels

Description

Time Frame

Weeks 0-57

Title

Number of Treatment-emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemic Episodes

Description

Time Frame

Weeks 0-57

Title

Participants With Treatment-emergent Severe or BG-confirmed Symptomatic Hypoglycaemic Episodes

Description

Time Frame

Weeks 0-57

Title

Change in DTSQs: Individual Items and Total Treatment Satisfaction Score (6 of the 8 Items Summed)

Description

Time Frame

Week 0, week 26, week 52

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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 at least 20 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 % (53-80.3 mmol/mol) (both inclusive) Stable daily dose of metformin (above or equal to 1500 mg or maximum tolerated dose as documented in the subject medical record) alone or in combination with a stable daily dose of a SGLT-2 (sodium-glucose co-transporter-2) inhibitor for at least 90 days prior to day of screening (fixed-dose combinations are allowed) 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 (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 Subjects presently classified as being in New York Heart Association (NYHA) Class IV Planned coronary, carotid or peripheral artery revascularisation known on the day of screening Subjects with ALT (alanine aminotransferase) above 2.5 × upper normal limit (UNL) Renal impairment defined as estimated Glomerular Filtration Rate (eGFR) below 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 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 carcinoma in situ) History of diabetic ketoacidosis

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Global Clinical Registry (GCR, 1452)

Organizational Affiliation

Novo Nordisk A/S

Official's Role

Study Director

Facility Information:

