ARCADIA study protocol: a phase II, randomised, double-blind, placebo-controlled clinical trial to assess the safety and efficacy of AZD1656 in patients with diabetes hospitalised with suspected or confirmed COVID-19

Abstract

IntroductionCOVID-19, caused by SARS-CoV-2, remains a global pandemic that has affected more than 100 million people worldwide with over 4.8 million deaths as of October 2021. Patients with diabetes have both an increased susceptibility to SARS-CoV-2 infection, enhanced disease severity and increased risk of mortality. The challenge presented in these patients is both to improve glycaemic control—which itself may confer a survival advantage—and to help maintain or restore immunological homeostasis. The specific glucokinase activator AZD1656 may address both of these challenges via its glucose-lowering effect and its immunological mechanism of action. The aim of the Alleviation of cardioRespiratory complications in patients with COVID-19 And DIAbetes (ARCADIA) trial is to investigate this hypothesis and determine whether AZD1656 can improve clinical outcomes for these patients.Methods and analysisARCADIA is a double-blind, placebo-controlled, interventional study of AZD1656 in 150 patients with either type 1 or type 2 diabetes who have been admitted to hospital with COVID-19. Eligible, consented patients will be randomised in a 1:1 manner to receive either active drug or matched placebo tablets while they are in hospital. All patients will receive the usual and current standard of care for patients with COVID-19 in that hospital. Clinical and laboratory data will be collected and assessed at baseline and throughout their participation in the study. Data will be captured in the case report form, which will be electronically archived at the end of the trial in the trial master file. The WHO 8-point Ordinal Scale for Clinical Improvement will be used to measure clinical outcome for the primary endpoint of the trial.Ethics and disseminationEthical approval has been obtained from the East Midlands-Leicester South Ethics Committee (REC 20/EM/0198) in the UK, from the National Bioethics Committee of Medicines and Medical Devices in Bucharest, Romania, and from the Ethics Committee IKEM a TN in Prague, Czech Republic. All study-related data will be used by the sponsor in accordance with local data protection law. In the UK, all patient identifiable data will be stored on a password-protected National Health Service N3 network with full audit trail. Anonymised data will be stored in an ISO27001 certificated data warehouse.Trial registration numberEudraCT 2020-002211-21, NCT04516759.

Dorzagliatin in drug-naïve patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial

“…Among the partial GKAs, AZD1656 and PF-04937319 are the two leading candidates evaluated in phase 2 trials. PF-04937319 is currently being studied in China in phase 3 trials 56 , and AZD1656 has shown encouraging outcomes for the reduction of overall coronavirus disease 2019 mortality in patients with diabetes in the ARCADIA study 50 . A liver-selective GKA, TTP399, which is chemically modified to optimize its uptake into hepatocytes and prevent its entry into pancreatic beta cells, has been developed for T2D and was shown to achieve sustained glycemic control without dyslipidemia with 6 months of treatment 33 .…”

“…GKAs have also been developed for diseases other than T2D, including TTP399 for type 1 diabetes (T1D) 49 and AZD1656 for reducing mortality in patients with diabetes who were infected with severe acute respiratory syndrome coronavirus 2 (ref. 50 ).…”

Predictive performance and clinical application of COV50, a urinary proteomic biomarker in early COVID-19 infection: a prospective multicentre cohort study

“…On days 0–3, 4–7, and 10–21 after diagnosis, participants who were alive were staged according to the 8-point WHO Clinical Progression Scale. 7 Electronic case report forms (MARVIN EDC; XClinical, Munich, Germany) were used for data compilation. For UPP, 10-mL urine samples were collected in borated test tubes (ExactoBac-U; Sarstedt, Nümbrecht, Germany) and kept at –20°C or less until assayed.…”