Primary outcomeMean· Week 0, week 26
Change in HbA1c (Week 26)
| Group | Value (Percentage of HbA1c) | Spread |
|---|---|---|
| Oral Semaglutide 14 mg | -1.2 | 0.9 |
| Liraglutide 1.8 mg | -1.1 | 0.9 |
| Placebo | -0.1 | 0.7 |
Trial · Interventional
CompletedPhase 3Results postedRegistry dataEfficacy and Safety of Oral Semaglutide Versus Liraglutide and Versus Placebo in Subjects With Type 2 Diabetes Mellitus
Short name PIONEER 4
NCTNCT02863419 (opens ClinicalTrials.gov in a new tab)Other idNN9924-4224Other id2015-005210-30Other idU1111-1176-6029Other id2015
Overview
- Status
- Completed
- Phase
- Phase 3
- Enrollment
- 711 participants (actual)
- Sponsor
- Novo Nordisk A/S · Industry
- Design
- Randomized · Double masking
- Countries
13 countries
United States, Croatia, Czechia, Germany, Hungary, Japan, Latvia, Poland, Puerto Rico, Slovakia, South Africa, Ukraine, United Arab Emirates
- Start
- 10 Aug 2016
- Primary completion
- 19 Aug 2017
- Completion
- 30 Mar 2018
- First posted
- 11 Aug 2016 (estimated)
- Last update posted
- 20 Jul 2022
- Conditions
- Diabetes · Diabetes Mellitus, Type 2
Timeline
1 trial · 1 completed · 1 with posted results
- Completed
- Ongoing
- Not yet recruiting
- Stopped
- Estimated dates (est.)
- Results posted
2016201720182019
- Ph 3
Registry summary
Text and fields below are the sponsor's entries at ClinicalTrials.gov, shown as posted.
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.
Interventions
- semaglutideDrug
- liraglutideDrug
- placeboDrug
Arms3
Experimental
Oral Semaglutide
Active comparator
Liraglutide
Placebo comparator
Placebo
Primary outcomes1
Outcomes the sponsor listed as primary.
Change in HbA1c (Week 26)
Time frame · Week 0, week 26
Registry description
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 outcomes(20)
Change in Body Weight (Week 26)
Time frame · Week 0, week 26
Registry description
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)
Time frame · Week 0, week 52
Registry description
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)
Time frame · Week 0, week 52
Registry description
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 (%)
Time frame · Week 0, Week 26, Week 52
Registry description
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
Time frame · Week 0, week 26, week 52
Registry description
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
Time frame · Week 0, week 26, week 52
Registry description
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
Time frame · Week 0, week 26, week 52
Registry description
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
Time frame · Week 0, week 26, week 52
Registry description
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
Time frame · Week 0, week 26, week 52
Registry description
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
Time frame · Week 0, week 26, week 52
Registry description
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
Time frame · Week 0, week 26, week 52
Registry description
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
Time frame · Week 0, week 26, week 52
Registry description
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
Time frame · Week 0, week 26, week 52
Registry description
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
Time frame · Week 0, week 26, week 52
Registry description
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
Time frame · Week 0, week 26, week 52
Registry description
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)
Time frame · Week 26, week 52
Registry description
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)
Time frame · Week 26, week 52
Registry description
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)
Time frame · Week 26, week 52
Registry description
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)
Time frame · Week 26, week 52
Registry description
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)
Time frame · Week 26, week 52
Registry description
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.
Posted results
Values are shown as posted at ClinicalTrials.gov, with their units. PepBank has not converted, pooled or compared them.
Primary outcome results
Secondary and other outcome results(7)
Secondary outcomeMean· Week 0, week 26
Change in Body Weight (Week 26)
| Group | Value (Kg) | Spread |
|---|---|---|
| Oral Semaglutide 14 mg | -4.4 | 4.4 |
| Liraglutide 1.8 mg | -3.2 | 3.7 |
| Placebo | -0.6 | 3.1 |
Secondary outcomeMean· Week 0, week 52
Change in HbA1c (Week 52)
| Group | Value (Percentage of HbA1c) | Spread |
|---|---|---|
| Oral Semaglutide 14 mg | -1.2 | 1.0 |
| Liraglutide 1.8 mg | -0.9 | 1.0 |
| Placebo | -0.1 | 0.9 |
Secondary outcomeMean· Week 0, week 52
Change in Body Weight (Week 52)
| Group | Value (Kg) | Spread |
|---|---|---|
| Oral Semaglutide 14 mg | -4.4 | 5.5 |
| Liraglutide 1.8 mg | -3.1 | 4.4 |
| Placebo | -1.0 | 3.8 |
Secondary outcomeMean· Week 0, Week 26, Week 52
Change in Body Weight (%)
| Group | Value (Percentage change) | Spread |
|---|---|---|
| Oral Semaglutide 14 mg | -4.89 | 4.95 |
| Liraglutide 1.8 mg | -3.33 | 3.78 |
| Placebo | -0.60 | 3.34 |
Secondary outcomeMean· Week 0, week 26, week 52
Change in Fasting Plasma Glucose
