Clinical trial NCT02849080: Efficacy and Safety of Oral Semaglutide Using a Flexible Dose Adjustment Based on Clinical Evaluation Versus Sitagliptin in Subjects With Type 2 Diabetes Mellitus.
Official title: Efficacy and Safety of Oral Semaglutide Using a Flexible Dose Adjustment Based on Clinical Evaluation Versus Sitagliptin 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: 2016-07-29
Enrollment: 504
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 globally conducted. The aim of this trial is to investigate Efficacy and Safety of Oral Semaglutide Using a Flexible Dose Adjustment Based on Clinical Evaluation versus Sitagliptin in Subjects with Type 2 Diabetes Mellitus.


Eligibility criteria: Inclusion Criteria:

Main phase (the inclusion criteria for the main phase are not reassessed for the extension phase):

* 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 Korea 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 90 days prior to day of screening
* HbA1c (glycosylated haemoglobin) 7.5-9.5% (58-80 mmol/mol) (both inclusive)
* Treatment target of HbA1c below 7.0% (53 mmol/mol), as judged by the investigator
* Stable daily dose(s) of 1-2 of the following anti-diabetic drugs within 90 days prior to the day of screening:
* Metformin (equal or above 1500 mg or maximum tolerated dose as documented in the subject medical record)
* Sulfonylureas (equal or above half of the maximum approved dose according to local label or maximum tolerated dose as documented in subject medical record)
* Sodium glucose co-transporter 2 inhibitors
* Thiazolidinediones (equal or above half of the maximum approved dose according to local label or maximum tolerated dose as documented in subject medical record)

Extension phase:

* Informed consent for the extension phase obtained before any trial-related activities for the extension phase.
* On randomised treatment with or without rescue medication at week 52.

Exclusion Criteria:

Main phase (the exclusion criteria for the main phase are not reassessed for the extension phase):

* 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 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 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 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

