NCT04109547: PIONEER 11

A Research Study Comparing a New Medicine Oral Semaglutide to Placebo in People With Type 2 Diabetes

Completed Phase 3 Results posted Last updated 19 September 2024

What this trial tests

Phase 3 trial testing Oral semaglutide in Diabetes Mellitus, Type 2 in 521 participants. Completed in 27 October 2021.

Timeline

1 October 2019

Primary endpoint
23 September 2021

27 October 2021

Quick facts

Lead sponsor	Novo Nordisk A/S
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	521
Start date	1 October 2019
Primary completion	23 September 2021
Estimated completion	27 October 2021
Sites	66 locations across Ukraine, Serbia, Taiwan, Hungary, Algeria, China

Drugs / interventions tested

• Oral semaglutide
• Placebo

Conditions studied

• Diabetes Mellitus, Type 2 — all drugs for Diabetes Mellitus, Type 2 →

Sponsor

Novo Nordisk A/S — full company profile →

Who can join

18 and older, any sex, with Diabetes Mellitus, Type 2. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change From Baseline in Glycosylated Haemoglobin (HbA1c) Primary · Baseline (Week 0), Week 26

Change from baseline (week 0) in HbA1c at week 26 is presented. The outcome data was evaluated based on the on-treatment without rescue medication observation period: from date of first dose of trial product following randomization up to the end date which was the first date of any of the following: the last dose of trial product plus 3 days or initiation of rescue medication.

Group	Value	95% CI
Oral Semaglutide 3 mg	-1.1	± 0.7
Oral Semaglutide 7 mg	-1.5	± 0.8
Oral Semaglutide 14 mg	-1.6	± 1.0
Placebo	-0.2	± 0.9

Change From Baseline in Body Weight (Kilograms [kg]) Secondary · Baseline (Week 0), Week 26

Change from baseline (week 0) in body weight at week 26 is presented. The outcome data was evaluated based on the on-treatment without rescue medication observation period: from date of first dose of trial product following randomization up to the end date which was the first date of any of the following: the last dose of trial product plus 3 days or initiation of rescue medication.

Group	Value	95% CI
Oral Semaglutide 3 mg	-1.1	± 3.3
Oral Semaglutide 7 mg	-2.2	± 3.4
Oral Semaglutide 14 mg	-3.1	± 3.7
Placebo	-1.1	± 2.7

Change From Baseline in Fasting Plasma Glucose (FPG) Secondary · Baseline (Week 0), Week 26

Change from baseline (week 0) in FPG at week 26 is presented. The outcome data was evaluated based on the on-treatment without rescue medication observation period: from date of first dose of trial product following randomization up to the end date which was the first date of any of the following: the last dose of trial product plus 3 days or initiation of rescue medication.

Group	Value	95% CI
Oral Semaglutide 3 mg	-19.07	± 32.44
Oral Semaglutide 7 mg	-32.28	± 27.95
Oral Semaglutide 14 mg	-32.50	± 24.91
Placebo	0.00	± 27.49

Change From Baseline in Fasting 7-point Self-measured Plasma Glucose (SMPG) Profile: Mean 7-point Profile Secondary · Baseline (Week 0), Week 26

Change from baseline (week 0) in mean 7-point SMPG profile at week 26 is presented. 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. The outcome data was evaluated based on the on-treatment without rescue medication observation period: from date of first dose of trial product following randomization up to the end date which was the first date of any of the following: the last dose of trial product plus 3 days or initiation of rescue medic

Group	Value	95% CI
Oral Semaglutide 3 mg	-29.4	± 29.3
Oral Semaglutide 7 mg	-43.0	± 36.1
Oral Semaglutide 14 mg	-44.5	± 36.9
Placebo	-10.3	± 37.5

Change From Baseline in Fasting 7-point Self-measured Plasma Glucose Profile: Mean Postprandial Increment (Over All Meals) Secondary · Baseline (Week 0), Week 26

Change from baseline (week 0) in fasting 7-point SMPG: Mean postprandial increment (over all meals) at week 26 is presented. The outcome data was evaluated based on the on-treatment without rescue medication observation period: from date of first dose of trial product following randomization up to the end date which was the first date of any of the following: the last dose of trial product plus 3 days or initiation of rescue medication.

Group	Value	95% CI
Oral Semaglutide 3 mg	-14.5	± 34.2
Oral Semaglutide 7 mg	-20.0	± 39.9
Oral Semaglutide 14 mg	-27.9	± 40.6
Placebo	-6.7	± 35.6

Change From Baseline in Body Weight (Percentage [%]) Secondary · Baseline (Week 0), Week 26

Change from baseline (week 0) in body weight (measured in kg) at week 26 is presented. The outcome data was evaluated based on the on-treatment without rescue medication observation period: from date of first dose of trial product following randomization up to the end date which was the first date of any of the following: the last dose of trial product plus 3 days or initiation of rescue medication.

