Clinical trial NCT02906930: Efficacy and Safety of Oral Semaglutide Versus Placebo in Subjects With Type 2 Diabetes Mellitus Treated With Diet and Exercise Only
Official title: Efficacy and Safety of Oral Semaglutide Versus Placebo in Subjects With Type 2 Diabetes Mellitus Treated With Diet and Exercise Only.
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: 2016-09-20
Enrollment: 703
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 placebo in subjects with type 2 diabetes mellitus treated with diet and exercise only.


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 above or equal to 20 years at the time of signing informed consent. For Algeria only: Male or female, age above or equal to 19 years at the time of signing informed consent - Diagnosed with type 2 diabetes mellitus for at least 30 days prior to day of screening - HbA1c (glycosylated haemoglobin) between 7.0-9.5% (53-80 mmol/mol) (both inclusive) - Treatment with diet and exercise for at least 30 days prior to 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 Japan only: Adequate contraceptive measures are abstinence (not having sex), diaphragm, condom (by the partner), intrauterine device, sponge, spermicide or oral contraceptives.For Czech Republic only: Adequate contraceptive measures are always one highly reliable method (such as intrauterine device, sterilisation of one of the partners, hormonal birth control methods) plus one supplementary barrier method (such as condom, diaphragm) with a spermicide. In justified cases, this combination may be replaced with a double-barrier method with a spermicide. Total sexual abstinence may also be considered contraception. (Please note: hormonal contraception should always be discussed with a gynaecologist) - 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 carcinomas - 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 and randomisation - 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 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 - Treatment with any medication for the indication of diabetes or obesity 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 in-situ carcinomas)

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 Fasting Plasma Glucose
timeFrame: Week 0, week 26
measure: Change in Mean 7-point SMPG Profile
timeFrame: Week 0, week 26
measure: Change in Mean Postprandial Increment Over All Meals in SMPG
timeFrame: Week 0, week 26
measure: Change in Fasting Insulin - Ratio to Baseline
timeFrame: Week 0, week 26
measure: Change in Fasting Pro-insulin - Ratio to Baseline
timeFrame: Week 0, week 26
measure: Change in Fasting Glucagon - Ratio to Baseline
timeFrame: Week 0, week 26
measure: Change in HOMA-IR (Insulin Resistance) - Ratio to Baseline
timeFrame: Week 0, week 26
measure: Change in HOMA-B (Beta-cell Function) - Ratio to Baseline
timeFrame: Week 0, week 26
measure: Change in CRP - Ratio to Baseline
timeFrame: Week 0, week 26
measure: Change in Body Weight (%)
timeFrame: Week 0, week 26
measure: Change in BMI
timeFrame: Week 0, week 26
measure: Change in Waist Circumference
timeFrame: Week 0, week 26
measure: Change in Fasting Total Cholesterol - Ratio to Baseline
timeFrame: Week 0, week 26
measure: Change in Fasting LDL Cholesterol - Ratio to Baseline
timeFrame: Week 0, week 26
measure: Change in Fasting HDL Cholesterol - Ratio to Baseline
timeFrame: Week 0, week 26
measure: Change in Fasting Triglycerides - Ratio to Baseline
timeFrame: Week 0, week 26
measure: Participants Who Achieve HbA1c < 7.0 % (53 mmol/Mol) ADA Target (Yes/no)
timeFrame: Week 26
measure: Participants Who Achieve HbA1c ≤ 6.5 % (48 mmol/Mol) AACE Target (Yes/no)
timeFrame: Week 26
measure: Participants Who Achieve Body Weight Loss ≥ 5 % (Yes/no)
timeFrame: Week 26
measure: Participants Who Achieve Body Weight Loss ≥ 10 % (Yes/no)
timeFrame: Week 26
measure: Participants Who Achieve HbA1c < 7.0 % (53 mmol/Mol) Without Hypoglycaemia (Severe or BG-confirmed Symptomatic Hypoglycaemia) and Without Body Weight Gain (Yes/no)
timeFrame: Week 26
measure: Participants Who Achieve HbA1c Reduction ≥ 1.0% (10.9 mmol/Mol) and Weight Loss ≥ 3% (Yes/no)
