Clinical trial NCT02863328: Efficacy and Safety of Oral Semaglutide Versus Empagliflozin in Subjects With Type 2 Diabetes Mellitus
Official title: Efficacy and Safety of Oral Semaglutide Versus Empagliflozin 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: 822
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 Empagliflozin 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
* Diagnosed with type 2 diabetes mellitus at least 90 days prior to day of screening
* HbA1c (glycosylated haemoglobin) of 7.0-10.5 % (53-91 mmol/mol) (both inclusive)
* Stable daily dose of metformin (at least 1500 mg or maximum tolerated dose as documented in the subject medical record) at least 90 days prior to the day of screening

Exclusion Criteria:

* Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using an adequate contraceptive method (adequate contraceptive measure as required by local regulation or practice).For 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 or Medullary Thyroid Carcinoma
* History of pancreatitis (acute or chronic)
* History of major surgical procedures involving the stomach potentially affecting absorption of trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery)
* Any of the following: myocardial infarction, stroke or hospitalisation for unstable angina or transient ischaemic attack within the past 180 days prior to the day of screening
* Subjects presently classified as being in New York Heart Association Class IV
* Planned coronary, carotid or peripheral artery revascularisation known on the day of screening
* Subjects with ALT (alanine aminotransferase) above 2.5 x upper normal limit
* Renal impairment defined as Estimated Glomerular Filtration Rate below 60 mL/min/1.73 m\^2 as per Chronic Kidney Disease Epidemiology Collaboration formula (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
timeFrame: Week 0, week 26
Secondary outcomes:
measure: Change in Body Weight (Kg)
timeFrame: Week 0, week 26
measure: Change in HbA1c (%)
timeFrame: Week 0, week 52
measure: Change in Body Weight (kg)
timeFrame: Week 0, week 52
measure: Change in Fasting Plasma Glucose
timeFrame: Week 0, week 26, week 52
measure: Change in SMPG : Mean of the 7-point Profile
timeFrame: Week 0, week 26 and week 52
measure: Change in SMPG : Mean Postprandial Increment Over All Meals
timeFrame: Week 0, week 26 and week 52
measure: Change in Fasting C-peptide (Ratio to Baseline)
timeFrame: Week 0, week 26 and week 52
measure: Change in Fasting Insulin (Ratio to Baseline)
timeFrame: Week 0, week 26 and week 52
measure: Change in Fasting Pro-insulin (Ratio to Baseline)
timeFrame: Week 0, week 26 and week 52
measure: Change in Fasting Glucagon (Ratio to Baseline)
timeFrame: Week 0, week 26 and week 52
measure: Change in HOMA-IR (Ratio to Baseline)
timeFrame: Week 0, week 26 and week 52
measure: Change in HOMA-B (Ratio to Baseline)
timeFrame: Week 0, week 26 and week 52
measure: Change in C-reactive Protein (Ratio to Baseline)
timeFrame: Week 0, week 26 and week 52
measure: Change in Body Weight (%)
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 Fasting Total Cholesterol (Ratio to Baseline)
timeFrame: Week 0, week 26 and week 52
measure: Change in Fasting LDL Cholesterol (Ratio to Baseline)
timeFrame: Week 0, week 26 and week 52
measure: Change in Fasting HDL Cholesterol (Ratio to Baseline)
timeFrame: Week 0, week 26 and week 52
measure: Change in Fasting VLDL Cholesterol (Ratio to Baseline)
timeFrame: Week 0, week 26 and week 52
measure: Change in Fasting Free Fatty Acids (Ratio to Baseline)
timeFrame: Week 0, week 26 and week 52
measure: Change in Fasting Triglycerides (Ratio to Baseline)
timeFrame: Week 0, week 26 and week 52
measure: Participants Who Achieve HbA1c <7.0 % (53 mmol/Mol) ADA Target (Yes/no)
timeFrame: Week 26 and week 52
measure: Participants Who Achieve HbA1c ≤6.5% (48 mmol/Mol), AACE Target (Yes/no)
timeFrame: Week 26 and week 52
measure: Participants Who Achieve Weight Loss ≥5% (Yes/no)
timeFrame: Week 26 and week 52
measure: Participants Who Achieve Weight Loss ≥10% (Yes/no)
timeFrame: Week 26 and 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 and week 52
measure: Participants Who Achieve HbA1c Reduction ≥1% (10.9 mmol/Mol) and Weight Loss ≥3% (Yes/no)
timeFrame: Week 26 and 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 (TEAE)
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 Blood Pressure (Systolic and Diastolic Blood Pressure)
timeFrame: Week 0, week 26, week 52
measure: Change in ECG
timeFrame: Week 0, week 26, week 52
measure: Change in Physical Examination
timeFrame: Week -2, week 52
measure: Change in Eye Examination
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: Weeks 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 (Yes/no)
timeFrame: Weeks 0-57
measure: Semaglutide Plasma Concentrations for Population PK Analyses
timeFrame: Weeks 0-52
measure: SNAC Plasma Concentrations
timeFrame: Weeks 0-52
