Clinical trial NCT03021187: Efficacy and Safety of Oral Semaglutide Versus Placebo in Subjects With Type 2 Diabetes Mellitus Treated With Insulin
Official title: Efficacy and Safety of Oral Semaglutide Versus Placebo in Subjects With Type 2 Diabetes Mellitus Treated With Insulin. A 52-week, Randomised, Double-blind, Placebo-controlled Trial (PIONEER 8 - Insulin add-on)
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: 2017-01-13
Enrollment: 731
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 the trial is to investigate the efficacy and safety of oral semaglutide versus placebo in subjects with Type 2 Diabetes Mellitus treated with insulin. All subjects should continue their pre-trial insulin therapy (basal, basal-bolus or premixed regimen including combinations of soluble insulins) throughout the trial. Subjects treated with metformin in addition to insulin treatment must continue their metformin treatment throughout the entire trial.


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. - Diagnosed with type 2 diabetes mellitus 90 days or more prior to the day of screening. - HbA1c (glycosylated haemoglobin) of 7.0-9.5% (53-80 mmol/mol) (both inclusive). - Stable treatment with one of the following insulin regimens (minimum 10 IU/day) 90 or more days prior to the day of screening. Maximum 20% change in total daily dose is acceptable: (1) Basal insulin alone or (2) Basal and bolus insulin in any combination or (3) Premixed insulin including combinations of soluble insulins 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 Greece only: adequate contraceptive measures are defined as combined hormonal contraception (containing oestrogen and progesterone), which suppress ovulation (oral, intravaginal, percutaneous), progesterone-only hormonal contraception which suppress ovulation (oral, injectable, implantable), intrauterine device, hormone-releasing intrauterine system, bilateral tubal occlusion, partner with vasectomy, sexual abstinence. For Japan only: Adequate contraceptive measures are abstinence (not having sex), diaphragm, condom (by the partner), intrauterine device, sponge, spermicide or oral contraceptives. For Canada only: adequate contraceptive measures are defined as combined hormonal contraception (containing oestrogen and progesterone), which suppress ovulation (oral, intravaginal, percutaneous), progesterone-only hormonal contraception which suppress ovulation (oral, injectable, implantable), intrauterine device, hormone-releasing intrauterine system, bilateral tubal occlusion, partner with vasectomy, sexual abstinence - 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 and randomisation. - Classified as being in New York Heart Association (NYHA) Class IV. - Planned coronary, carotid or peripheral artery revascularisation known on the day of screening. - Renal impairment defined as estimated Glomerular Filtration Rate (eGFR) less than 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 change of insulin treatment for acute illness for a total of 14 days or less. - Known hypoglycaemic unawareness according to Clarke's questionnaire. - 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). - Subjects with alanine aminotransferase (ALT) more than 2.5 x upper normal limit (UNL).

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 (kg) (Week 52)
timeFrame: Week 0, week 52
measure: Change in Fasting Plasma Glucose (FPG)
timeFrame: Week 0, week 26, week 52
measure: Change in Self-measured Plasma Glucose (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: Change in Body Weight (Percentage)
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 LDL Cholesterol - Ratio to Baseline
timeFrame: Week 0, week 26, week 52
measure: Change in 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 Total Daily Insulin Dose
timeFrame: Week 0, week 26, week 52
measure: Participants Who Achieve: HbA1c < 7.0% (53 mmol/Mol) (American Diabetes Association (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 Body Weight Loss ≥5% (Yes/no)
timeFrame: Week 26, week 52
measure: Participants Who Achieve Body 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: Number of Treatment-emergent Severe or BG-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 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: Semaglutide Plasma Concentrations for Population PK Analyses
timeFrame: Weeks 0-52
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 26, week 52
measure: Change in IWQoL-Lite-CT: Total Score and Scores From the 4 Domains
timeFrame: Week 0, week 26, week 52
measure: Change in DTSQs: Individual Items and Treatment Satisfaction Score (6 of the 8 Items Summed)
timeFrame: Week 0, week 26, week 52
Other outcomes:
Locations:
city: Anniston
country: United States
facility: Novo Nordisk Investigational Site
state: Alabama
city: Birmingham
country: United States