Extension phase: There are no new exclusion criteria for the extension phase

Primary outcomes:
measure: Participants Who Achieve HbA1c <7.0% (53 mmol/Mol) ADA Target (Yes/no)
timeFrame: Week 52
Secondary outcomes:
measure: Change in Body Weight
timeFrame: Week 0, week 52
measure: Change in HbA1c
timeFrame: Week 0, week 52
measure: Change in FPG
timeFrame: Week 0, week 52
measure: Change in Body Weight (%)
timeFrame: Week 0, week 52
measure: Change in BMI
timeFrame: Week 0, Week 52
measure: Change in Waist Circumference
timeFrame: Week 0, week 52
measure: Change in Total Cholesterol (Ratio to Baseline)
timeFrame: Week 0, Week 52
measure: Change in LDL Cholesterol (Ratio to Baseline)
timeFrame: Week 0, week 52
measure: Change in HDL Cholesterol (Ratio to Baseline)
timeFrame: Week 0, week 52
measure: Change in Triglycerides (Ratio to Baseline)
timeFrame: Week 0, week 52
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 52
measure: Change in DTSQ
timeFrame: Week 0, Week 52
measure: Participants Who Achieve HbA1c ≤6.5% (48 mmol/Mol) AACE Target (Yes/no)
timeFrame: Week 52
measure: Participants Who Achieve Weight Loss ≥5% (Yes/no)
timeFrame: Week 52
measure: Participants Who Achieve Weight Loss ≥10% (Yes/no)
timeFrame: 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 52
measure: Participants Who Achieve HbA1c Reduction ≥1% (10.9 mmol/Mol) and Weight Loss ≥3% (Yes/no)
timeFrame: Week 52
measure: Time to Rescue Medication
timeFrame: Weeks 0-52
measure: Time to Additional Anti-diabetic Medication
timeFrame: Weeks 0-52
measure: Number of TEAEs During Exposure to Trial Product
timeFrame: Week 0-57
measure: Number of Treatment-emergent Severe or BG-confirmed Symptomatic Hypoglycaemic Episodes
timeFrame: Week 0-57
measure: Paticipants With Treatment-emergent Severe or BG-confirmed Symptomatic Hypoglycaemic Episodes (Yes/no)
timeFrame: Week 0-57
measure: Change in Amylase (Ratio to Baseline)
timeFrame: Week 0, Week 52
measure: Change in Lipase (Ratio to Baseline)
timeFrame: Week 0, Week 52
measure: Change in Pulse Rate
timeFrame: Week 0, week 52
measure: Change in Blood Pressure (Systolic and Diastolic Blood Pressure)
timeFrame: Week 0, week 52
measure: Change in HbA1c- Switch
timeFrame: Week 52, week 104
measure: Change in Body Weight- Switch
timeFrame: Week 52, week 104
measure: Change in Body Weight (%)- Switch
timeFrame: Week 52, week 104
measure: Change in FPG- Switch
timeFrame: Week 52, week 104
measure: Change in BMI- Switch
timeFrame: Week 52, Week 104
measure: Change in Waist Circumference- Switch
timeFrame: Week 52, week 104
measure: Participants Who Achieve HbA1c <7.0% (53 mmol/Mol) ADA Target (Yes/no)- Switch
timeFrame: Week 104 (i.e., after 52 weeks of treatment in the extension phase)
measure: Participants Who Achieve HbA1c ≤6.5% (48 mmol/Mol) AACE Target (Yes/no)- Switch
timeFrame: Week 104 (i.e., after 52 weeks of treatment in the extension phase)
measure: Participants Who Achieve Weight Loss ≥5% (Yes/no)- Switch
timeFrame: Week 104 (i.e., after 52 weeks of treatment in the extension phase)
measure: Participants Who Achieve HbA1c <7.0% (53 mmol/Mol) Without Hypoglycaemia (Severe or BG Confirmed Symptomatic Hypoglycaemia) and no Weight Gain (Yes/no)- Switch
timeFrame: Week 104 (i.e., after 52 weeks of treatment in the extension phase)
measure: Participants Who Achieve HbA1c <7.0% (53 mmol/Mol) ADA Target and no Need for Rescue Medication (Yes/no)- Switch
timeFrame: Week 104 (i.e., after 52 weeks of treatment in the extension phase)
measure: Time to Additional Anti-diabetic Medication- Switch
timeFrame: Weeks 53-104
measure: Time to Rescue Medication- Switch
timeFrame: Weeks 53-104
measure: Number of TEAEs During Exposure to Trial Product- Switch
timeFrame: Week 53-109
measure: Change in Amylase (Ratio to Baseline)- Switch
timeFrame: Week 52, Week 104
measure: Change in Lipase (Ratio to Baseline)- Switch
timeFrame: Week 52, Week 104
measure: Change in Pulse Rate- Switch
timeFrame: Week 52, week 104
measure: Change in Blood Pressure (Systolic and Diastolic Blood Pressure)- Switch
timeFrame: Week 52, week 104
measure: Number of Treatment-emergent Severe or BG-confirmed Symptomatic Hypoglycaemic Episodes- Switch
timeFrame: Week 53-109
measure: Paticipants With Treatment-emergent Severe or BG-confirmed Symptomatic Hypoglycaemic Episodes (Yes/no)- Switch
timeFrame: Week 53-109
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)- Switch
timeFrame: Week 52, week 104
measure: Change in DTSQ- Switch
timeFrame: Week 52, week 104
measure: Change in HbA1c- Sustainability
timeFrame: Week 0, week 104
measure: Change in Body Weight (kg)- Sustainability
