Study Protocol for the Initial Choice of DPP-4 Inhibitor in Japanese Patients with Type 2 diabetes Mellitus: Effect of Linagliptin on QOL (INTEL-QOL) Trial

The Initial choice of DPP-4 inhibitor in Japanese T2DM patients: Effect of Linagliptin on QOL (INTEL-QOL) study is a prospective, randomized, open-label, multicenter, parallel-group, comparative trial. This study is planned solely to evaluate the QOL. This study has been registered on the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR), a non-profit organization in Japan that meets the requirements of the International Committee of Medical Journal Editors (ICMJE) (UMIN000022953).

Japanese patients with T2DM who regularly attended the outpatient diabetes clinics of 14 institutions (Chimori Clinic, Ikeda Clinic, Yamamoto Clinic, Japanese Red Cross Medical Center, Juntendo Tokyo Koto Geriatric Medical Center (Department of Medicine, Diabetology and Endocrinology), Juntendo University Graduate School of Medicine (Department of Metabolism and Endocrinology), Juntendo University Shizuoka Hospital (Department of Diabetes, Endocrinology, and Metabolism), Sawaki Internal Medicine and Diabetes Clinic, Shimizu Clinic, Tanaka Clinic, Menju Clinic, Misaki Naika Clinic, Musashino Family Clinic, and Yasuda Clinic) in Japan were asked to participate in this study. The inclusion criteria are as follows: (1) T2DM not at target blood glucose control as specified in the Treatment Guide for Diabetes by the Japan Diabetes Society [13] despite the introduction of diet and/or exercise therapy; (2) patients who are considered to newly initiate OHAs in addition to dietary and/or exercise therapy; (3) age ≥ 20 years and < 75 years, regardless of gender; and (4) written informed consent for study participation. The following exclusion criteria are used: (1) type 1 or secondary diabetes; (2) acute diabetic complications within the past 6 months; (3) congestive heart failure or myocardial infarction requiring pharmacotherapy; (4) unstable angina pectoris or coronary bypass surgery within the past 6 months; (5) chronic cirrhosis or chronic active hepatitis; (6) artificial dialysis or moderate renal dysfunction; (7) aspartate aminotransferase or alanine aminotransferase levels more than three times higher than the upper limit of the normal range; (8) direct bilirubin more than three times higher than the upper limit of the normal range, clinically abnormal thyroid-stimulating hormone level, or fasting triglyceride levels > 7.9 mmol/L; (9) treatment with any type of antidiabetic drug; (10) dementia, possible dementia, or mental disorder; (11) insufficient judgment ability or illiteracy; (12) requiring consent for study participation from a legal representative; (13) pregnancy, lactation, possibly pregnancy, or planning to become pregnant during the study period; (14) history of hypersensitivity to investigational drugs; (15) present or past history of a malignant tumor, unless there was no current medical therapy, no recurrence to date, and no risk of recurrence during this study; and (16) judged as ineligible by the clinical investigators.

The subjects were screened consecutively. Patients that met the above eligibility criteria were asked to participate in the present study. All patients who agreed to participate were enrolled in the study. The protocol has been approved by the institutional review board of each participating institution in compliance with the Declaration of Helsinki and current legal regulations in Japan. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the 1964 Declaration of Helsinki, as revised in 2013. Informed consent was obtained from all patients for being included in the study.

Patients were registered at the INTEL-QOL trial’s administration office via the internet. Once enrolled, patients were randomly assigned to either the linagliptin group or the metformin group. Randomization was performed using a dynamic allocation method based on age (< 65 or ≥ 65 years) and gender (male or female).

Patients in the linagliptin group were started on linagliptin 5 mg once daily. Patients in the metformin group were started on metformin 500 mg twice daily. The dose of metformin was increased to a maximum dose of 2250 mg once daily when HbA1c was ≥ 7.0% [13]. The addition of OHAs other than the study drugs and insulin is not permitted in both groups during the study.

The study variables and schedule are shown in Table 1 and Fig. 1. The study period consists of 24 weeks after registration (registration period, June 2016 to December 2017; full study duration, June 2016 to September 2018). All randomized participants will be followed until the end of the scheduled study, regardless of adherence to or discontinuation of the study medication for any reason. Clinical outcome, adherence, and adverse events will be ascertained. Clinical and biochemical data are collected at baseline and 24 weeks after randomization. Blood samples are obtained after overnight fasting at baseline and 24 weeks after randomization. Urinary albumin excretion is measured by latex agglutination assay using a spot urine sample at baseline and 24 weeks after randomization. In addition, participants were asked to record usage of their study drug on a medication record during the study period.