Clinical trial NCT02863419: Efficacy and Safety of Oral Semaglutide Versus Liraglutide and Versus Placebo in Subjects With Type 2 Diabetes Mellitus
Official title: Efficacy and Safety of Oral Semaglutide Versus Liraglutide and Versus Placebo in Subjects With Type 2 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetes
Diabetes Mellitus, Type 2
Lead sponsor: Novo Nordisk A/S
Sponsor class: INDUSTRY
First posted: 2016-08-11
Enrollment: 711
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Change in HbA1c (Week 26)
timeFrame: Week 0, week 26
Secondary outcomes:
measure: Change in Body Weight (Week 26)
timeFrame: Week 0, week 26
measure: Change in HbA1c (Week 52)
timeFrame: Week 0, week 52
measure: Change in Body Weight (Week 52)
timeFrame: Week 0, week 52
measure: Change in Body Weight (%)
timeFrame: Week 0, Week 26, Week 52
measure: Change in Fasting Plasma Glucose
timeFrame: Week 0, week 26, week 52
measure: Change in Body Mass Index
timeFrame: Week 0, week 26, week 52
measure: Change in Waist Circumference
timeFrame: Week 0, week 26, week 52
measure: Change in Total Cholesterol - Ratio to Baseline
timeFrame: Week 0, week 26, week 52
measure: Change in Low-density Lipoprotein (LDL) Cholesterol - Ratio to Baseline
timeFrame: Week 0, week 26, week 52
measure: Change in Very Low Density Lipoprotein (VLDL) Cholesterol - Ratio to Baseline
timeFrame: Week 0, week 26, week 52
measure: Change in High-density Lipoprotein (HDL) Cholesterol - Ratio to Baseline
timeFrame: Week 0, week 26, week 52
measure: Change in Triglycerides - Ratio to Baseline
timeFrame: Week 0, week 26, week 52
measure: Change in Free Fatty Acids - Ratio to Baseline
timeFrame: Week 0, week 26, week 52
measure: Change in SMPG - Mean 7-point Profile
timeFrame: Week 0, week 26, week 52
measure: Change in SMPG - Mean Postprandial Increment Over All Meals
timeFrame: Week 0, week 26, week 52
measure: Participants Who Achieve HbA1c <7.0% (53 mmol/Mol) ADA Target (Yes/no)
timeFrame: Week 26, week 52
measure: Participants Who Achieve HbA1c <6.5% (48 mmol/Mol) AACE Target (Yes/no)
timeFrame: Week 26, week 52
measure: Participants Who Achieve Weight Loss ≥5% (Yes/no)
timeFrame: Week 26, week 52
measure: Participants Who Achieve Weight Loss ≥ 10% (Yes/no)
timeFrame: Week 26, week 52
measure: Participants Who Achieve HbA1c <7.0 % (53 mmol/Mol) Without Hypoglycaemia (Severe or BG Confirmed Symptomatic Hypoglycaemia) and no Weight Gain (Yes/no)
timeFrame: Week 26, week 52
measure: Participants Who Achieve HbA1c Reduction ≥1% (10.9 mmol/Mol) and Weight Loss ≥3% (Yes/no)
timeFrame: Week 26, week 52
measure: Time to Additional Anti-diabetic Medication
timeFrame: Weeks 0-52
measure: Time to Rescue Medication
timeFrame: Weeks 0-52
measure: Number of Treatment-emergent Adverse Events (TEAEs) During Exposure to Trial Product
timeFrame: Weeks 0-57
measure: Change in Amylase - Ratio to Baseline
timeFrame: Week 0, week 26, week 52
measure: Change in Lipase - Ratio to Baseline
timeFrame: Week 0, week 26, week 52
measure: Change in Pulse Rate
timeFrame: Week 0, week 26, week 52
measure: Change in SBP and DBP
timeFrame: Week 0, week 26, week 52
measure: Change in ECG Evaluation
timeFrame: Week 0, week 26, week 52
measure: Change in Physical Examination
timeFrame: Week -2, week 52
measure: Change in Eye Examination Category
timeFrame: Week -2, Week 52
measure: Occurrence of Anti-semaglutide Binding Antibodies (Yes/no)
timeFrame: Weeks 0-57
measure: Occurrence of Anti-semaglutide Neutralising Antibodies (Yes/no)
timeFrame: Weeks 0-57
measure: Occurrence of Anti-semaglutide Binding Antibodies Cross Reacting With Native GLP-1 (Yes/no)
timeFrame: Week 0-57
measure: Occurrence of Anti-semaglutide Neutralising Antibodies Cross Reacting With Native GLP-1 (Yes/no)
timeFrame: Weeks 0-57
measure: Anti-semaglutide Binding Antibody Levels
timeFrame: Weeks 0-57
measure: Number of Treatment-emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemic Episodes
timeFrame: Weeks 0-57
measure: Participants With Treatment-emergent Severe or BG-confirmed Symptomatic Hypoglycaemic Episodes
timeFrame: Weeks 0-57
measure: Change in DTSQs: Individual Items and Total Treatment Satisfaction Score (6 of the 8 Items Summed)
timeFrame: Week 0, week 26, week 52
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Novo Nordisk Investigational Site
state: Alabama
city: Los Alamitos
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: San Diego
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: Denver
country: United States
facility: Novo Nordisk Investigational Site