timeFrame: Week 0, week 104
measure: Change in Body Weight (%)- Sustainability
timeFrame: Week 0, week 104
measure: Change in FPG- Sustainability
timeFrame: Week 0, week 104
measure: Change in BMI- Sustainability
timeFrame: Week 0, Week 104
measure: Change in Waist Circumference- Sustainability
timeFrame: Week 0, week 104
measure: Participants Who Achieve HbA1c <7.0% (53 mmol/Mol) ADA Target (Yes/no)- Sustainability
timeFrame: Week 104
measure: Participants Who Achieve HbA1c ≤6.5% (48 mmol/Mol) AACE Target (Yes/no)- Sustainability
timeFrame: Week 104
measure: Participants Who Achieve Weight Loss ≥5% (Yes/no)- Sustainability
timeFrame: Week 104
measure: Participants Who Achieve HbA1c <7.0 % (53 mmol/Mol) Without Hypoglycaemia (Severe or BG Confirmed Symptomatic Hypoglycaemia) and no Weight Gain (Yes/no)- Sustainability
timeFrame: Week 104
measure: Participants Who Achieve HbA1c <7.0% (53 mmol/Mol) ADA Target or HbA1c Reduction ≥ 1%-Point (10.9 mmol/Mol) (Yes/no)- Sustainability
timeFrame: Week 104
measure: Number of TEAEs During Exposure to Trial Product- Sustainability
timeFrame: Week 0-109
measure: Change in Amylase (Ratio to Baseline)- Sustainability
timeFrame: Week 0, week 104
measure: Change in Lipase (Ratio to Baseline)- Sustainability
timeFrame: Week 0, Week 104
measure: Change in Pulse Rate- Sustainability
timeFrame: Week 0, week 104
measure: Change in Blood Pressure (Systolic and Diastolic Blood Pressure)- Sustainability
timeFrame: Week 0, week 104
measure: Number of Treatment-emergent Severe or BG-confirmed Symptomatic Hypoglycaemic Episodes)- Sustainability
timeFrame: Week 0-109
measure: Paticipants With Treatment-emergent Severe or BG-confirmed Symptomatic Hypoglycaemic Episodes (Yes/no)- Sustainability
timeFrame: Week 0-109
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)- Sustainability
timeFrame: Week 0, week 104
measure: Change in DTSQ- Sustainability
timeFrame: Week 0, week 104
Other outcomes:
Locations:
city: Glendale
country: United States
facility: Novo Nordisk Investigational Site
state: Arizona
city: Phoenix
country: United States
facility: Novo Nordisk Investigational Site
state: Arizona
city: Lancaster
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: West Hills
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: Boynton Beach
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Lake Worth
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Miami Lakes
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Port Orange
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Tampa
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Tampa
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Atlanta
country: United States
facility: Novo Nordisk Investigational Site
state: Georgia
city: Blackfoot
country: United States
facility: Novo Nordisk Investigational Site
state: Idaho
city: Evanston
country: United States
facility: Novo Nordisk Investigational Site
state: Illinois
city: Greenfield
country: United States
facility: Novo Nordisk Investigational Site
state: Indiana
city: Muncie
country: United States
facility: Novo Nordisk Investigational Site
state: Indiana
city: Louisville
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state: Kentucky
city: Metairie
country: United States
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state: Louisiana
city: Oxon Hill
country: United States
facility: Novo Nordisk Investigational Site
state: Maryland
city: Flint
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state: Michigan
city: Billings
country: United States
facility: Novo Nordisk Investigational Site
state: Montana
city: Henderson
country: United States
facility: Novo Nordisk Investigational Site
state: Nevada
city: Albuquerque
country: United States
facility: Novo Nordisk Investigational Site
state: New Mexico
city: Chapel Hill
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: Greenville
country: United States
facility: Novo Nordisk Investigational Site
state: North Carolina
city: Whiteville
country: United States
facility: Novo Nordisk Investigational Site
state: North Carolina
city: Cleveland
country: United States
facility: Novo Nordisk Investigational Site
state: Ohio
city: Mentor
country: United States
facility: Novo Nordisk Investigational Site
state: Ohio
city: Wadsworth
country: United States
facility: Novo Nordisk Investigational Site
state: Ohio
city: Pittsburgh
country: United States
facility: Novo Nordisk Investigational Site
state: Pennsylvania
city: Murrells Inlet
country: United States
facility: Novo Nordisk Investigational Site
state: South Carolina