Facility Name

Novo Nordisk Investigational Site

City

Birmingham

State/Province

Alabama

ZIP/Postal Code

35222

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Los Alamitos

State/Province

California

ZIP/Postal Code

90720

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

San Diego

State/Province

California

ZIP/Postal Code

92111

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Denver

State/Province

Colorado

ZIP/Postal Code

80246

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Hallandale Beach

State/Province

Florida

ZIP/Postal Code

33009

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Jacksonville

State/Province

Florida

ZIP/Postal Code

32256

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Miami

State/Province

Florida

ZIP/Postal Code

33155

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Ocala

State/Province

Florida

ZIP/Postal Code

34470

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Orlando

State/Province

Florida

ZIP/Postal Code

32801

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Orlando

State/Province

Florida

ZIP/Postal Code

32804

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Ormond Beach

State/Province

Florida

ZIP/Postal Code

32174-6302

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Saint Petersburg

State/Province

Florida

ZIP/Postal Code

33713

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

West Palm Beach

State/Province

Florida

ZIP/Postal Code

33401

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Peoria

State/Province

Illinois

ZIP/Postal Code

61603

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Topeka

State/Province

Kansas

ZIP/Postal Code

66606

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Slidell

State/Province

Louisiana

ZIP/Postal Code

70461-4231

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Butte

State/Province

Montana

ZIP/Postal Code

59701

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Lebanon

State/Province

New Hampshire

ZIP/Postal Code

03756

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Teaneck

State/Province

New Jersey

ZIP/Postal Code

07666

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Albany

State/Province

New York

ZIP/Postal Code

12203

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Mineola

State/Province

New York

ZIP/Postal Code

11501

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Greensboro

State/Province

North Carolina

ZIP/Postal Code

27408

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Morganton

State/Province

North Carolina

ZIP/Postal Code

28655

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Wilmington

State/Province

North Carolina

ZIP/Postal Code

28401

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Dublin

State/Province

Ohio

ZIP/Postal Code

43016

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Maumee

State/Province

Ohio

ZIP/Postal Code

43537

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Norman

State/Province

Oklahoma

ZIP/Postal Code

73069

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

McMurray

State/Province

Pennsylvania

ZIP/Postal Code

15317

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Summerville

State/Province

South Carolina

ZIP/Postal Code

29485

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Bristol

State/Province

Tennessee

ZIP/Postal Code

37620-7352

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Arlington

State/Province

Texas

ZIP/Postal Code

76012-4637

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Dallas

State/Province

Texas

ZIP/Postal Code

75230

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Dallas

State/Province

Texas

ZIP/Postal Code

75390-9302

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Houston

State/Province

Texas

ZIP/Postal Code

77004-7000

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

North Richland Hills

State/Province

Texas

ZIP/Postal Code

76180

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

San Antonio

State/Province

Texas

ZIP/Postal Code

78229

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

San Antonio

State/Province

Texas

ZIP/Postal Code

78249

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Newport News

State/Province

Virginia

ZIP/Postal Code

23606

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Richmond

State/Province

Virginia

ZIP/Postal Code

23219

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Virginia Beach

State/Province

Virginia

ZIP/Postal Code

23454

Country

United States

Facility Name

Novo Nordisk Investigational Site

City

Karlovac

ZIP/Postal Code

47000

