A randomised, double-blind, placebo-controlled, multicentre clinical trial of AZD1656 in diabetic patients hospitalised with COVID-19: The ARCADIA Trial - implications for therapeutic immune modulation.

Background: A potential immunotherapeutic role for AZD1656 (a glucokinase activator) in the treatment of COVID-19 was hypothesized. The ARCADIA trial investigated the safety and efficacy of AZD1656 in diabetic patients admitted to hospital with COVID-19. Methods: The ARCADIA trial was a Phase II randomised, double-blind, placebo-controlled clinical trial. Adult diabetic patients, admitted with COVID-19, were recruited at 28 hospitals in the UK, Romania and Czech Republic and randomly assigned (1:1) to receive AZD1656 tablets (100mg twice a day), or matched placebo, for up to 21 days, in addition to usual care. All involved were masked to treatment allocation. The primary endpoint was clinical improvement measured at Day 14. The Full Analysis Set (FAS) included all patients who received at least one dose of assigned treatment. ARCADIA is complete and registered with ClinicalTrials.gov (NCT04516759). Findings: Between 29 September 2020 to 16 April 2021, 170 patients were screened and 156 patients were randomised, three of whom did not commence treatment. Of the remaining 153, 80 were assigned to AZD1656 and 73 were assigned to placebo and included in the Full Analysis Set (FAS). The primary analysis showed no statistically significant difference between groups (AZD1656: 76·3%; Placebo: 69·9%, p=0·19). There was no difference in the number of adverse events between groups (AZD1656: 35·7%; Placebo: 33·3%). Mortality was lower in the AZD1656 group compared to the placebo group (AZD1656: four (5%); Placebo: nine (12·3%), p=0·090)). At Day 7 there were zero deaths in the AZD1656 group compared to six deaths in the placebo group (p=0·011, post hoc). A difference between groups in time to hospital discharge was also seen (p=0·16). Immunophenotyping data suggested that AZD1656-treated patients had a less pro-inflammatory immune response and a better adaptive immune response than those treated with placebo. Interpretation: Although the trial did not achieve its primary endpoint, AZD1656 was associated with a decrease in deaths and a reduction in the duration of hospitalisation, as compared to Placebo. Immunophenotyping and immunochemistry indicated an immunomodulatory effect of AZD1656. The trial suggests a beneficial therapeutic effect of AZD1656 and identifies a new therapeutic concept: small molecule activation of endogenous homeostatic immune cells which themselves become the therapeutic agent within the body. Phase 2 trials of this size carry the risk of false positive results and confirmation of these results in a larger clinical trial is now required. Funding: UK Research and Innovation (UKRI) 'Innovate UK' programme and Excalibur Medicines Ltd.

A randomised, double-blind, placebo-controlled, multicentre clinical trial of AZD1656 in diabetic patients hospitalised with COVID-19: The ARCADIA Trial - implications for therapeutic immune modulation

Background A potential immunotherapeutic role for AZD1656 (a glucokinase activator) in the treatment of COVID-19 was hypothesized. The ARCADIA trial investigated the safety and efficacy of AZD1656 in diabetic patients admitted to hospital with COVID-19. Methods The ARCADIA trial was a Phase II randomised, double-blind, placebo-controlled clinical trial. Adult diabetic patients, admitted with COVID-19, were recruited at 28 hospitals in the UK, Romania and Czech Republic and randomly assigned (1:1) to receive AZD1656 tablets (100mg twice a day), or matched placebo, for up to 21 days, in addition to usual care. All involved were masked to treatment allocation. The primary endpoint was clinical improvement measured at Day 14. The Full Analysis Set (FAS) included all patients who received at least one dose of assigned treatment. ARCADIA is complete and registered with ClinicalTrials.gov (NCT04516759). Findings Between 29 September 2020 to 16 April 2021, 170 patients were screened and 156 patients were randomised, three of whom did not commence treatment. Of the remaining 153, 80 were assigned to AZD1656 and 73 were assigned to placebo and included in the Full Analysis Set (FAS). The primary analysis showed no statistically significant difference between groups (AZD1656: 76·3%;Placebo: 69·9%, p=0·19). There was no difference in the number of adverse events between groups (AZD1656: 35·7%;Placebo: 33·3%). Mortality was lower in the AZD1656 group compared to the placebo group (AZD1656: four (5%);Placebo: nine (12·3%), p=0·090)). At Day 7 there were zero deaths in the AZD1656 group compared to six deaths in the placebo group (p=0·011, post hoc). A difference between groups in time to hospital discharge was also seen (p=0·16). Immunophenotyping data suggested that AZD1656-treated patients had a less pro-inflammatory immune response and a better adaptive immune response than those treated with placebo. Interpretation Although the trial did not achieve its primary endpoint, AZD1656 was associated with a decrease in deaths and a reduction in the duration of hospitalisation, as compared to Placebo. Immunophenotyping and immunochemistry indicated an immunomodulatory effect of AZD1656. The trial suggests a beneficial therapeutic effect of AZD1656 and identifies a new therapeutic concept: small molecule activation of endogenous homeostatic immune cells which themselves become the therapeutic agent within the body. Phase 2 trials of this size carry the risk of false positive results and confirmation of these results in a larger clinical trial is now required. Funding UK Research and Innovation (UKRI) ‘Innovate UK’ programme and Excalibur Medicines Ltd.