city: Myrtle Beach
country: United States
facility: Novo Nordisk Investigational Site
state: South Carolina
city: Kingsport
country: United States
facility: Novo Nordisk Investigational Site
state: Tennessee
city: Corpus Christi
country: United States
facility: Novo Nordisk Investigational Site
state: Texas
city: Dallas
country: United States
facility: Novo Nordisk Investigational Site
state: Texas
city: Chesapeake
country: United States
facility: Novo Nordisk Investigational Site
state: Virginia
city: Renton
country: United States
facility: Novo Nordisk Investigational Site
state: Washington
city: Caba
country: Argentina
facility: Novo Nordisk Investigational Site
city: Corrientes
country: Argentina
facility: Novo Nordisk Investigational Site
city: Rosario
country: Argentina
facility: Novo Nordisk Investigational Site
city: Graz
country: Austria
facility: Novo Nordisk Investigational Site
city: Saint Stefan
country: Austria
facility: Novo Nordisk Investigational Site
city: Wien
country: Austria
facility: Novo Nordisk Investigational Site
city: Bonheiden
country: Belgium
facility: Novo Nordisk Investigational Site
city: Boussu
country: Belgium
facility: Novo Nordisk Investigational Site
city: Bruxelles
country: Belgium
facility: Novo Nordisk Investigational Site
city: Edegem
country: Belgium
facility: Novo Nordisk Investigational Site
city: Gent
country: Belgium
facility: Novo Nordisk Investigational Site
city: Leuven
country: Belgium
facility: Novo Nordisk Investigational Site
city: Liège
country: Belgium
facility: Novo Nordisk Investigational Site
city: São Paulo
country: Brazil
facility: Novo Nordisk Investigational Site
state: Sao Paulo
city: Alexandria
country: Egypt
facility: Novo Nordisk Investigational Site
city: Cairo
country: Egypt
facility: Novo Nordisk Investigational Site
city: Cairo
country: Egypt
facility: Novo Nordisk Investigational Site
city: Gangwon-do
country: Korea, Republic of
facility: Novo Nordisk Investigational Site
city: Gyeonggi-do
country: Korea, Republic of
facility: Novo Nordisk Investigational Site
city: Pusan
country: Korea, Republic of
facility: Novo Nordisk Investigational Site
city: Seoul
country: Korea, Republic of
facility: Novo Nordisk Investigational Site
city: Seoul
country: Korea, Republic of
facility: Novo Nordisk Investigational Site
city: Seoul
country: Korea, Republic of
facility: Novo Nordisk Investigational Site
city: Suwon
country: Korea, Republic of
facility: Novo Nordisk Investigational Site
city: Hamar
country: Norway
facility: Novo Nordisk Investigational Site
city: Oslo
country: Norway
facility: Novo Nordisk Investigational Site
city: Oslo
country: Norway
facility: Novo Nordisk Investigational Site
city: Stavanger
country: Norway
facility: Novo Nordisk Investigational Site
city: Trondheim
country: Norway
facility: Novo Nordisk Investigational Site
city: Bern
country: Switzerland
facility: Novo Nordisk Investigational Site
city: Einsiedeln
country: Switzerland
facility: Novo Nordisk Investigational Site
city: Genève 14
country: Switzerland
facility: Novo Nordisk Investigational Site
city: Luzern 16
country: Switzerland
facility: Novo Nordisk Investigational Site
city: Olten
country: Switzerland
facility: Novo Nordisk Investigational Site
city: St. Gallen
country: Switzerland
facility: Novo Nordisk Investigational Site
city: St. Gallen
country: Switzerland
facility: Novo Nordisk Investigational Site
city: Winterthur
country: Switzerland
facility: Novo Nordisk Investigational Site
city: Adana
country: Turkey
facility: Novo Nordisk Investigational Site
city: Ankara
country: Turkey
facility: Novo Nordisk Investigational Site
city: Antalya
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: Rize
country: Turkey
facility: Novo Nordisk Investigational Site
Study officials:
References:
citation: Pieber TR, Bode B, Mertens A, Cho YM, Christiansen E, Hertz CL, Wallenstein SOR, Buse JB; PIONEER 7 investigators. Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial. Lancet Diabetes Endocrinol. 2019 Jul;7(7):528-539. doi: 10.1016/S2213-8587(19)30194-9. Epub 2019 Jun 9.
citation: Buse JB, Bode BW, Mertens A, Cho YM, Christiansen E, Hertz CL, Nielsen MA, Pieber TR; PIONEER 7 investigators. Long-term efficacy and safety of oral semaglutide and the effect of switching from sitagliptin to oral semaglutide in patients with type 2 diabetes: a 52-week, randomized, open-label extension of the PIONEER 7 trial. BMJ Open Diabetes Res Care. 2020 Dec;8(2):e001649. doi: 10.1136/bmjdrc-2020-001649.
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: 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.