timeFrame: Week 26
measure: Time to Additional Anti-diabetic Medication
timeFrame: Weeks 0-26
measure: Time to Rescue Medication
timeFrame: Weeks 0-26
measure: Number of Treatment-emergent Adverse Events (TEAEs)
timeFrame: Approximately upto week 31
measure: Change in Amylase - Ratio to Baseline
timeFrame: Week 0, week 26
measure: Change in Lipase - Ratio to Baseline
timeFrame: Week 0, week 26
measure: Change in Pulse Rate
timeFrame: Week 0, week 26
measure: Change in Systolic Blood Pressure (SBP)
timeFrame: Week 0, week 26
measure: Change in Diastolic Blood Pressure (DBP)
timeFrame: Week 0, week 26
measure: Change in Electrocardiogram (ECG) Evaluation
timeFrame: Week 0, week 26
measure: Change in Physical Examination
timeFrame: Week 0, week 26
measure: Change in Eye Examination Category
timeFrame: Week 0, week 26
measure: Occurrence of Anti-semaglutide Binding Antibodies (Yes/no)
timeFrame: Weeks 0-31
measure: Occurrence of Anti-semaglutide Neutralising Antibodies (Yes/no)
timeFrame: Weeks 0-31
measure: Occurrence of Anti-semaglutide Binding Antibodies Cross Reacting With Native GLP-1 (Yes/no)
timeFrame: Weeks 0-31
measure: Occurrence of Anti-semaglutide Neutralising Antibodies Cross Reacting With Native GLP-1 (Yes/no)
timeFrame: Weeks 0-31
measure: Anti-semaglutide Binding Antibody Levels
timeFrame: Weeks 0-31
measure: Number of Treatment-emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemic Episodes During Exposure to Trial Product
timeFrame: Weeks 0-31
measure: Participants With Treatment-emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemic Episodes During Exposure to Trial Product
timeFrame: Weeks 0-31
measure: SNAC Plasma Concentrations
timeFrame: Weeks 0-26
measure: Semaglutide Plasma Concentrations for Population PK Analysis
timeFrame: Weeks 0 - 26
measure: Change in SF-36v2 (Acute Version) Health Survey: Scores From the 8 Domains, the Physical Component Summary (PCS) and the Mental Component Summary (MCS)
timeFrame: Week 0, week 26
measure: IWQOL-Lite Clinical Trial Version: Total Score of the 22 Items (Used for Validation of the Questionnaire)
timeFrame: Week 0, week 26
measure: PGI-S Item: Scores of the Two Individual Items (Used for Validation of the IWQOL Questionnaire)
timeFrame: Week 26
measure: PGI-C Item: Scores of the Two Individual Items (Used for Validation of the IWQOL Questionnaire)
timeFrame: Week 26
Other outcomes:
Locations:
city: Lancaster
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: Los Angeles
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: Montclair
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: North Hollywood
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: Riverside
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: San Diego
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: San Jose
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: San Mateo
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: Doral
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Hialeah
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Miami
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Miami
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Miami
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Palm Harbor
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Pembroke Pines
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Port Charlotte
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Spring Hill
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Tampa
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Woodstock
country: United States
facility: Novo Nordisk Investigational Site
state: Georgia
city: Honolulu
country: United States
facility: Novo Nordisk Investigational Site
state: Hawaii
city: Blackfoot
country: United States
facility: Novo Nordisk Investigational Site
state: Idaho
city: Nampa
country: United States
facility: Novo Nordisk Investigational Site
state: Idaho
city: Skokie
country: United States
facility: Novo Nordisk Investigational Site
state: Illinois
city: Muncie
country: United States