facility: Novo Nordisk Investigational Site
state: Alabama
city: Fountain Hills
country: United States
facility: Novo Nordisk Investigational Site
state: Arizona
city: Glendale
country: United States
facility: Novo Nordisk Investigational Site
state: Arizona
city: Mesa
country: United States
facility: Novo Nordisk Investigational Site
state: Arizona
city: Phoenix
country: United States
facility: Novo Nordisk Investigational Site
state: Arizona
city: Tucson
country: United States
facility: Novo Nordisk Investigational Site
state: Arizona
city: Tucson
country: United States
facility: Novo Nordisk Investigational Site
state: Arizona
city: Anaheim
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: Fresno
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: Los Angeles
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: Los Angeles
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: Riverside
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: Van Nuys
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: Vista
country: United States
facility: Novo Nordisk Investigational Site
state: California
city: Colorado Springs
country: United States
facility: Novo Nordisk Investigational Site
state: Colorado
city: Denver
country: United States
facility: Novo Nordisk Investigational Site
state: Colorado
city: Hialeah
country: United States
facility: Novo Nordisk Investigational Site
state: Florida
city: Atlanta
country: United States
facility: Novo Nordisk Investigational Site
state: Georgia
city: Chicago
country: United States
facility: Novo Nordisk Investigational Site
state: Illinois
city: Franklin
country: United States
facility: Novo Nordisk Investigational Site
state: Indiana
city: Lexington
country: United States
facility: Novo Nordisk Investigational Site
state: Kentucky
city: Paducah
country: United States
facility: Novo Nordisk Investigational Site
state: Kentucky
city: Metairie
country: United States
facility: Novo Nordisk Investigational Site
state: Louisiana
city: Natchitoches
country: United States
facility: Novo Nordisk Investigational Site
state: Louisiana
city: Hyattsville
country: United States
facility: Novo Nordisk Investigational Site
state: Maryland
city: Rockville
country: United States
facility: Novo Nordisk Investigational Site
state: Maryland
city: Boston
country: United States
facility: Novo Nordisk Investigational Site
state: Massachusetts
city: Troy
country: United States
facility: Novo Nordisk Investigational Site
state: Michigan
city: Henderson
country: United States
facility: Novo Nordisk Investigational Site
state: Nevada
city: Las Vegas
country: United States
facility: Novo Nordisk Investigational Site
state: Nevada
city: West Seneca
country: United States
facility: Novo Nordisk Investigational Site
state: New York
city: Asheville
country: United States
facility: Novo Nordisk Investigational Site
state: North Carolina
city: Chapel Hill
country: United States
facility: Novo Nordisk Investigational Site
state: North Carolina
city: Cincinnati
country: United States
facility: Novo Nordisk Investigational Site
state: Ohio
city: Dayton
country: United States
facility: Novo Nordisk Investigational Site
state: Ohio
city: Beaver
country: United States
facility: Novo Nordisk Investigational Site
state: Pennsylvania
city: Lansdale
country: United States
facility: Novo Nordisk Investigational Site
state: Pennsylvania
city: Summerville
country: United States
facility: Novo Nordisk Investigational Site
state: South Carolina
city: Chattanooga
country: United States
facility: Novo Nordisk Investigational Site
state: Tennessee
city: Kingsport
country: United States
facility: Novo Nordisk Investigational Site
state: Tennessee
city: Austin
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: Mesquite
country: United States
facility: Novo Nordisk Investigational Site
state: Texas
city: Midland
country: United States
facility: Novo Nordisk Investigational Site
state: Texas
city: Round Rock
country: United States
facility: Novo Nordisk Investigational Site
state: Texas
city: Murray
country: United States
facility: Novo Nordisk Investigational Site
state: Utah
city: Winchester
country: United States
facility: Novo Nordisk Investigational Site
state: Virginia
city: Winnipeg
country: Canada
facility: Novo Nordisk Investigational Site
state: Manitoba
city: Moncton
country: Canada
facility: Novo Nordisk Investigational Site
state: New Brunswick
city: Brampton
country: Canada
facility: Novo Nordisk Investigational Site
state: Ontario
city: Etobicoke
country: Canada
facility: Novo Nordisk Investigational Site
state: Ontario
city: London
country: Canada
facility: Novo Nordisk Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: Novo Nordisk Investigational Site
state: Ontario
city: Waterloo
country: Canada
facility: Novo Nordisk Investigational Site