| Group | Value (mmol/L) | Spread |
|---|---|---|
| Oral Semaglutide 14 mg | -2.04 | 2.28 |
| Liraglutide 1.8 mg | -1.91 | 2.05 |
| Placebo | -0.33 | 2.03 |
Secondary outcomeMean· Week 0, week 26, week 52
Change in Body Mass Index
| Group | Value (kg/m^2) | Spread |
|---|---|---|
| Oral Semaglutide 14 mg | -1.6 | 1.6 |
| Liraglutide 1.8 mg | -1.1 | 1.3 |
| Placebo | -0.2 | 1.1 |
Secondary outcomeMean· Week 0, week 26, week 52
Change in Waist Circumference
| Group | Value (cm) | Spread |
|---|---|---|
| Oral Semaglutide 14 mg | -4.2 | 5.4 |
| Liraglutide 1.8 mg | -3.0 | 4.5 |
| Placebo | -1.2 | 3.9 |
Adverse events, as posted
| Group | Deaths | Serious events | Other events |
|---|---|---|---|
| Oral Semaglutide 14 mgParticipants were to take once-daily oral semaglutide tablets for 52 weeks. Participants started oral semaglutide at 3 mg and were dose-escalated in 4-week increments until the final maintenance dose of 14 mg once-daily was reached (i.e. 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 8 to week 52). In addition, participants were to take liraglutide placebo once-daily as a subcutaneous injection (under the skin) from week 0 to week 52. Participants were to continue their anti-diabetic background medication (metformin alone or in combination with a sodium-glucose co-transporter-2 \[SGLT-2\] inhibitor) throughout the entire trial. | 3 / 285 | 31 / 285 | 148 / 285 |
| Liraglutide 1.8 mgParticipants were to take once-daily liraglutide subcutaneous injection (under the skin) for 52 weeks. Participants started liraglutide at 0.6 mg and were dose-escalated in one-week increments until the final maintenance dose of 1.8 mg once-daily was reached (i.e. 0.6 mg from week 0 to week 1, 1.2 mg from week 1 to week 2 and 1.8 mg from week 2 to week 52). In addition, participants were to take oral semaglutide placebo tablets once-daily from week 0 to week 52. Participants were to continue their anti-diabetic background medication (metformin alone or in combination with a sodium-glucose co-transporter-2 \[SGLT-2\] inhibitor) throughout the entire trial. | 4 / 284 | 22 / 284 | 120 / 284 |
| PlaceboParticipants were to take both oral semaglutide placebo tablets and liraglutide placebo once-daily as a subcutaneous injection (under the skin) from week 0 to week 52. Participants were to continue their anti-diabetic background medication (metformin alone or in combination with a sodium-glucose co-transporter-2 \[SGLT-2\] inhibitor) throughout the entire trial. | 1 / 142 | 15 / 142 | 47 / 142 |
Each cell reads participants affected / participants at risk, as the registry posted them.
Registry data comes from ClinicalTrials.gov. Study results come from studies, not from the registry. How PepBank works
Studies7
Studies that cite this trial.
Studies with results
1 study on this page
Indexing hint: Randomized controlled trial · 2021
10 results
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.
Araki et al. 2021Diabetes, obesity & metabolismcited by 9
PMID 34472698PMC9293331DOI 10.1111/dom.14536PUB-34472698
Free to read · publisher termsCC BY-NC10 results
More studies
6 studies on this page
PubMed tag: none · 2023
Early use of oral semaglutide in the UK: A cost-effectiveness analysis versus continuing metformin and SGLT-2 inhibitor therapy.
Ren et al. 2023BMJ opencited by 2
PMID 37775297PMC10546165DOI 10.1136/bmjopen-2022-070473PUB-37775297
Free to read · publisher termsCC BY-NC
PubMed tag: none · 2022
Efficacy and safety of oral semaglutide by subgroups of patient characteristics in the PIONEER phase 3 programme.
Aroda et al. 2022Diabetes, obesity & metabolismcited by 32
PMID 35373893PMC9321749DOI 10.1111/dom.14710PUB-35373893
Free to read · publisher termsCC BY-NC
PubMed tag: none · 2021
Oral Semaglutide Reduces HbA1c and Body Weight in Patients with Type 2 Diabetes Regardless of Background Glucose-Lowering Medication: PIONEER Subgroup Analyses.
Pratley et al. 2021Diabetes therapy : research, treatment and education of diabetes and related disorderscited by 10
PMID 33660198PMC7994454DOI 10.1007/s13300-020-00994-9PUB-33660198
Free to read · publisher termsCC BY-NC
PubMed tag: none · 2020
Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk.
Husain et al. 2020Diabetes, obesity & metabolismcited by 154
PMID 31903692PMC7064975DOI 10.1111/dom.13955PUB-31903692
Free to read · publisher termsCC BY-NC
Indexing hint: Review · 2020
Efficacy, safety and cardiovascular outcomes of once-daily oral semaglutide in patients with type 2 diabetes: The PIONEER programme.
Thethi et al. 2020Diabetes, obesity & metabolismcited by 98
PMID 32267058PMC7384149DOI 10.1111/dom.14054PUB-32267058
Free to read · publisher termsCC BY-NC
Indexing hint: Randomized controlled trial · 2019
Corrected
Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial.
Pratley et al. 2019Lancet (London, England)cited by 423
PMID 31186120DOI 10.1016/s0140-6736(19)31271-1PUB-31186120
Full text at the publisher
Eligibility
Who could join, as posted.
- Sex
- All
- Age
- from 18 Years
- Healthy volunteers
- Not accepted
Inclusion and exclusion criteria, as posted
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
PepBank is a research reference. Talk to a doctor before you use any peptide.