facility: Novo Nordisk Investigational Site
state: Indiana
city: Louisville
country: United States
facility: Novo Nordisk Investigational Site
state: Kentucky
city: Metairie
country: United States
facility: Novo Nordisk Investigational Site
state: Louisiana
city: Hyattsville
country: United States
facility: Novo Nordisk Investigational Site
state: Maryland
city: Kalamazoo
country: United States
facility: Novo Nordisk Investigational Site
state: Michigan
city: Rochester
country: United States
facility: Novo Nordisk Investigational Site
state: Michigan
city: Troy
country: United States
facility: Novo Nordisk Investigational Site
state: Michigan
city: Elkhorn
country: United States
facility: Novo Nordisk Investigational Site
state: Nebraska
city: Brooklyn
country: United States
facility: Novo Nordisk Investigational Site
state: New York
city: West Seneca
country: United States
facility: Novo Nordisk Investigational Site
state: New York
city: Asheboro
country: United States
facility: Novo Nordisk Investigational Site
state: North Carolina
city: Charlotte
country: United States
facility: Novo Nordisk Investigational Site
state: North Carolina
city: Greensboro
country: United States
facility: Novo Nordisk Investigational Site
state: North Carolina
city: Fargo
country: United States
facility: Novo Nordisk Investigational Site
state: North Dakota
city: Cincinnati
country: United States
facility: Novo Nordisk Investigational Site
state: Ohio
city: Willoughby Hills
country: United States
facility: Novo Nordisk Investigational Site
state: Ohio
city: Norman
country: United States
facility: Novo Nordisk Investigational Site
state: Oklahoma
city: Oklahoma City
country: United States
facility: Novo Nordisk Investigational Site
state: Oklahoma
city: Philadelphia
country: United States
facility: Novo Nordisk Investigational Site
state: Pennsylvania
city: Spartanburg
country: United States
facility: Novo Nordisk Investigational Site
state: South Carolina
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: Mesquite
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: 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: Sugar Land
country: United States
facility: Novo Nordisk Investigational Site
state: Texas
city: Waco
country: United States
facility: Novo Nordisk Investigational Site
state: Texas
city: Bountiful
country: United States
facility: Novo Nordisk Investigational Site
state: Utah
city: Norfolk
country: United States
facility: Novo Nordisk Investigational Site
state: Virginia
city: Richmond
country: United States
facility: Novo Nordisk Investigational Site
state: Virginia
city: Salem
country: United States
facility: Novo Nordisk Investigational Site
state: Virginia
city: Algiers
country: Algeria
facility: Novo Nordisk Investigational Site
city: Algiers
country: Algeria
facility: Novo Nordisk Investigational Site
city: Algiers
country: Algeria
facility: Novo Nordisk Investigational Site
city: Algiers
country: Algeria
facility: Novo Nordisk Investigational Site
city: Sofia
country: Bulgaria
facility: Novo Nordisk Investigational Site
city: Sofia
country: Bulgaria
facility: Novo Nordisk Investigational Site
city: Broumov
country: Czechia
facility: Novo Nordisk Investigational Site
city: Chrudim
country: Czechia
facility: Novo Nordisk Investigational Site
city: Mlada Boleslav
country: Czechia
facility: Novo Nordisk Investigational Site
city: Olomouc
country: Czechia
facility: Novo Nordisk Investigational Site
city: Prague 1
country: Czechia
facility: Novo Nordisk Investigational Site
city: Como
country: Italy
facility: Novo Nordisk Investigational Site
city: Palermo
country: Italy
facility: Novo Nordisk Investigational Site
city: Pisa
country: Italy
facility: Novo Nordisk Investigational Site
city: Rome
country: Italy
facility: Novo Nordisk Investigational Site
city: Siena
country: Italy
facility: Novo Nordisk Investigational Site
city: Suita-shi, Osaka
country: Japan
facility: Novo Nordisk Investigational Site
city: Tokyo
country: Japan
facility: Novo Nordisk Investigational Site
city: Tokyo
country: Japan
facility: Novo Nordisk Investigational Site
city: Tokyo