state: Colorado
city: Hallandale Beach
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Jacksonville
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Miami
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Ocala
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Orlando
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Orlando
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Ormond Beach
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Saint Petersburg
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: West Palm Beach
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Peoria
country: United States
facility: Novo Nordisk Investigational Site
state: Illinois
city: Topeka
country: United States
facility: Novo Nordisk Investigational Site
state: Kansas
city: Slidell
country: United States
facility: Novo Nordisk Investigational Site
state: Louisiana
city: Butte
country: United States
facility: Novo Nordisk Investigational Site
state: Montana
city: Lebanon
country: United States
facility: Novo Nordisk Investigational Site
state: New Hampshire
city: Teaneck
country: United States
facility: Novo Nordisk Investigational Site
state: New Jersey
city: Albany
country: United States
facility: Novo Nordisk Investigational Site
state: New York
city: Mineola
country: United States
facility: Novo Nordisk Investigational Site
state: New York
city: Greensboro
country: United States
facility: Novo Nordisk Investigational Site
state: North Carolina
city: Morganton
country: United States
facility: Novo Nordisk Investigational Site
state: North Carolina
city: Wilmington
country: United States
facility: Novo Nordisk Investigational Site
state: North Carolina
city: Dublin
country: United States
facility: Novo Nordisk Investigational Site
state: Ohio
city: Maumee
country: United States
facility: Novo Nordisk Investigational Site
state: Ohio
city: Norman
country: United States
facility: Novo Nordisk Investigational Site
state: Oklahoma
city: McMurray
country: United States
facility: Novo Nordisk Investigational Site
state: Pennsylvania
city: Summerville
country: United States
facility: Novo Nordisk Investigational Site
state: South Carolina
city: Bristol
country: United States
facility: Novo Nordisk Investigational Site
state: Tennessee
city: Arlington
country: United States
facility: Novo Nordisk Investigational Site
state: Texas
city: Dallas
country: United States
facility: Novo Nordisk Investigational Site
state: Texas
city: Dallas
country: United States
facility: Novo Nordisk Investigational Site
state: Texas
city: Houston
country: United States
facility: Novo Nordisk Investigational Site
state: Texas
city: North Richland Hills
country: United States
facility: Novo Nordisk Investigational Site
state: Texas
city: San Antonio
country: United States
facility: Novo Nordisk Investigational Site
state: Texas
city: San Antonio
country: United States
facility: Novo Nordisk Investigational Site
state: Texas
city: Newport News
country: United States
facility: Novo Nordisk Investigational Site
state: Virginia
city: Richmond
country: United States
facility: Novo Nordisk Investigational Site
state: Virginia
city: Virginia Beach
country: United States
facility: Novo Nordisk Investigational Site
state: Virginia
city: Karlovac
country: Croatia
facility: Novo Nordisk Investigational Site
city: Osijek
country: Croatia
facility: Novo Nordisk Investigational Site
city: Slavonski Brod
country: Croatia
facility: Novo Nordisk Investigational Site
city: Zagreb
country: Croatia
facility: Novo Nordisk Investigational Site
city: Zagreb
country: Croatia
facility: Novo Nordisk Investigational Site
city: Nachod
country: Czechia
facility: Novo Nordisk Investigational Site
city: Plzen
country: Czechia
facility: Novo Nordisk Investigational Site
city: Praha 5
country: Czechia
facility: Novo Nordisk Investigational Site
city: Bochum
country: Germany
facility: Novo Nordisk Investigational Site
city: Duisburg
country: Germany
facility: Novo Nordisk Investigational Site
city: Falkensee
country: Germany
facility: Novo Nordisk Investigational Site
city: Hamburg
country: Germany
facility: Novo Nordisk Investigational Site
city: Ludwigshafen
country: Germany
facility: Novo Nordisk Investigational Site
city: Oldenburg I. Holst
country: Germany
facility: Novo Nordisk Investigational Site
city: Saint Ingbert-Oberwürzbach
country: Germany
facility: Novo Nordisk Investigational Site
city: Villingen-Schwenningen
country: Germany
facility: Novo Nordisk Investigational Site
city: Budapest
country: Hungary
facility: Novo Nordisk Investigational Site
