Effects of Insulin Degludec and Insulin Glargine U300 on Day-to-Day Fasting Plasma Glucose Variability in Individuals with Type 1 Diabetes: A Multicenter, Randomized, Crossover Study (Kobe Best Basal Insulin Study 2)

This randomized, crossover, open-label, parallel-group, multicenter study (Kobe Best Basal Insulin Study 2) will be performed over 2 months with Japanese subjects with type 1 diabetes in accordance with the Declaration of Helsinki and its amendments. The trial was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as UMIN 000029630 on 20 June 2017, and it has been approved by the ethics committees of 13 participating institutions listed in “Acknowledgements”. The study is to be conducted according to the Ethical Guidelines for Clinical Research published by the Japanese Ministry of Education, Culture, Sports, Science, and Technology and Ministry of Health, Labor, and Welfare (2014 revision), the ICH Consolidated Guideline for Good Clinical Practice, and applicable local laws and regulations. Written informed consent will be obtained from all subjects prior to their randomization.

Patients must satisfy all of the following inclusion criteria and not meet any exclusion criteria. Inclusion criteria for the trial include (1) individuals with type 1 diabetes aged at least 20 years whose serum C-peptide immunoreactivity is less than 0.2 ng/mL (as confirmed at least twice); (2) treatment for at least 1 year with basal-bolus insulin injections, with IGar U100, IGlar U300, or IDeg as the basal insulin and a rapid-acting insulin analogue or regular insulin as the bolus insulin; (3) the ability to perform self-monitoring of blood glucose (SMBG); and (4) the ability to perform FGM. Exclusion criteria include (1) a glycated hemoglobin (HbA_1c) level of 9.0% or higher; (2) use of medications that affect glucose metabolism (such as beta-blockers, corticosteroids, and monoamine oxidase inhibitors); (3) a history of myocardial infarction, angina, coronary bypass surgery, or heart failure within the previous 6 months; (4) severe hypertension (systolic blood pressure of at least 180 mmHg or diastolic blood pressure of at least 100 mmHg); (5) severe liver dysfunction (serum aspartate aminotransferase or alanine aminotransferase levels of at least 2.5 times the upper limit of normal); (6) severe renal impairment (serum creatinine concentration of at least 2.0 mg/dL); (7) frequently recurring severe hypoglycemia or hospitalization because of serious hypoglycemia or diabetic ketoacidosis within the previous year; (8) proliferative diabetic retinopathy with a high risk of hemorrhage; (9) existing or possible pregnancy or breastfeeding or no use of an adequate contraceptive method (adequate contraceptive measures as recommended by local regulation or practice); (10) a diagnosis of cancer; (11) a complicating psychiatric disorder; (12) alcoholism or other drug addiction; (13) diabetes other than type 1, or type 1 diabetes with remaining insulin secretory capacity; (14) rejection of SMBG or FGM; (15) declaration by an investigator that the individual is otherwise inappropriate for the study. The use of previous FGM or CGM is not included in exclusion criteria. Severe hypoglycemia is defined as an event associated with central nervous system manifestations during which the patient requires the assistance of another person. The judgment of frequent recurrence of hypoglycemia will be made by each attending physician. Participants are required both to be able to understand instructions for SMBG and FGM and to provide informed consent in order to be enrolled.

We previously found that the mean value for the SD of FPG was approximately 10 mg/dL smaller with IDeg than with IGlar U100 in individuals with type 1 diabetes [12]. To determine the sample size for the present study, we performed a preliminary analysis of the day-to-day variability in FPG for individuals with type 1 diabetes treated with IDeg as the basal insulin at Kobe University Hospital. The mean and SD values for the SD of FPG in 30 patients over 7 days were determined to be 48.5 and 30.8 mg/dL, respectively. The SD for the intrapatient difference was calculated on the basis of \( \sqrt {30.8^{2} + 30.8^{2} } \) and the noninferiority margin was set as ± 20 mg/dL. At a significance level of 5% and power of 80%, the sample size needed is 19 patients per group. Taking into account subject dropout and withdrawal of informed consent during the study period, we set the sample size at 23 patients per group, for a total of 46 patients.