country: Japan
facility: Novo Nordisk Investigational Site
city: Tokyo
country: Japan
facility: Novo Nordisk Investigational Site
city: Yokohama-shi, Kanagawa
country: Japan
facility: Novo Nordisk Investigational Site
city: Ciudad Madero
country: Mexico
facility: Novo Nordisk Investigational Site
state: Tamaulipas
city: Aguascalientes
country: Mexico
facility: Novo Nordisk Investigational Site
city: Targoviste
country: Romania
facility: Novo Nordisk Investigational Site
state: Dambovita
city: Targoviste
country: Romania
facility: Novo Nordisk Investigational Site
state: Dambovita
city: Ploiesti
country: Romania
facility: Novo Nordisk Investigational Site
state: Prahova
city: Bucharest
country: Romania
facility: Novo Nordisk Investigational Site
city: Bucharest
country: Romania
facility: Novo Nordisk Investigational Site
city: Dzerzhinskiy
country: Russian Federation
facility: Novo Nordisk Investigational Site
city: Kazan
country: Russian Federation
facility: Novo Nordisk Investigational Site
city: Novosibirsk
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: Tomsk
country: Russian Federation
facility: Novo Nordisk Investigational Site
city: Voronezh
country: Russian Federation
facility: Novo Nordisk Investigational Site
city: Yaroslavl
country: Russian Federation
facility: Novo Nordisk Investigational Site
city: Yoshkar-Ola
country: Russian Federation
facility: Novo Nordisk Investigational Site
city: Belgrade
country: Serbia
facility: Novo Nordisk Investigational Site
city: Adana
country: Turkey
facility: Novo Nordisk Investigational Site
city: Istanbul
country: Turkey
facility: Novo Nordisk Investigational Site
city: Istanbul
country: Turkey
facility: Novo Nordisk Investigational Site
city: Istanbul
country: Turkey
facility: Novo Nordisk Investigational Site
city: Istanbul
country: Turkey
facility: Novo Nordisk Investigational Site
city: Istanbul
country: Turkey
facility: Novo Nordisk Investigational Site
city: Istanbul
country: Turkey
facility: Novo Nordisk Investigational Site
city: Istanbul
country: Turkey
facility: Novo Nordisk Investigational Site
city: Istanbul
country: Turkey
facility: Novo Nordisk Investigational Site
city: Istanbul
country: Turkey
facility: Novo Nordisk Investigational Site
Study officials:
affiliation: Novo Nordisk A/S
name: Global Clinical Registry (GCR, 1452)
role: STUDY_DIRECTOR
References:
citation: Kolotkin RL, Williams VSL, Ervin CM, Williams N, Meincke HH, Qin S, von Huth Smith L, Fehnel SE. Validation of a new measure of quality of life in obesity trials: Impact of Weight on Quality of Life-Lite Clinical Trials Version. Clin Obes. 2019 Jun;9(3):e12310. doi: 10.1111/cob.12310. Epub 2019 Apr 16.
citation: Aroda VR, Saugstrup T, Buse JB, Donsmark M, Zacho J, Davies MJ. Incorporating and interpreting regulatory guidance on estimands in diabetes clinical trials: The PIONEER 1 randomized clinical trial as an example. Diabetes Obes Metab. 2019 Oct;21(10):2203-2210. doi: 10.1111/dom.13804. Epub 2019 Jun 30.
citation: Aroda VR, Rosenstock J, Terauchi Y, Altuntas Y, Lalic NM, Morales Villegas EC, Jeppesen OK, Christiansen E, Hertz CL, Haluzik M; PIONEER 1 Investigators. PIONEER 1: Randomized Clinical Trial of the Efficacy and Safety of Oral Semaglutide Monotherapy in Comparison With Placebo in Patients With Type 2 Diabetes. Diabetes Care. 2019 Sep;42(9):1724-1732. doi: 10.2337/dc19-0749. Epub 2019 Jun 11.
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: Gorst-Rasmussen A, Tarp-Johansen MJ. Fast tipping point sensitivity analyses in clinical trials with missing continuous outcomes under multiple imputation. J Biopharm Stat. 2022 Nov 2;32(6):942-953. doi: 10.1080/10543406.2022.2058525. Epub 2022 Jun 2.
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: Husain M, Bain SC, Holst AG, Mark T, Rasmussen S, Lingvay I. Effects of semaglutide on risk of cardiovascular events across a continuum of cardiovascular risk: combined post hoc analysis of the SUSTAIN and PIONEER trials. Cardiovasc Diabetol. 2020 Sep 30;19(1):156. doi: 10.1186/s12933-020-01106-4.
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.