Multicenter, open-label, two-arm, pilot trial for safe reduction of basal insulin dose combined with SGLT2 inhibitor in type 1 diabetes mellitus: study protocol for a RISING-STAR trial.
Authors: Hamaguchi Masahide , Hashimoto Yoshitaka , Tanaka Toru , Hasegawa Goji , Ishii Michiyo , Okada Hiroshi , Mitsuhashi Kazuteru , Kitagawa Noriyuki , Ushigome Emi , Yamazaki Masahiro , Fukui Michiaki 
Published: March 2021

Abstract
Background: The sodium–glucose cotransporter 2 (SGLT2) inhibitor combined with insulin is a novel therapy for type 1 diabetes mellitus. Without reducing basal insulin, hypoglycemia could occur frequently in this therapy. However, ketoacidosis is an undesirable adverse effect in patients with basal insulin reduction. The RISING-STAR study aimed to explore whether reducing the basal insulin dose combined with the SGLT2 inhibitor can safely reduce the frequency of hypoglycemia. We hypothesized that the frequency of hypoglycemia is higher if the basal insulin dose is not reduced when combined with an SGLT2 inhibitor.Methods: The study has a multicenter, open-label, two-arm design; 60 type 1 diabetes mellitus patients are being recruited from 7 hospitals. Twenty-six subjects are to be analyzed in each group for the pilot objectives. The basal insulin dose before initiating SGLT2 inhibitor combination therapy is the reference. Study subjects have been stratified into two groups based on the ratio of basal insulin daily dose (Basal) to total daily insulin dose (TDD). The subjects whose Basal/TDD ratio is < 0.4 are instructed not to reduce Basal but to reduce bolus insulin dose by 10% (group A), and subjects with a Basal/TDD ratio > 0.4 will be instructed to reduce Basal by 10% (group B). The primary outcome is the daily frequency of hypoglycemia during the intervention period (SGLT2 inhibitor administration), as determined by self-monitoring of blood glucose. We aimed to confirm a greater reduction in frequency of hypoglycemia in group B (reduced Basal), than in group A (non-reduction of Basal and reduced insulin effect levels by 10%). Baseline hypoglycemia was set at 7 ± 6 times/month. The minimum sample size required to achieve a significance of 0.05 for a one-sided t-test with a statistical power at 80% is determined. When the sample size is 26 patients in one group, the percentage increase in hypoglycemia exceeds 60%, and the sample size is considered sufficient. The secondary outcome is the frequency of ketosis pre- and post-intervention. We aimed to confirm that the frequency of ketosis did not increase in group B compared to that in group A. The frequency of adverse events, including frequency of hypoglycemia detected by flash glucose monitoring, was set as a safety endpoint.Discussion: In this pilot study, we assumed that, given a sufficient Basal, hypoglycemia would be more frequent in patients with type 1 diabetes when combined with SGLT2 inhibitors, provided the Basal was not reduced. A 10% basal insulin reduction decreased hypoglycemia but did not increase ketosis in cases where the Basal/TTD ratio was 0.4 or higher, which improves the efficacy and safety of SGLT2 inhibitor treatment in type 1 diabetes mellitus.Trial registration: Registered with Japan Registry of Clinical Trials (jRCTs051190114) on March 2, 2020. (https://rctportal.niph.go.jp/detail/jr?trial_id=jRCTs051190114)