state: Ontario
city: Besançon cedex
country: France
facility: Novo Nordisk Investigational Site
city: Bourgoin-jallieu
country: France
facility: Novo Nordisk Investigational Site
city: Brest
country: France
facility: Novo Nordisk Investigational Site
city: LA ROCHE-sur-YON cedex 9
country: France
facility: Novo Nordisk Investigational Site
city: LA ROCHELLE cedex
country: France
facility: Novo Nordisk Investigational Site
city: Le Coudray
country: France
facility: Novo Nordisk Investigational Site
city: Le Creusot
country: France
facility: Novo Nordisk Investigational Site
city: Narbonne
country: France
facility: Novo Nordisk Investigational Site
city: Paris
country: France
facility: Novo Nordisk Investigational Site
city: Saint Herblain
country: France
facility: Novo Nordisk Investigational Site
city: TOULOUSE cedex
country: France
facility: Novo Nordisk Investigational Site
city: Venissieux
country: France
facility: Novo Nordisk Investigational Site
city: Athens
country: Greece
facility: Novo Nordisk Investigational Site
city: Athens
country: Greece
facility: Novo Nordisk Investigational Site
city: Ioannina
country: Greece
facility: Novo Nordisk Investigational Site
city: Larissa
country: Greece
facility: Novo Nordisk Investigational Site
city: Piraeus
country: Greece
facility: Novo Nordisk Investigational Site
city: Thessaloniki
country: Greece
facility: Novo Nordisk Investigational Site
city: Ahmedabad
country: India
facility: Novo Nordisk Investigational Site
state: Gujarat
city: Bangalore
country: India
facility: Novo Nordisk Investigational Site
state: Karnataka
city: Kozhikode
country: India
facility: Novo Nordisk Investigational Site
state: Kerala
city: Indore
country: India
facility: Novo Nordisk Investigational Site
state: Madhya Pradesh
city: Mumbai
country: India
facility: Novo Nordisk Investigational Site
state: Maharashtra
city: Mumbai
country: India
facility: Novo Nordisk Investigational Site
state: Maharashtra
city: Pune
country: India
facility: Novo Nordisk Investigational Site
state: Maharashtra
city: New Dehli
country: India
facility: Novo Nordisk Investigational Site
state: New Delhi
city: Jaipur
country: India
facility: Novo Nordisk Investigational Site
state: Rajasthan
city: Chennai
country: India
facility: Novo Nordisk Investigational Site
state: Tamil Nadu
city: Kolkata
country: India
facility: Novo Nordisk Investigational Site
state: West Bengal
city: Kolkata
country: India
facility: Novo Nordisk Investigational Site
city: Amagasaki-shi, Hyogo
country: Japan
facility: Novo Nordisk Investigational Site
city: Chuo-ku, Tokyo
country: Japan
facility: Novo Nordisk Investigational Site
city: Ebina-shi, Kanagawa
country: Japan
facility: Novo Nordisk Investigational Site
city: Iruma-shi, Saitama
country: Japan
facility: Novo Nordisk Investigational Site
city: Kanagawa
country: Japan
facility: Novo Nordisk Investigational Site
city: Kumamoto-shi, Kumamoto
country: Japan
facility: Novo Nordisk Investigational Site
city: Kumamoto
country: Japan
facility: Novo Nordisk Investigational Site
city: Miyazaki
country: Japan
facility: Novo Nordisk Investigational Site
city: Naka-shi
country: Japan
facility: Novo Nordisk Investigational Site
city: Osaka
country: Japan
facility: Novo Nordisk Investigational Site
city: Saga-shi, Saga
country: Japan
facility: Novo Nordisk Investigational Site
city: Sapporo-shi
country: Japan
facility: Novo Nordisk Investigational Site
city: Shimotsuke-shi, Tochigi
country: Japan
facility: Novo Nordisk Investigational Site
city: Shizuoka-shi, Shizuoka
country: Japan
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: Ube-shi, Yamaguchi
country: Japan
facility: Novo Nordisk Investigational Site
city: Durango
country: Mexico
facility: Novo Nordisk Investigational Site
city: San Luis Potosi
country: Mexico
facility: Novo Nordisk Investigational Site
city: Bialystok
country: Poland
facility: Novo Nordisk Investigational Site
city: Lublin
country: Poland
facility: Novo Nordisk Investigational Site
city: Poznan
country: Poland
facility: Novo Nordisk Investigational Site
city: Pulawy
country: Poland
facility: Novo Nordisk Investigational Site
city: Manati
country: Puerto Rico
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: Penza
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: St. Petersburg
country: Russian Federation
facility: Novo Nordisk Investigational Site
Study officials:
References:
citation: Zinman B, Aroda VR, Buse JB, Cariou B, Harris SB, Hoff ST, Pedersen KB, Tarp-Johansen MJ, Araki E; PIONEER 8 Investigators. Efficacy, Safety, and Tolerability of Oral Semaglutide Versus Placebo Added to Insulin With or Without Metformin in Patients With Type 2 Diabetes: The PIONEER 8 Trial. Diabetes Care. 2019 Dec;42(12):2262-2271. doi: 10.2337/dc19-0898. Epub 2019 Sep 17.
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.