Enrollment and follow-up visits are outlined in Fig. 1. Individuals found to satisfy the study criteria will be randomly assigned to the IGlar U300 (first period)/IDeg (second period) and the IDeg (first period)/IGlar U300 (second period) groups by a centralized allocation process. In the IGlar U300/IDeg group, the basal insulin will be switched after 4 weeks from IGlar U300 (Lantus XR, SoloSTAR; Sanofi, Paris, France) to IDeg (Tresiba, FlexTouch; Novo Nordisk, Bagsvaerd, Denmark). In the IDeg/IGlar U300 group, the basal insulin will be switched after 4 weeks from IDeg to IGlar U300. The participants will be directed to determine their plasma glucose level four times a day (before breakfast, lunch, and dinner as well as at bedtime) by SMBG during the entire trial period. According to the half-life of IDeg (25.4 h) and IGlar U300 (19.0 h), 3 weeks is considered to be enough to washout the effect of previous insulin. The last week of each treatment period constitutes the data collection phase, during which the participants will be directed to determine their plasma glucose level seven times a day (before breakfast, 2 h after breakfast, before lunch, 2 h after lunch, before dinner, 2 h after dinner, and at bedtime). All subjects will be provided with the same device (OneTouch VerioVue; Johnson & Johnson, New Brunswick, NJ, USA) for SMBG and directed on its use. They will also be equipped with an FGM device (Freestyle Libre Pro; Abbott Diabetes Care, Alameda, California, USA) by medical staff on a visit midway through each treatment period, and the device will be removed by the subjects after 2 weeks for collection of data for the final week. Participants will store the detached FGM device until the next visit, when the data will be uploaded at the hospital or clinic. The data of FGM would be blinded to participants until the study end.

Subjects will be instructed to administer basal insulin at the same time of day in both treatment periods. It should be started at a dose 10% lower than the previous insulin dose at switching in order to prevent unexpected hypoglycemia. If the FPG level is less than 130 mg/dL for more than 3 days, the addition of 1 U of basal insulin will be allowed (self-titration). On the other hand, if FPG is less than 70 mg/dL even for 1 day, the subject will be instructed to reduce the basal insulin dose by 2 U in order to avoid hypoglycemia. Attending physicians will be available to advise patients on basal insulin dose. The type of bolus insulin preparation will not be changed during the trial, and the preprandial bolus insulin dose will be adjusted by each participant. The target plasma glucose level before breakfast, lunch, and dinner as well as at bedtime will initially be less than 130 mg/dL and will subsequently be reduced to less than 110 mg/dL for individuals capable of achieving a reduction on the basis of patients-centered approach. Participants will be directed to avoid hypoglycemia (less than 70 mg/dL) at any time during the day.

The primary end point of the study is the day-to-day variability of FPG level as evaluated by the SD of the plasma glucose concentration determined by SMBG before breakfast during the last week of each 4-week treatment period (Fig. 1). Secondary end points include (1) the coefficient of variance for the plasma glucose level determined by SMBG before breakfast during the last week of each 4-week treatment period as an indicator of interday glycemic variability independent of FPG level itself; (2) the intraday glycemic variability calculated from the seven daily measurements of plasma glucose by SMBG or from FGM data during the last week of each treatment period; (3) the frequency of hypoglycemic events; (4) the duration of hypoglycemia determined by FGM; and (5) the administered basal and bolus insulin dose (the mean for the last week of each treatment period).

All adverse events that occur during the intervention period must be reported irrespective of their suspected causal relation to the study drug. They must be followed up until they have disappeared or for at least 2 weeks after completion of the study period (after discontinuation) and will be assessed with respect to insulin type, onset, outcome, severity, and causal relation to the study drug.

Intergroup differences of normally or non-normally distributed data will be tested for significance with the unpaired Student’s t test or Mann–Whitney U test, respectively. A P value of less than 0.05 will be considered statistically significant. All statistical analysis will be performed with SPSS version 22.0 software.