city: Budapest
country: Hungary
facility: Novo Nordisk Investigational Site
city: Gyula
country: Hungary
facility: Novo Nordisk Investigational Site
city: Kalocsa
country: Hungary
facility: Novo Nordisk Investigational Site
city: Nagykanizsa
country: Hungary
facility: Novo Nordisk Investigational Site
city: Szeged
country: Hungary
facility: Novo Nordisk Investigational Site
city: Szigetvár
country: Hungary
facility: Novo Nordisk Investigational Site
city: Szolnok
country: Hungary
facility: Novo Nordisk Investigational Site
city: Székesfehérvár
country: Hungary
facility: Novo Nordisk Investigational Site
city: Tatabánya
country: Hungary
facility: Novo Nordisk Investigational Site
city: Bunkyo-ku, Tokyo
country: Japan
facility: Novo Nordisk Investigational Site
city: Kumamoto-shi,Kumamoto
country: Japan
facility: Novo Nordisk Investigational Site
city: Mito-shi, Ibaraki
country: Japan
facility: Novo Nordisk Investigational Site
city: Okawa-shi, Fukuoka
country: Japan
facility: Novo Nordisk Investigational Site
city: Sapporo-shi, Hokkaido
country: Japan
facility: Novo Nordisk Investigational Site
city: Shimotsuke-shi, Tochigi
country: Japan
facility: Novo Nordisk Investigational Site
city: Suita-shi, Osaka
country: Japan
facility: Novo Nordisk Investigational Site
city: Tochigi
country: Japan
facility: Novo Nordisk Investigational Site
city: Yamato-shi, Kanagawa
country: Japan
facility: Novo Nordisk Investigational Site
city: Ogre
country: Latvia
facility: Novo Nordisk Investigational Site
city: Riga
country: Latvia
facility: Novo Nordisk Investigational Site
city: Riga
country: Latvia
facility: Novo Nordisk Investigational Site
city: Riga
country: Latvia
facility: Novo Nordisk Investigational Site
city: Bialystok
country: Poland
facility: Novo Nordisk Investigational Site
city: Bydgoszcz
country: Poland
facility: Novo Nordisk Investigational Site
city: Gdansk
country: Poland
facility: Novo Nordisk Investigational Site
city: Gniewkowo
country: Poland
facility: Novo Nordisk Investigational Site
city: Krakow
country: Poland
facility: Novo Nordisk Investigational Site
city: Poznan
country: Poland
facility: Novo Nordisk Investigational Site
city: Szczecin
country: Poland
facility: Novo Nordisk Investigational Site
city: Warszawa
country: Poland
facility: Novo Nordisk Investigational Site
city: Wroclaw
country: Poland
facility: Novo Nordisk Investigational Site
city: Toa Baja
country: Puerto Rico
facility: Novo Nordisk Investigational Site
city: Bardejov
country: Slovakia
facility: Novo Nordisk Investigational Site
city: Bratislava
country: Slovakia
facility: Novo Nordisk Investigational Site
city: Kosice
country: Slovakia
facility: Novo Nordisk Investigational Site
city: Nitra
country: Slovakia
facility: Novo Nordisk Investigational Site
city: Roznava
country: Slovakia
facility: Novo Nordisk Investigational Site
city: Vrutky
country: Slovakia
facility: Novo Nordisk Investigational Site
city: Benoni
country: South Africa
facility: Novo Nordisk Investigational Site
state: Gauteng
city: Johannesburg
country: South Africa
facility: Novo Nordisk Investigational Site
state: Gauteng
city: Durban
country: South Africa
facility: Novo Nordisk Investigational Site
state: KwaZulu-Natal
city: Durban
country: South Africa
facility: Novo Nordisk Investigational Site
state: KwaZulu-Natal
city: Cape Town
country: South Africa
facility: Novo Nordisk Investigational Site
state: Western Cape
city: Kyiv
country: Ukraine
facility: Novo Nordisk Investigational Site
city: Odesa
country: Ukraine
facility: Novo Nordisk Investigational Site
city: Vinnytsia
country: Ukraine
facility: Novo Nordisk Investigational Site
city: Ajman
country: United Arab Emirates
facility: Novo Nordisk Investigational Site
city: Al Mafraq
country: United Arab Emirates
facility: Novo Nordisk Investigational Site
city: Dubai
country: United Arab Emirates
facility: Novo Nordisk Investigational Site
city: Rahba City
country: United Arab Emirates
facility: Novo Nordisk Investigational Site
city: Umm Al Quwain
country: United Arab Emirates
facility: Novo Nordisk Investigational Site
Study officials:
affiliation: Novo Nordisk A/S
name: Global Clinical Registry (GCR, 1452)
role: STUDY_DIRECTOR
References:
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.
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.
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.
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.
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.
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.