Outcome and effect of vaccination in SARS-CoV-2 Omicron infection in hemodialysis patients: a cohort study.

BACKGROUND: Hemodialysis patients are at high risk of Covid-19, though vaccination has significant efficacy in preventing and reducing the severity of infection. Little information is available on disease severity and vaccine efficacy since the dissemination of the Omicron variant. METHODS: In a multi-center study, during a period of the epidemic driven by the Omicron variant, all hemodialysis patients positive for SARS-CoV-2 were identified. Outcomes were analyzed according to predictor variables including vaccination status. Risk of infection was analyzed using a Cox proportional hazards model. RESULTS: SARS-CoV-2 infection was identified in 1126 patients including 200 (18%) unvaccinated, 56 (5%) post first dose, 433 (38%) post second dose, and 437 (39%) at least 7 days beyond their third dose. The majority of patients had a mild course but 160 (14%) were hospitalized and 28 (2%) died. In regression models adjusted for age and comorbidity, two-dose vaccination was associated with a 39% (95%CI: 2%-62%) reduction in admissions, but third doses provided additional protection, with a 51% (95%CI: 25%-69%) further reduction in admissions. Among 1265 patients at risk at the start of the observation period, SARS-CoV-2 infection was observed in 211 (17%). Two-dose vaccination was associated with a 41% (95%CI: 3%-64%) reduction in the incidence of infection, with no clear additional effect provided by third doses. CONCLUSIONS: These data demonstrate lower incidence of SARS-CoV-2 infection after vaccination in dialysis patients during an Omicron dominant period of the epidemic. Among those developing infection, severe illness was less common with prior vaccination, particularly after third vaccine doses.

Severity of COVID-19 after Vaccination among Hemodialysis Patients: An Observational Cohort Study.

BACKGROUND AND OBJECTIVES: Patients receiving hemodialysis are at high risk from coronavirus disease 2019 (COVID-19) and demonstrate impaired immune responses to vaccines. There have been several descriptions of their immunologic responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, but few studies have described the clinical efficacy of vaccination in patients on hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a multicenter observational study of the London hemodialysis population undergoing surveillance PCR testing during the period of vaccine rollout with BNT162b2 and AZD1222, all of those positive for SARS-CoV-2 were identified. Clinical outcomes were analyzed according to predictor variables, including vaccination status, using a mixed effects logistic regression model. Risk of infection was analyzed in a subgroup of the base population using a Cox proportional hazards model with vaccination status as a time-varying covariate. RESULTS: SARS-CoV-2 infection was identified in 1323 patients of different ethnicities (Asian/other, 30%; Black, 38%; and White, 32%), including 1047 (79%) unvaccinated, 86 (7%) after first-dose vaccination, and 190 (14%) after second-dose vaccination. The majority of patients had a mild course; however, 515 (39%) were hospitalized, and 172 (13%) died. Older age, diabetes, and immune suppression were associated with greater illness severity. In regression models adjusted for age, comorbidity, and time period, prior two-dose vaccination was associated with a 75% (95% confidence interval, 56 to 86) lower risk of admission and 88% (95% confidence interval, 70 to 95) fewer deaths compared with unvaccinated patients. No loss of protection was seen in patients over 65 years or with increasing time since vaccination, and no difference was seen between vaccine types. CONCLUSIONS: These data demonstrate a substantially lower risk of severe COVID-19 after vaccination in patients on dialysis who become infected with SARS-CoV-2.

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.

INTRODUCTION: COVID-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 ANALYSIS: ARCADIA 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 DISSEMINATION: Ethical 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 NUMBER: EudraCT 2020-002211-21, NCT04516759.

The management of dialysis access thrombosis during the COVID-19 pandemic.