Group	Value	95% CI
Oral Semaglutide 3 mg	-1	± 4
Oral Semaglutide 7 mg	-3	± 4
Oral Semaglutide 14 mg	-4	± 5
Placebo	-1	± 3

Change From Baseline in Body Mass Index (BMI) Secondary · Baseline (Week 0), Week 26

Change from baseline (week 0) in BMI at week 26 is presented. The outcome data was evaluated based on the on-treatment without rescue medication observation period: from date of first dose of trial product following randomization up to the end date which was the first date of any of the following: the last dose of trial product plus 3 days or initiation of rescue medication.

Group	Value	95% CI
Oral Semaglutide 3 mg	-0.4	± 1.2
Oral Semaglutide 7 mg	-0.8	± 1.2
Oral Semaglutide 14 mg	-1.1	± 1.3
Placebo	-0.4	± 0.9

Change From Baseline in Waist Circumference Secondary · Baseline (Week 0), Week 26

Change from baseline (week 0) in waist circumference at week 26 is presented. The outcome data was evaluated based on the on-treatment without rescue medication observation period: from date of first dose of trial product following randomization up to the end date which was the first date of any of the following: the last dose of trial product plus 3 days or initiation of rescue medication.

Group	Value	95% CI
Oral Semaglutide 3 mg	-2.1	± 4.5
Oral Semaglutide 7 mg	-2.2	± 4.8
Oral Semaglutide 14 mg	-2.8	± 4.4
Placebo	-1.4	± 3.3

Change From Baseline in Fasting Lipid Profile: Total Cholesterol (Ratio to Baseline) Secondary · Baseline (Week 0), Week 26

Change from baseline (week 0) in total cholesterol (measured in mg/dL) at week 26 is presented as ratio to baseline. The outcome data was evaluated based on the on-treatment without rescue medication observation period: from date of first dose of trial product following randomization up to the end date which was the first date of any of the following: the last dose of trial product plus 3 days or initiation of rescue medication.

Group	Value	95% CI
Oral Semaglutide 3 mg	0.99	± 14.75
Oral Semaglutide 7 mg	0.98	± 16.62
Oral Semaglutide 14 mg	0.94	± 19.92
Placebo	1.00	± 14.45

Change From Baseline in Fasting Lipid Profile: Low-density Lipoprotein (LDL) Cholesterol (Ratio to Baseline) Secondary · Baseline (Week 0), Week 26

Change from baseline (week 0) in LDL cholesterol (measured in mg/dL) at week 26 is presented as ratio to baseline. The outcome data was evaluated based on the on-treatment without rescue medication observation period: from date of first dose of trial product following randomization up to the end date which was the first date of any of the following: the last dose of trial product plus 3 days or initiation of rescue medication.

Group	Value	95% CI
Oral Semaglutide 3 mg	1.00	± 29.65
Oral Semaglutide 7 mg	1.00	± 28.35
Oral Semaglutide 14 mg	0.94	± 31.12
Placebo	1.00	± 25.32

Change From Baseline in Fasting Lipid Profile: High-density Lipoprotein (HDL) Cholesterol (Ratio to Baseline) Secondary · Baseline (Week 0), Week 26

Change from baseline (week 0) in HDL cholesterol (measured in mg/dL) at week 26 is presented as ratio to baseline. The outcome data was evaluated based on the on-treatment without rescue medication observation period: from date of first dose of trial product following randomization up to the end date which was the first date of any of the following: the last dose of trial product plus 3 days or initiation of rescue medication.

Group	Value	95% CI
Oral Semaglutide 3 mg	1.03	± 15.78
Oral Semaglutide 7 mg	1.02	± 15.41
Oral Semaglutide 14 mg	1.02	± 17.72
Placebo	1.04	± 14.61

Change From Baseline in Fasting Lipid Profile: Triglycerides (Ratio to Baseline) Secondary · Baseline (Week 0), Week 26

Change from baseline (week 0) in triglycerides (measured in mg/dL) at week 26 is presented as ratio to baseline. The outcome data was evaluated based on the on-treatment without rescue medication observation period: from date of first dose of trial product following randomization up to the end date which was the first date of any of the following: the last dose of trial product plus 3 days or initiation of rescue medication.

Group	Value	95% CI
Oral Semaglutide 3 mg	0.96	± 45.32
Oral Semaglutide 7 mg	0.90	± 45.56
Oral Semaglutide 14 mg	0.87	± 51.82
Placebo	0.93	± 49.08

Adverse events — posted to ClinicalTrials.gov

Time frame: From week 0 to week 31. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Oral Semaglutide 3 mg

Serious: 6/130 (5%)

Deaths: 0/130

Oral Semaglutide 7 mg

Serious: 10/130 (8%)

Deaths: 0/130

Oral Semaglutide 14 mg

Serious: 5/129 (4%)

Deaths: 0/129

Placebo

Serious: 2/131 (2%)

Deaths: 0/131

Serious adverse events (23 terms)