measure: Change in Short Form Health Survey Version 2.0 (SF-36v2™, Acute Version) Health Survey: Scores From the 8 Domains and Summaries of the Physical Component Score (PCS) and the Mental Component Score (MCS)
timeFrame: Week 0, week 26, week 52
measure: Change in CoEQ: Scores From the 4 Domains and the 19 Items
timeFrame: Week 0, week 26, week 52
Other outcomes:
Locations:
city: Tuscumbia
country: United States
facility: Novo Nordisk Investigational Site
state: Alabama
city: Encino
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: La Mesa
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: Northridge
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: Palm Springs
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: Poway
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: Riverside
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: Spring Valley
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: Bradenton
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Jacksonville
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Jacksonville
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Jacksonville
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Miami Lakes
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Miami
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Orlando
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Oviedo
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Atlanta
country: United States
facility: Novo Nordisk Investigational Site
state: Georgia
city: Perry
country: United States
facility: Novo Nordisk Investigational Site
state: Georgia
city: Meridian
country: United States
facility: Novo Nordisk Investigational Site
state: Idaho
city: Peoria
country: United States
facility: Novo Nordisk Investigational Site
state: Illinois
city: Evansville
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state: Indiana
city: Indianapolis
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state: Indiana
city: Lexington
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state: Kentucky
city: Lexington
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state: Kentucky
city: Baton Rouge
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state: Louisiana
city: Rockville
country: United States
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state: Maryland
city: Boston
country: United States
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state: Massachusetts
city: Buckley
country: United States
facility: Novo Nordisk Investigational Site
state: Michigan
city: Kalamazoo
country: United States
facility: Novo Nordisk Investigational Site
state: Michigan
city: Butte
country: United States
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state: Montana
city: Albany
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state: New York
city: Northport
country: United States
facility: Novo Nordisk Investigational Site
state: New York
city: Wilmington
country: United States
facility: Novo Nordisk Investigational Site
state: North Carolina
city: Cincinnati
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state: Ohio
city: Mason
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state: Ohio
city: Philadelphia
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state: Pennsylvania
city: Greer
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state: South Carolina
city: Humboldt
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state: Tennessee
city: Kingsport
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state: Tennessee
city: Arlington
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facility: Novo Nordisk Investigational Site
state: Texas
city: Dallas
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state: Texas
city: Houston
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state: Texas
city: Houston
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state: Texas
city: Katy
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state: Texas
city: San Antonio
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state: Texas
city: San Antonio
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state: Texas
city: San Antonio
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facility: Novo Nordisk Investigational Site
state: Texas
city: Richmond
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state: Virginia
city: Caba
country: Argentina
facility: Novo Nordisk Investigational Site
city: Capital Federal
country: Argentina
facility: Novo Nordisk Investigational Site
city: Córdoba
country: Argentina
facility: Novo Nordisk Investigational Site
city: Córdoba
country: Argentina
facility: Novo Nordisk Investigational Site
city: São Paulo
country: Brazil
facility: Novo Nordisk Investigational Site
state: Sao Paulo
city: Porto Alegre
country: Brazil
facility: Novo Nordisk Investigational Site
city: Sao Paulo
country: Brazil
facility: Novo Nordisk Investigational Site
city: Karlovac
country: Croatia
facility: Novo Nordisk Investigational Site
city: Krapinske Toplice
country: Croatia
facility: Novo Nordisk Investigational Site