BACKGROUND: Maintaining patent access is essential for haemodialysis dependent end stage renal failure patients. The COVID-19 pandemic has significantly affected surgical and interventional radiology services worldwide. We aimed to review the impact COVID-19 has caused to the management of acute dialysis access thrombosis. METHODS: We conducted a single centre retrospective review of outcomes of patients with arteriovenous fistula and arteriovenous graft thrombosis between March and May 2020, which coincided with the first peak of the COVID-19 pandemic in London, and a similar period in the previous year, March-May 2019. Outcomes in both cohorts of patients were compared, including attempts at salvage, salvage success, 1-month patency rates after salvage and subsequent surgery on the same access. We also analysed the use of tunnelled haemodialysis lines (THL), either due to failed salvage attempts or when salvage was not attempted. RESULTS: There was a similar incidence of access thrombosis in both periods (26 cases in 2019, 38 in 2020). There were 601 patients dialysing via an arteriovenous fistula or graft in 2019, and 568 patients in 2020. Access salvage, when attempted, had similar success rates and 1-month patency (salvage success 74% vs 80%, p = 0.39; 1-month patency 55% vs 62%, p = 0.69). The proportion of patients where access salvage was not attempted and a THL inserted was significantly higher in 2020 compared to 2019 (32% vs 4%, p = 0.007). There were more patients who subsequently had surgery to salvage or revise the same access in 2019 compared to 2020 (62% vs 13%, p < 0.001). CONCLUSIONS: During the peak of the COVID-19 pandemic, there were fewer attempts at access salvage. This was a conscious decision due to increased pressure on the healthcare system, access to emergency interventional radiology or operative theatres and the perceived risk/benefit ratio of access salvage. The long-term effects of this change in practice remain unknown.

Risk of COVID-19 Disease, Dialysis Unit Attributes, and Infection Control Strategy among London In-Center Hemodialysis Patients.

BACKGROUND AND OBJECTIVES: Patients receiving in-center hemodialysis treatment face unique challenges during the coronavirus disease 2019 (COVID-19) pandemic, specifically the need to attend for treatment that prevents self-isolation. Dialysis unit attributes and isolation strategies that might reduce dialysis center COVID-19 infection rates have not been previously examined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We explored the role of variables, including community disease burden, dialysis unit attributes (size and layout), and infection control strategies, on rates of COVID-19 among patients receiving in-center hemodialysis in London, United Kingdom, between March 2, 2020 and May 31, 2020. The two outcomes were defined as (1) a positive test for infection or admission with suspected COVID-19 and (2) admission to the hospital with suspected infection. Associations were examined using a discrete time multilevel time-to-event analysis. RESULTS: Data on 5755 patients dialyzing in 51 units were analyzed; 990 (17%) tested positive and 465 (8%) were admitted with suspected COVID-19 between March 2 and May 31, 2020. Outcomes were associated with age, diabetes, local community COVID-19 rates, and dialysis unit size. A greater number of available side rooms and the introduction of mask policies for asymptomatic patients were inversely associated with outcomes. No association was seen with sex, ethnicity, or deprivation indices, nor with any of the different isolation strategies. CONCLUSIONS: Rates of COVID-19 in the in-center hemodialysis population relate to individual factors, underlying community transmission, unit size, and layout.

Persistence of antibody response to SARS-CoV-2 in a cohort of haemodialysis patients with COVID-19.

BACKGROUND: Haemodialysis patients are extremely vulnerable to COVID-19. Their immune response after infection is unclear. We have found high seroconversion rates in this population with 95% developing antibodies. It is unclear if and how long these antibodies persist. Here we investigate this with serial antibody testing. METHODS: We identified haemodialysis patients who had confirmed SARS-CoV-2 between March-May 2020 and measured monthly antibodies (IgG/IgM) in those who survived. We used a semi-quantitative cut-off index (COI) to create a qualitative result and plotted optical density (OD) over time. We used linear regression to examine the slope, as well as noting peak OD and time to peak OD. We correlated these against baseline demographics, markers of illness severity, and comorbidities. RESULTS: 122 patients were analysed. All remained antibody positive during follow-up; for a minimum of 148 days. 71% had a positive gradient indicating increasing antibody positivity over time. We found that age (p = 0.01), duration of PCR positivity (p = 0.06) and presence of symptoms (p = 0.05) were associated with a longer time to peak OD. Immunosuppression did not alter peak OD but did lead to a non-significant increase in time to peak OD and more patients had a subsequent fall in Ab levels (p = 0.02). Diabetic patients were more likely to have a positive slope (OR 2.26). CONCLUSIONS: These results indicate that haemodialysis patients have a robust and sustained antibody response after confirmed COVID-19 infection with no suggestion that immunosuppression weakens this response. Although unclear what protection these antibodies confer, this encouraging that haemodialysis patients should respond to vaccination.