Clinical trial NCT03018028: Dose-response, Safety and Efficacy of Oral Semaglutide Versus Placebo and Versus Liraglutide, All as Monotherapy in Japanese Subjects With Type 2 Diabetes
Official title: Dose-response, Safety and Efficacy of Oral Semaglutide Versus Placebo and Versus Liraglutide, All as Monotherapy in Japanese Subjects With Type 2 Diabetes
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: 2017-01-11
Enrollment: 243
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This trial is conducted in Asia. The aim of this trial is to investigate the dose-response relationship of once-daily dosing of three dose levels (3, 7 and 14 mg) of oral semaglutide versus placebo as monotherapy on glycaemic control in Japanese 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
* Japanese male or female, age above or equal to 20 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 6.5%-9.5% (48-80 mmol/mol) (both inclusive) for subjects treated with oral antidiabetic drug as monotherapy and 7.0%-10.0% (53-86 mmol/mol) (both inclusive) for subjects treated with diet and exercise therapy alone
* Treatment for at least 30 days prior to day of screening with;- stable daily dose of oral anti-diabetic drug as monotherapy (allowed oral anti-diabetic drugs are: metformin, sulphonylurea, glinide, α-glucosidase inhibitor, dipeptidyl peptidase-4 inhibitor and sodium-glucose cotransporter-2 inhibitor) at a half-maximum approved dose or below according to Japanese labelling in addition to diet and exercise therapy. or - diet and exercise therapy alone

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 measures are abstinence (not having sex), diaphragm, condom (by the partner), intrauterine device, sponge, spermicide or oral contraceptives
* 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, stroke or hospitalisation for unstable angina or transient ischaemic attack within the past 180 days prior to the day of screening and randomisation
* Subject 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 alanine aminotransferase (ALT) above 2.5 x upper normal limit (UNL)
* Renal impairment defined as estimated Glomerular Filtration Rate (eGFR) below 30 mL/min/1.73 m\^2 as per Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI)
* Treatment with once-weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA), once weekly dipeptidyl peptidase-4 (DPP-4) inhibitor or thiazolidinedione in a period of 90 days before the day of screening
* Treatment with any medication for the indication of diabetes or obesity other than stated in the inclusion criteria in a period of 60 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)
* Initiation of anti-diabetic medication between the day of screening and the day of randomisation

Primary outcomes:
measure: Change in HbA1c (Week 26)
timeFrame: Week 0, week 26
Secondary outcomes:
measure: Change in HbA1c (Week 52)
timeFrame: Week 0, week 52
measure: Change in Body Weight (kg)
timeFrame: Week 0, week 26, week 52
measure: Change in Fasting Plasma Glucose
timeFrame: Week 0, week 26, week 52
measure: Change in Self-measured Plasma Glucose 7-point Profile (SMPG) - Mean 7-point Profile
timeFrame: Week 0, week 26, week 52
measure: Change in Mean Postprandial Increment Over All Meals in SMPG
timeFrame: Week 0, week 26 and week 52
measure: Change in Body Weight (%)
timeFrame: Week 0, week 26 and week 52
measure: Change in Body Mass Index
timeFrame: Week 0, week 26 and week 52
measure: Change in Waist Circumference
timeFrame: Week 0, week 26 and week 52
measure: Change in Total Cholesterol (Ratio to Baseline)
timeFrame: Week 0, week 26 and week 52
measure: Change in HDL Cholesterol (Ratio to Baseline)
timeFrame: Week 0, week 26 and week 52
measure: Change in LDL Cholesterol (Ratio to Baseline)
timeFrame: Week 0, week 26 and week 52
measure: Change in VLDL Cholesterol (Ratio to Baseline)
timeFrame: Week 0, week 26 and week 52
measure: Change in Triglycerides (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 C-peptide (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 Fasting Pro-insulin (Ratio to Baseline)
timeFrame: Week 0, week 26 and week 52
