AZD1656 in Diabetic Patients Hospitalised With Suspected or Confirmed COVID-19 (ARCADIA)

• ClinicalTrials.gov Identifier: NCT04516759
• Recruitment Status: Completed
• First Posted: August 18, 2020
• Results First Posted: April 25, 2022
• Last Update Posted: April 25, 2022
• Sponsor: St George Street Capital
• Information provided by (Responsible Party): St George Street Capital

Tracking Information

• First Submitted Date: August 14, 2020
• First Posted Date: August 18, 2020
• Results First Submitted Date: April 12, 2022
• Results First Posted Date: April 25, 2022
• Last Update Posted Date: April 25, 2022
• Actual Study Start Date: August 12, 2020
• Actual Primary Completion Date: April 25, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 21, 2022)

Clinical Improvement by Day 14 [ Time Frame: Day 1 to Day 14 ]

The World Health Organization (WHO) 8-point Ordinal Scale for Clinical Improvement (OSCI) was used to measure Clinical Improvement at Day 14 versus baseline, comparing AZD1656 treatment with placebo. The WHO OSCI score ranges from 0-8 (0 = no symptoms, 8 = death). The higher the score the worse the condition of the patient. Results are presented as number of responders. Patients who were assigned a WHO score of 1, 2 or 3 at Day 14 were considered a treatment responder. A patient who was discharged before Day 14 was also considered a responder. All other patients (WHO scores 4-8 at Day 14) were considered treatment failures.

Original Primary Outcome Measures (submitted: August 16, 2020)

Clinical Improvement by Day 14 [ Time Frame: Day 1 to Day 14 ]

Clinical Improvement measured as the percentage of subjects at Day 14 who are in categories 1-3 according to the WHO 8-point Ordinal Scale for Clinical Improvement, comparing AZD1656 treatment to placebo

Current Secondary Outcome Measures (submitted: April 21, 2022)

• Clinical Improvement at Day 7, 14 and 21 [ Time Frame: Day 1 to Day 21 ]
  The World Health Organization (WHO) 8-point Ordinal Scale for Clinical Improvement (OSCI) was used to measure Clinical Improvement at Day 7, Day 14 and Day 21 versus baseline, comparing AZD1656 treatment with placebo. Results are presented as the percentage of patients categorised at each severity rating at each timepoint on the WHO 8-point OSCI scale. The WHO OSCI score ranges from 0-8 (0 = no symptoms, 8 = death). The higher the score the worse the condition of the patient. Study Drug Discontinuation was the date on which a patient discontinued treatment. Treatment was given for a maximum of 21 days, or until date of hospital discharge (WHO score 1 or 2), or date mechanical ventilation was required (WHO score 6 or 7) or until date of death (WHO score 8).
• Glycaemic Control [ Time Frame: Day 1 to Day 21 ]
  Degree of glycaemic control as measured by the need to increase baseline medication requirements or the need to add additional diabetic medications to maintain appropriate blood glucose levels in patients receiving AZD1656 compared with placebo
• Occurrence of Adverse Events [ Time Frame: Day 1 to Day 28 ]
  Proportion of Treatment Emergent Adverse Events (TEAEs) leading to study drug discontinuation in patients receiving AZD1656 compared with placebo
• Occurrence of Serious Adverse Events [ Time Frame: Day 1 to Day 28 ]
  Proportion of Serious Adverse Events (SAEs) in patients receiving AZD1656 compared with placebo
• Duration of Hospitalisation [ Time Frame: Day 1 to Day 21 ]
  Time from hospital admission to hospital discharge (in hours) in patients receiving AZD1656 compared with placebo
• Mortality Rate [ Time Frame: Day 1 to Day 28 ]
  Mortality rate in patients receiving AZD1656 compared with placebo.
• Intubation/Mechanical Ventilation [ Time Frame: Day 1 to Day 21 ]
  Number of Patients Receiving Intubation/Mechanical Ventilation

Original Secondary Outcome Measures (submitted: August 16, 2020)