Country

Croatia

Facility Name

Novo Nordisk Investigational Site

City

Osijek

ZIP/Postal Code

31 000

Country

Croatia

Facility Name

Novo Nordisk Investigational Site

City

Slavonski Brod

ZIP/Postal Code

35 000

Country

Croatia

Facility Name

Novo Nordisk Investigational Site

City

Zagreb

ZIP/Postal Code

10 000

Country

Croatia

Facility Name

Novo Nordisk Investigational Site

City

Zagreb

ZIP/Postal Code

10000

Country

Croatia

Facility Name

Novo Nordisk Investigational Site

City

Nachod

ZIP/Postal Code

54701

Country

Czechia

Facility Name

Novo Nordisk Investigational Site

City

Plzen

ZIP/Postal Code

304 60

Country

Czechia

Facility Name

Novo Nordisk Investigational Site

City

Praha 5

ZIP/Postal Code

150 00

Country

Czechia

Facility Name

Novo Nordisk Investigational Site

City

Bochum

ZIP/Postal Code

44791

Country

Germany

Facility Name

Novo Nordisk Investigational Site

City

Duisburg

ZIP/Postal Code

47051

Country

Germany

Facility Name

Novo Nordisk Investigational Site

City

Falkensee

ZIP/Postal Code

14612

Country

Germany

Facility Name

Novo Nordisk Investigational Site

City

Hamburg

ZIP/Postal Code

22607

Country

Germany

Facility Name

Novo Nordisk Investigational Site

City

Ludwigshafen

ZIP/Postal Code

67059

Country

Germany

Facility Name

Novo Nordisk Investigational Site

City

Oldenburg I. Holst

ZIP/Postal Code

23758

Country

Germany

Facility Name

Novo Nordisk Investigational Site

City

Saint Ingbert-Oberwürzbach

ZIP/Postal Code

66386

Country

Germany

Facility Name

Novo Nordisk Investigational Site

City

Villingen-Schwenningen

ZIP/Postal Code

78048

Country

Germany

Facility Name

Novo Nordisk Investigational Site

City

Budapest

ZIP/Postal Code

1032

Country

Hungary

Facility Name

Novo Nordisk Investigational Site

City

Budapest

ZIP/Postal Code

1042

Country

Hungary

Facility Name

Novo Nordisk Investigational Site

City

Gyula

ZIP/Postal Code

5700

Country

Hungary

Facility Name

Novo Nordisk Investigational Site

City

Kalocsa

ZIP/Postal Code

6300

Country

Hungary

Facility Name

Novo Nordisk Investigational Site

City

Nagykanizsa

ZIP/Postal Code

8800

Country

Hungary

Facility Name

Novo Nordisk Investigational Site

City

Szeged

ZIP/Postal Code

H-6725

Country

Hungary

Facility Name

Novo Nordisk Investigational Site

City

Szigetvár

ZIP/Postal Code

7900

Country

Hungary

Facility Name

Novo Nordisk Investigational Site

City

Szolnok

ZIP/Postal Code

5004

Country

Hungary

Facility Name

Novo Nordisk Investigational Site

City

Székesfehérvár

ZIP/Postal Code

8000

Country

Hungary

Facility Name

Novo Nordisk Investigational Site

City

Tatabánya

ZIP/Postal Code

2800

Country

Hungary

Facility Name

Novo Nordisk Investigational Site

City

Bunkyo-ku, Tokyo

ZIP/Postal Code

113-8655

Country

Japan

Facility Name

Novo Nordisk Investigational Site

City

Kumamoto-shi,Kumamoto

ZIP/Postal Code

862 0976

Country

Japan

Facility Name

Novo Nordisk Investigational Site

City

Mito-shi, Ibaraki

ZIP/Postal Code

310-0826

Country

Japan

Facility Name

Novo Nordisk Investigational Site

City

Okawa-shi, Fukuoka

ZIP/Postal Code

831-0016

Country

Japan

Facility Name

Novo Nordisk Investigational Site

City

Sapporo-shi, Hokkaido

ZIP/Postal Code

060-0001

Country

Japan

Facility Name

Novo Nordisk Investigational Site

City

Shimotsuke-shi, Tochigi

ZIP/Postal Code

329-0433

Country

Japan

Facility Name

Novo Nordisk Investigational Site

City

Suita-shi, Osaka

ZIP/Postal Code

564-0051

Country

Japan

Facility Name

Novo Nordisk Investigational Site

City

Tochigi

ZIP/Postal Code

323-0022

Country

Japan

Facility Name

Novo Nordisk Investigational Site

City

Yamato-shi, Kanagawa

ZIP/Postal Code

242-0004

Country

Japan

Facility Name

Novo Nordisk Investigational Site

City

Ogre

ZIP/Postal Code

LV-5001

Country

Latvia

Facility Name

Novo Nordisk Investigational Site

City

Riga

ZIP/Postal Code

LV-1002

Country

Latvia

Facility Name

Novo Nordisk Investigational Site

City

Riga

ZIP/Postal Code

LV-1011

Country

Latvia

Facility Name

Novo Nordisk Investigational Site

City

Riga

ZIP/Postal Code

LV-1038

Country

Latvia

Facility Name

Novo Nordisk Investigational Site

City

Bialystok

ZIP/Postal Code

15-445

Country

Poland

Facility Name

Novo Nordisk Investigational Site

City

Bydgoszcz

ZIP/Postal Code

85-822

Country

Poland

Facility Name

Novo Nordisk Investigational Site

City

Gdansk

ZIP/Postal Code

80-214

Country

Poland

Facility Name

Novo Nordisk Investigational Site

City

Gniewkowo

ZIP/Postal Code

88-140

Country

Poland

Facility Name

Novo Nordisk Investigational Site