measure: Change in Fasting Pro-insulin/Insulin Ratio (Ratio to Baseline)
timeFrame: Week 0, week 26 and week 52
measure: Change in Insulin Resistance (HOMA-IR) (Ratio to Baseline)
timeFrame: Week 0, week 26 and week 52
measure: Change in Beta-cell Function (HOMA-B) (Ratio to Baseline)
timeFrame: Week 0, week 26 and week 52
measure: Participants Who Achieved HbA1c < 7.0% (53 mmol/Mol) ADA Target (Yes/no)
timeFrame: Week 26 and week 52
measure: Participants Who Achieved HbA1c Below or Equal to 6.5% (48 mmol/Mol), AACE Target (Yes/No)
timeFrame: Week 26 and week 52
measure: Participants Who Achieved HbA1c Below 7.0% (53 mmol/Mol) Without Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemia Episodes and no Weight Gain (Yes/No)
timeFrame: Week 26 and week 52
measure: Participants Who Achieved HbA1c Reduction Above or Equal to 1% (10.9 mmol/Mol) and Weight Loss Above or Equal to 3%
timeFrame: Week 26 and week 52
measure: Participants Who Achieved Weight Loss Above or Equal to 5% (Yes/No)
timeFrame: Week 26 and week 52
measure: Participants Who Achieved Weight Loss Above or Equal to 10% (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 (TEAEs)
timeFrame: Weeks 0 - 57
measure: Change in Amylase (Ratio to Baseine)
timeFrame: Week 0, week 26, week 52
measure: Change in Lipase (Ratio to Baseine)
timeFrame: Week 0, week 26, week 52
measure: Change in Pulse Rate
timeFrame: Week 0, week 26, week 52
measure: Change in Blood Pressure
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: Baseline (Week -8), week 26, week 52
measure: Change in Eye Examination Category
timeFrame: Week -8, Week 52
measure: Anti-semaglutide Binding Antibodies (Yes/no)
timeFrame: Week 0 - 57
measure: Anti-semaglutide Neutralising Antibodies (Yes/no)
timeFrame: Week 0 - 57
measure: Anti-semaglutide Binding Antibodies Cross Reacting With Native GLP-1 (Yes/no)
timeFrame: Week 0 - 57
measure: Anti-semaglutide Neutralising Antibodies Cross Reacting With Native GLP-1 (Yes/no)
timeFrame: Week 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: Week 0 - 57
measure: Participants With Treatment-emergent Severe or Blood Glucose-confirmed Symptomatic Hypoglycaemic Episodes
timeFrame: Weeks 0 - 57
measure: Semaglutide Plasma Concentration
timeFrame: Week 26 and week 52
measure: Change in SF-36: Sub-domains
timeFrame: Week 0, week 26, week 52
measure: Change in SF-36: Physical Component Summary (PCS)
timeFrame: Week 0, week 26, week 52
measure: Change in SF-36: Mental Component Summary (MCS)
timeFrame: Week 0, week 26, week 52
measure: Change From Baseline in DTR-QOL: Total Score
timeFrame: Week 0, week 26, week 52
measure: Change From Baseline in DTR-QOL: Sub-domains
timeFrame: Week 0, week 26, week 52
Other outcomes:
Locations:
city: Akita-shi, Akita
country: Japan
facility: Novo Nordisk Investigational Site
city: Arakawa-ku, Tokyo
country: Japan
facility: Novo Nordisk Investigational Site
city: Ebina-shi, Kanagawa
country: Japan
facility: Novo Nordisk Investigational Site
city: Gunma
country: Japan
facility: Novo Nordisk Investigational Site
city: Kanagawa
country: Japan
facility: Novo Nordisk Investigational Site
city: Minato-ku, Tokyo
country: Japan
facility: Novo Nordisk Investigational Site
city: Naka-shi
country: Japan
facility: Novo Nordisk Investigational Site
city: Osaka-shi, Osaka
country: Japan
facility: Novo Nordisk Investigational Site
city: Ota-ku, Tokyo
country: Japan
facility: Novo Nordisk Investigational Site
city: Saga-shi, Saga
country: Japan
facility: Novo Nordisk Investigational Site
city: Sendai-shi, Miyagi
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: Tokyo
country: Japan
facility: Novo Nordisk Investigational Site
Study officials:
References:
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: Yamada Y, Katagiri H, Hamamoto Y, Deenadayalan S, Navarria A, Nishijima K, Seino Y; PIONEER 9 investigators. Dose-response, efficacy, and safety of oral semaglutide monotherapy in Japanese patients with type 2 diabetes (PIONEER 9): a 52-week, phase 2/3a, randomised, controlled trial. Lancet Diabetes Endocrinol. 2020 May;8(5):377-391. doi: 10.1016/S2213-8587(20)30075-9.
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.