• *Title: Clinical Improvement at Day 7, 14 and 21 [ Time Frame: Day 1 to Day 21 ]
  Clinical Improvement measured as the percentage of patients categorised at each severity rating on the WHO 8-point Ordinal Scale at Day 7, Day 14 and Day 21 versus baseline, comparing AZD1656 treatment with placebo.
• Glycaemic Control [ Time Frame: Day 1 to Day 21 ]
  Degree of glycaemic control as measured by the need to increase baseline medication requirements or the need to add additional diabetic medications to maintain appropriate blood glucose levels in patients receiving AZD1656 compared with placebo
• Occurrence of Adverse Events [ Time Frame: Day 1 to Day 28 ]
  Proportion of Treatment Emergent Adverse Events (TEAEs) leading to study drug discontinuation in patients receiving AZD1656 compared with placebo
• Occurrence of Serious Adverse Events [ Time Frame: Day 1 to Day 28 ]
  Proportion of Serious Adverse Events (SAEs) in patients receiving AZD1656 compared with placebo
• Duration of Hospitalisation [ Time Frame: Day 1 to Day 21 ]
  Time from hospital admission to hospital discharge (in hours) in patients receiving AZD1656 compared with placebo
• Time to Intubation/ Mechanical Intervention [ Time Frame: Day 1 to Day 21 ]
  Time from hospital admission to receiving intubation/mechanical ventilation in patients receiving AZD1656 compared with placebo
• Mortality Rate [ Time Frame: Day 1 to Day 28 ]
  Mortality rate in patients receiving AZD1656 compared with placebo.

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: August 16, 2020)

• Pharmacokinetic Analysis [ Time Frame: Day 1 to Day 7 ]
  Plasma AZD1656 levels during first 7 days of treatment in patients receiving AZD1656 compared with placebo.
• Immunophenotyping Analysis [ Time Frame: Day 1 to Day 21 ]
  Immunophenotyping panel to be conducted by Flow Cytometry: between group comparison (AZD1656 versus placebo)
• Immunochemistry Analysis [ Time Frame: Day 1 to Day 21 ]
  Immunochemistry panel to be conducted using the Meso Scale Discovery (MSD) U-Plex multiplex assay.
• Cardiac Injury [ Time Frame: Day 1 to Day 21 ]
  Measurement of hsTroponin and NTproBNP to determine extent of cardiac injury in patients receiving AZD1656 compared with placebo
• Correlation of clinical outcomes with pre-treatment vitamin D levels (by measurement of 25-hydroxyvitamin D levels). [ Time Frame: Day 1 to Day 21 ]
  Measurement of 25-hydroxyvitamin D levels before treatment to determine whether there is any correlation between baseline vitamin D level and clinical improvement in patients treated with AZD1656 versus placebo.
• Correlation of patient ethnicity with clinical improvement [ Time Frame: Day 1 to Day 21 ]
  Sub group analysis of patient ethnicity, to determine whether there is any correlation between patient ethnicity and clinical improvement in patients treated with AZD1656 versus placebo.

Descriptive Information

• Brief Title: AZD1656 in Diabetic Patients Hospitalised With Suspected or Confirmed COVID-19
• Official Title: A Phase II, Randomised, Double-blind, Placebo-controlled Clinical Trial to Assess the Safety and Efficacy of AZD1656 in Diabetic Patients Hospitalised With Suspected or Confirmed COVID-19
• Brief Summary: The ARCADIA Trial is a randomised, double-blind, placebo-controlled clinical trial to assess the safety and efficacy of AZD1656 in patients with either Type 1 or Type 2 diabetes, hospitalised with COVID-19.

Detailed Description

The ARCADIA Trial will assess the safety and efficacy of AZD1656 in 150 patients with either Type 1 or Type 2 diabetes who have been hospitalised with COVID-19.

AZD1656 is a glucokinase (GK; hexokinase 4) activator which has been shown to reduce blood glucose for up to 4 months in humans. Diabetic patients admitted to hospital with COVID-19 often present with hyperglycaemia and are particularly vulnerable to progression to severe COVID-19. Treatment with AZD1656 (in addition to their usual care) may provide additional glucose control which could help improve clinical outcomes in both Type 1 and Type 2 diabetic populations.

In addition to its glucose lowering effect, AZD1656 may have additional benefits to COVID-19 patients via its effects on immune function. In many patients with severe COVID-19, an overreaction of the body's own immune system can cause severe problems including damage to the lungs and heart, which can lead to breathing problems necessitating intubation and ventilation. AZD1656 has been shown to activate the migration of T regulatory cells to sites of inflammation in preclinical experiments. This migration of Treg cells to inflamed tissue is crucial for their immune-modulatory function (Kishore et al (2017)). AZD1656 could enhance Treg migratory capacity and may prevent the development of cardiorespiratory complications observed in hospitalised patients with COVID-19, leading to lower requirements for oxygen therapy and assisted ventilation, and reduced incidences of pneumonia and acute respiratory distress syndrome (ARDS).