City

Krakow

ZIP/Postal Code

30-363

Country

Poland

Facility Name

Novo Nordisk Investigational Site

City

Poznan

ZIP/Postal Code

60-589

Country

Poland

Facility Name

Novo Nordisk Investigational Site

City

Szczecin

ZIP/Postal Code

70-506

Country

Poland

Facility Name

Novo Nordisk Investigational Site

City

Warszawa

ZIP/Postal Code

02-507

Country

Poland

Facility Name

Novo Nordisk Investigational Site

City

Wroclaw

ZIP/Postal Code

52-416

Country

Poland

Facility Name

Novo Nordisk Investigational Site

City

Toa Baja

ZIP/Postal Code

00949

Country

Puerto Rico

Facility Name

Novo Nordisk Investigational Site

City

Bardejov

ZIP/Postal Code

08501

Country

Slovakia

Facility Name

Novo Nordisk Investigational Site

City

Bratislava

ZIP/Postal Code

851 01

Country

Slovakia

Facility Name

Novo Nordisk Investigational Site

City

Kosice

ZIP/Postal Code

040 01

Country

Slovakia

Facility Name

Novo Nordisk Investigational Site

City

Nitra

ZIP/Postal Code

949 01

Country

Slovakia

Facility Name

Novo Nordisk Investigational Site

City

Roznava

ZIP/Postal Code

04801

Country

Slovakia

Facility Name

Novo Nordisk Investigational Site

City

Vrutky

ZIP/Postal Code

038 61

Country

Slovakia

Facility Name

Novo Nordisk Investigational Site

City

Benoni

State/Province

Gauteng

ZIP/Postal Code

1501

Country

South Africa

Facility Name

Novo Nordisk Investigational Site

City

Johannesburg

State/Province

Gauteng

ZIP/Postal Code

2193

Country

South Africa

Facility Name

Novo Nordisk Investigational Site

City

Durban

State/Province

KwaZulu-Natal

ZIP/Postal Code

4092

Country

South Africa

Facility Name

Novo Nordisk Investigational Site

City

Durban

State/Province

KwaZulu-Natal

ZIP/Postal Code

4450

Country

South Africa

Facility Name

Novo Nordisk Investigational Site

City

Cape Town

State/Province

Western Cape

ZIP/Postal Code

7500

Country

South Africa

Facility Name

Novo Nordisk Investigational Site

City

Kyiv

ZIP/Postal Code

04114

Country

Ukraine

Facility Name

Novo Nordisk Investigational Site

City

Odesa

ZIP/Postal Code

65059

Country

Ukraine

Facility Name

Novo Nordisk Investigational Site

City

Vinnytsia

ZIP/Postal Code

21010

Country

Ukraine

Facility Name

Novo Nordisk Investigational Site

City

Ajman

ZIP/Postal Code

21499

Country

United Arab Emirates

Facility Name

Novo Nordisk Investigational Site

City

Al Mafraq

ZIP/Postal Code

2951

Country

United Arab Emirates

Facility Name

Novo Nordisk Investigational Site

City

Dubai

ZIP/Postal Code

4545

Country

United Arab Emirates

Facility Name

Novo Nordisk Investigational Site

City

Rahba City

ZIP/Postal Code

34555

Country

United Arab Emirates

Facility Name

Novo Nordisk Investigational Site

City

Umm Al Quwain

ZIP/Postal Code

Country

United Arab Emirates

12. IPD Sharing Statement

Citations:

PubMed Identifier

31186120

Citation

Pratley R, Amod A, Hoff ST, Kadowaki T, Lingvay I, Nauck M, Pedersen KB, Saugstrup T, Meier JJ; PIONEER 4 investigators. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. Lancet. 2019 Jul 6;394(10192):39-50. doi: 10.1016/S0140-6736(19)31271-1. Epub 2019 Jun 8. Erratum In: Lancet. 2019 Jul 6;394(10192):e1.

Results Reference

result

PubMed Identifier

34472698

Citation

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.

Results Reference

result

PubMed Identifier

35373893

Citation

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.

Results Reference

result

PubMed Identifier

33660198

Citation

Pratley RE, Crowley MJ, Gislum M, Hertz CL, Jensen TB, Khunti K, Mosenzon O, Buse JB. Oral Semaglutide Reduces HbA1c and Body Weight in Patients with Type 2 Diabetes Regardless of Background Glucose-Lowering Medication: PIONEER Subgroup Analyses. Diabetes Ther. 2021 Apr;12(4):1099-1116. doi: 10.1007/s13300-020-00994-9. Epub 2021 Mar 4.

Results Reference

derived

PubMed Identifier

32267058

Citation

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.

Results Reference

derived

PubMed Identifier

31903692

Citation

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.

Results Reference

derived

Links:

URL

http://novonordisk-trials.com

Description

Clinical Trials at Novo Nordisk

Learn more about this trial

Efficacy and Safety of Oral Semaglutide Versus Liraglutide and Versus Placebo in Subjects With Type 2 Diabetes Mellitus

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Efficacy and Safety of Oral Semaglutide Versus Liraglutide and Versus Placebo in Subjects With Type 2 Diabetes Mellitus (PIONEER 4)

Diabetes, Diabetes Mellitus, Type 2

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial