Practical use of apomorphine infusion in Parkinson's disease: lessons from the TOLEDO study and clinical experience.

Subcutaneous apomorphine infusion is a device-aided therapy for Parkinson's disease that can be considered when motor fluctuations become persistent and are no longer adequately controlled by oral/transdermal medication. Apomorphine infusion is less invasive than enteral levodopa, deep brain stimulation or focused ultrasound, and is often indicated even when neurosurgical approaches are contraindicated. This article aims to provide practical guidance for doctors and nurses initiating and treating patients with apomorphine infusion, and is based on both trial data and clinical experience from movement disorders specialists. A post hoc analysis of data from the TOLEDO randomized clinical trial of apomorphine infusion was conducted along with an analysis of 'real world' experience from 13 movement disorders specialists using a questionnaire that focused on starting patients on apomorphine infusion. Practical guidelines for starting treatment with apomorphine infusion are provided taking into consideration the regional disparities in healthcare. Apomorphine infusion is straightforward to administer but to be successful it requires concordance from the patient and family, and clinical support from an experienced team of doctors and nurses, particularly in the early months of treatment.

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.

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.

Long-term safety and efficacy of apomorphine infusion in Parkinson's disease patients with persistent motor fluctuations: Results of the open-label phase of the TOLEDO study.

INTRODUCTION: The randomized, double-blind phase (DBP) of the TOLEDO study confirmed the efficacy of apomorphine infusion (APO) in reducing OFF time in PD patients with persistent motor fluctuations despite optimized oral/transdermal therapy. Here we report safety and efficacy results including the 52-week open-label phase (OLP). METHODS: All patients completing the 12-week DBP (including those switching early to open-label treatment) were offered OLP entry. The primary objective was the evaluation of long-term safety of APO. RESULTS: Eighty-four patients entered the OLP (40 previously on APO, 44 on placebo) and 59 patients (70.2%) completed the study. The safety profile of APO was consistent with experience from extensive clinical use. Common treatment-related adverse events (AEs) were mild or moderate infusion site nodules, somnolence and nausea. Fourteen (16.7%) patients discontinued the OLP due to AEs, those involving >1 patient were infusion site reactions (n = 4) and fatigue (n = 2); hemolytic anemia occurred in one case. Reduction in daily OFF time and improvement in ON time without troublesome dyskinesia were sustained for up to 64 weeks. Pooled data for week 64 (n = 55) showed a mean (SD) change from DBP baseline in daily OFF time of -3.66 (2.72) hours and in ON time without troublesome dyskinesia of 3.31 (3.12) hours. Mean (±SD) daily levodopa-equivalent dose decreased from DBP baseline to week 64 by 543 mg (±674) and levodopa dose by 273 mg (±515). CONCLUSIONS: The safety and efficacy of APO infusion were demonstrated with long-term use for persistent motor fluctuations, allowing substantial reductions in oral PD medication.