city: Pula
country: Croatia
facility: Novo Nordisk Investigational Site
city: Virovitica
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: Athens
country: Greece
facility: Novo Nordisk Investigational Site
city: Athens
country: Greece
facility: Novo Nordisk Investigational Site
city: Thessaloniki
country: Greece
facility: Novo Nordisk Investigational Site
city: Thessaloniki
country: Greece
facility: Novo Nordisk Investigational Site
city: Thessaloniki
country: Greece
facility: Novo Nordisk Investigational Site
city: Thessaloniki
country: Greece
facility: Novo Nordisk Investigational Site
city: Thessaloniki
country: Greece
facility: Novo Nordisk Investigational Site
city: Budapest
country: Hungary
facility: Novo Nordisk Investigational Site
city: Budapest
country: Hungary
facility: Novo Nordisk Investigational Site
city: Cegléd
country: Hungary
facility: Novo Nordisk Investigational Site
city: Nyíregyhaza
country: Hungary
facility: Novo Nordisk Investigational Site
city: Salgótarján
country: Hungary
facility: Novo Nordisk Investigational Site
city: Szekszárd
country: Hungary
facility: Novo Nordisk Investigational Site
city: Bologna
country: Italy
facility: Novo Nordisk Investigational Site
city: Lucca
country: Italy
facility: Novo Nordisk Investigational Site
city: Palermo
country: Italy
facility: Novo Nordisk Investigational Site
city: Roma
country: Italy
facility: Novo Nordisk Investigational Site
city: Roma
country: Italy
facility: Novo Nordisk Investigational Site
city: Siena
country: Italy
facility: Novo Nordisk Investigational Site
city: Bialystok
country: Poland
facility: Novo Nordisk Investigational Site
city: Lublin
country: Poland
facility: Novo Nordisk Investigational Site
city: Pulawy
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: Zabrze
country: Poland
facility: Novo Nordisk Investigational Site
city: Kazan
country: Russian Federation
facility: Novo Nordisk Investigational Site
city: Moscow
country: Russian Federation
facility: Novo Nordisk Investigational Site
city: Saint Petersburg
country: Russian Federation
facility: Novo Nordisk Investigational Site
city: Saint-Petersburg
country: Russian Federation
facility: Novo Nordisk Investigational Site
city: Saratov
country: Russian Federation
facility: Novo Nordisk Investigational Site
city: Tumen
country: Russian Federation
facility: Novo Nordisk Investigational Site
city: Kragujevac
country: Serbia
facility: Novo Nordisk Investigational Site
city: Nis
country: Serbia
facility: Novo Nordisk Investigational Site
city: Novi Sad
country: Serbia
facility: Novo Nordisk Investigational Site
city: Almería
country: Spain
facility: Novo Nordisk Investigational Site
city: Centelles (Barcelona)
country: Spain
facility: Novo Nordisk Investigational Site
city: Hospitalet de Llobregat
country: Spain
facility: Novo Nordisk Investigational Site
city: La Roca del Vallés
country: Spain
facility: Novo Nordisk Investigational Site
city: Pozuelo de Alarcon
country: Spain
facility: Novo Nordisk Investigational Site
city: Sevilla
country: Spain
facility: Novo Nordisk Investigational Site
city: Sevilla
country: Spain
facility: Novo Nordisk Investigational Site
city: Valencia
country: Spain
facility: Novo Nordisk Investigational Site
city: Vic (Barcelona)
country: Spain
facility: Novo Nordisk Investigational Site
city: Bangkoknoi, Bangkok
country: Thailand
facility: Novo Nordisk Investigational Site
city: Bangkok
country: Thailand
facility: Novo Nordisk Investigational Site
Study officials:
affiliation: Novo Nordisk A/S
name: Global Clinical Registry (GCR, 1452)
role: STUDY_DIRECTOR
References:
citation: Rodbard HW, Rosenstock J, Canani LH, Deerochanawong C, Gumprecht J, Lindberg SO, Lingvay I, Sondergaard AL, Treppendahl MB, Montanya E; PIONEER 2 Investigators. Oral Semaglutide Versus Empagliflozin in Patients With Type 2 Diabetes Uncontrolled on Metformin: The PIONEER 2 Trial. Diabetes Care. 2019 Dec;42(12):2272-2281. doi: 10.2337/dc19-0883. Epub 2019 Sep 17.
citation: Eliasson B, Ericsson A, Fridhammar A, Nilsson A, Persson S, Chubb B. Long-Term Cost Effectiveness of Oral Semaglutide Versus Empagliflozin and Sitagliptin for the Treatment of Type 2 Diabetes in the Swedish Setting. Pharmacoecon Open. 2022 May;6(3):343-354. doi: 10.1007/s41669-021-00317-z. Epub 2022 Jan 21.
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: Mosenzon O, Capehorn MS, De Remigis A, Rasmussen S, Weimers P, Rosenstock J. Impact of semaglutide on high-sensitivity C-reactive protein: exploratory patient-level analyses of SUSTAIN and PIONEER randomized clinical trials. Cardiovasc Diabetol. 2022 Sep 2;21(1):172. doi: 10.1186/s12933-022-01585-7.
citation: Lingvay I, Capehorn MS, Catarig AM, Johansen P, Lawson J, Sandberg A, Shaw R, Paine A. Efficacy of Once-Weekly Semaglutide vs Empagliflozin Added to Metformin in Type 2 Diabetes: Patient-Level Meta-analysis. J Clin Endocrinol Metab. 2020 Dec 1;105(12):e4593-604. doi: 10.1210/clinem/dgaa577.
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.