Diabetic patients hospitalised with COVID-19 will be randomised to receive either AZD1656 tablets or placebo tablets on a 1:1 basis until they are discharged from hospital or until they require intubation/mechanical ventilation. The aim of the study is to determine whether AZD1656 improves clinical outcomes in diabetic patients hospitalised with COVID-19. The World Health Organization (WHO) 8-point Ordinal Scale for Clinical Improvement will be used as the standard methodology for measuring patient outcomes.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

This is a randomised double-blind study. Eligible patients will be randomly assigned to one of two groups (AZD1656 plus usual care or placebo plus usual care) on a 1:1 basis

Masking: Double (Participant, Investigator)
Primary Purpose: Treatment

• Condition: Covid19

Intervention

• Drug: AZD1656
  50mg film-coated tablets (at daily dose of 100mg BID)
• Other: Placebo
  Matched placebo tablets

Study Arms

• Experimental: AZD1656 (plus Usual Hospital Care)
  50mg film-coated tablets at a dose of 100mg BID
  Intervention: Drug: AZD1656
• Placebo Comparator: Matched Placebo (plus Usual Hospital Care)
  Matched placebo tablets
  Intervention: Other: Placebo

• Publications *: McCafferty K, Hollowood Z, Allen M, Lockhart D, Chorlton J, Martin J. 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. BMJ Open. 2021 Dec 1;11(12):e049650. doi: 10.1136/bmjopen-2021-049650.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 21, 2022): 170
• Original Estimated Enrollment (submitted: August 16, 2020): 150
• Actual Study Completion Date: May 12, 2021
• Actual Primary Completion Date: April 25, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Male or Female.
2. Aged 18 and older.
3. Have either Type I or Type II Diabetes Mellitus.
4. Hospitalised with suspected or confirmed novel coronavirus (Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)) infection at time of enrolment, categorised as stage 3, 4 or 5 on the WHO Ordinal Scale for Clinical Improvement.
5. Blood glucose level at or above 4 mmol/L.
6. Able to take oral (tablet) formulation of medication.
7. Patient is able to provide written informed consent prior to initiation of any study procedures.

Exclusion Criteria:

1. In the opinion of the clinical team, progression to intubation or mechanical ventilation is imminent and inevitable, within the next 24 hours, irrespective of the provision of treatments.
2. Patients admitted with primary suspected or proven Mycoplasma pneumoniae, Chlamydia pneumoniae and bacterial pneumonia, who acquired COVID-19 while hospitalized.
3. Treatment with immunomodulators or anti-rejection drugs within the last 3 months.
4. Pregnant or breast feeding.
5. Men, and women of child-bearing potential, unwilling to use highly effective contraception during their participation in the trial and for 2 weeks after study completion.
6. Anticipated transfer to another hospital which is not a study site within 72 hours.
7. Known sensitivity to any of the study medication/placebo excipients.
8. Prior dosing with AZD1656 on a previous clinical trial.
9. Patients admitted as a result of and receiving immediate treatment for an acute asthmatic attack, acute myocardial infarction, acute cerebrovascular event.
10. Any known non-COVID-19, non-diabetes related, serious condition which, in the opinion of the clinical team, makes the patient unsuitable for the trial.
11. Known history of drug or alcohol abuse within previous 12 months of screening.
12. Known history of HIV, hepatitis C or unresolved hepatitis B or severe liver disease.
13. Current or planned use of gemfibrozil or any other strong inhibitors of CYP2C8.
14. Current or previous participation in another clinical trial where the patient has received a dose of an Investigational Medicinal Product (IMP) containing small molecule treatment(s) within 30 days or 5 half-lives (whichever is longer) prior to enrolment into this study, or containing biological treatment(s) within 3 months prior to entry into this study.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Czechia, Romania, United Kingdom

Administrative Information

• NCT Number: NCT04516759
• Other Study ID Numbers: SGS.1656.201; 2020-002211-21 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers can request access to deidentified individual participant data (IDP) that underlie the published clinical trial results.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Time Frame: Requests for access to the data will be accepted beginning 6 months after article publication and will continue to be accepted for up to 5 years after publication.
• Access Criteria: Researchers must submit a methodologically sound research proposal to St George Street using the contact details provided on our website. See link below.
• URL: http://www.sgscapital.org

• Responsible Party: St George Street Capital
• Study Sponsor: St George Street Capital
• Collaborators: Not Provided

Investigators

• Principal Investigator: Kieran McCafferty, MD; Barts & The London NHS Trust

• PRS Account: St George Street Capital
• Verification Date: April 2022