Reaction	System	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
COVID-19 pneumonia	Infections and infestations	—	—	—	—
Cholelithiasis	Hepatobiliary disorders	—	—	—	—
Angina unstable	Cardiac disorders	—	—	—	—
Asthma	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Atrial fibrillation	Cardiac disorders	—	—	—	—
Cataract	Eye disorders	—	—	—	—
Cholecystitis acute	Hepatobiliary disorders	—	—	—	—
Dermal cyst	Skin and subcutaneous tissue disorders	—	—	—	—
Epilepsy	Nervous system disorders	—	—	—	—
Limb injury	Injury, poisoning and procedural complications	—	—	—	—
Lung abscess	Infections and infestations	—	—	—	—
Myocardial ischaemia	Cardiac disorders	—	—	—	—
Nail injury	Injury, poisoning and procedural complications	—	—	—	—
Neck injury	Injury, poisoning and procedural complications	—	—	—	—
Nephrolithiasis	Renal and urinary disorders	—	—	—	—
Papillary thyroid cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—
Pelvic fracture	Injury, poisoning and procedural complications	—	—	—	—
Respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Rib fracture	Injury, poisoning and procedural complications	—	—	—	—
Spinal fracture	Injury, poisoning and procedural complications	—	—	—	—
Spinal osteoarthritis	Musculoskeletal and connective tissue disorders	—	—	—	—
Splenic rupture	Injury, poisoning and procedural complications	—	—	—	—
Ulna fracture	Injury, poisoning and procedural complications	—	—	—	—

Other adverse events (8 terms — click to expand)

Reaction	System	Oral Semaglutide 3 mg	Oral Semaglutide 7 mg	Oral Semaglutide 14 mg	Placebo
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—
Lipase increased	Investigations	—	—	—	—
Abdominal distension	Gastrointestinal disorders	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—
Hyperlipidaemia	Metabolism and nutrition disorders	—	—	—	—

Most-reported serious reactions: COVID-19 pneumonia, Cholelithiasis, Angina unstable, Asthma, Atrial fibrillation, Cataract, Cholecystitis acute, Dermal cyst.

Data from ClinicalTrials.gov NCT04109547 adverse events section.

Sponsor's own description

The study compares 2 medicines for type 2 diabetes: oral semaglutide (a new medicine) and placebo (a dummy medicine). Researchers will test semaglutide to see how well it works compared to placebo. The study will also test if semaglutide is safe. Participants will either get semaglutide or placebo - which treatment is decided by chance. Participants will get 1 tablet a day to take with up to half a glass of water. Participants must take the tablet first thing in the morning on an empty stomach. After taking the tablet, participants must not eat or drink anything for at least 30 minutes. After the 30 minutes, participants can have their first meal of the day and take any other medicines they may need. The study will last for about 8 months (36 weeks). Participants will have 9 clinic visits and 2 phone calls with the study doctor. At all 9 of the clinic visits, participants will have blood samples taken. At 5 of the clinic visits, participants must arrive fasting. This means they cannot eat for 8 hours before the visit. It is fine to drink water up to 2 hours before the visit. This is for some of the blood samples that will be taken at the visit. Women cannot take part if pregnant, breastfeeding or planning to become pregnant during the study period.

Publications & conference data

7 peer-reviewed publications reference this trial (live from Europe PMC):

1. Semaglutide, a glucagon like peptide-1 receptor agonist with cardiovascular benefits for management of type 2 diabetes.
   Mahapatra MK, Karuppasamy M, Sahoo BM. · · 2022 · cited 92× · PMID 34993760 · DOI 10.1007/s11154-021-09699-1
2. Therapeutic Potential of Semaglutide, a Newer GLP-1 Receptor Agonist, in Abating Obesity, Non-Alcoholic Steatohepatitis and Neurodegenerative diseases: A Narrative Review.
   Mahapatra MK, Karuppasamy M, Sahoo BM. · · 2022 · cited 84× · PMID 35650449 · DOI 10.1007/s11095-022-03302-1
3. Effect of glucagon-like peptide-1 receptor agonists on glycemic control, and weight reduction in adults: A multivariate meta-analysis.
   Yeh TL, Tsai MC, Tsai WH, Tu YK, et al · · 2023 · cited 33× · PMID 36696429 · DOI 10.1371/journal.pone.0278685
4. Efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes (PIONEER 11): a double-blind, Phase IIIa, randomised trial.
   Wang W, Bain SC, Bian F, Chen R, et al · · 2024 · cited 13× · PMID 38985162 · DOI 10.1007/s00125-024-06142-3
5. Effect of semaglutide on arrhythmic, major cardiovascular, and microvascular outcomes in patients with type 2 diabetes: a systematic review and meta-analysis.
   Wu R, Xing B, Huang Y, Zhou Z, et al · · 2025 · cited 1× · PMID 40933383 · DOI 10.3389/fendo.2025.1554795
6. Efficacy and safety of oral semaglutide in Chinese participants with type 2 diabetes: Subgroup analyses by baseline characteristics in the PIONEER 11 and 12 randomised controlled trials.
   Ji L, Yuan G, Liu J, Zhang B, et al · · 2025 · cited 1× · PMID 40843773 · DOI 10.1111/dom.70031
7. Comparative Efficacy and Safety of Oral Semaglutide in Asians and Non-Asians Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.
   Wang T, Cui Y, Liao L. · · 2025 · PMID 39797937 · DOI 10.1007/s13300-024-01689-1