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

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

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.

Study Overview

• Status: Completed
• Conditions: Covid19
• Intervention / Treatment: Drug: AZD1656; Other: Placebo

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
• Enrollment (Actual): 170
• Phase: Phase 2

Contacts and Locations

Study Locations

• Czechia
  • Brno, Czechia
    • Masarykova Univerzita - Fakultni Nemocnice U SV Anny V Brne (308)
  • Hořovice, Czechia
    • Nemocnice Hořovice (309)
  • Kolín, Czechia
    • Oblastni Nemocnice Kolín (306)
  • Mladá Boleslav, Czechia
    • Klaudianova Nemonice (302)
  • Prague, Czechia
    • Fakultni Nemocnice V Motole (303)
  • Prague, Czechia
    • Thomayerova Nemonice (310)
  • Třebíč, Czechia
    • Nemocnice Třebíč (305)
• Romania
  • Bucharest, Romania
    • Colentina Clinical Hospital (204)
  • Cluj-Napoca, Romania
    • Spitalul Clinic de Boli Infectioase Cluj-Napoca (203)
  • Cluj-Napoca, Romania
    • Spitalul Clinic de Pneumoftiziologie "Leon Daniello" Cluj-Napoca (202)
  • Constanţa, Romania
    • Spitalul Clinic de Boli Infectioase Constanţa (207)
  • Craiova, Romania
    • Spitalul Clinic de Boli Infectioase si Pneumoftiziologie Dr Victor Babes Craiova (206)
  • Deva, Romania
    • Spitalul Judetean de Urgenta Deva (208)
  • Iaşi, Romania
    • Spitalul Clinic de Boli Infectioase "Sfanta Parascheva" Iaşi (205)
  • Timişoara, Romania
    • Spitalul Clinic de Boli Infectioase si Pneumoftiziologie Dr Victor Babes Timişoara (201)
• United Kingdom
  • Barnsley, United Kingdom
    • Barnsley Hospital NHS Foundation Trust (105)
  • Bolton, United Kingdom
    • Bolton NHS Foundation Trust (122)
  • Bradford, United Kingdom, BD9 6RJ
    • Bradford Teaching Hospitals NHS Foundation Trust (103)
  • Bristol, United Kingdom, BS10 5NB
    • North Bristol NHS Trust (116)
  • Darlington, United Kingdom
    • County Durham and Darlington NHS Foundation Trust (121)
  • Dudley, United Kingdom, DY1 2HQ
    • The Dudley Group NHS Foundation Trust (107)
  • Gillingham, United Kingdom, ME7 5NY
    • Medway NHS Foundation Trust (108)
  • Hull, United Kingdom
    • Hull & East Yorkshire NHS Trust (102)
  • London, United Kingdom, E1 1FR
    • Barts Health NHS Trust (101 and 111)
  • London, United Kingdom, NW3 2QG
    • Royal Free London NHS Foundation Trust (119)
  • London, United Kingdom
    • St George's University Hospitals NHS Foundation Trust (114)
  • Salford, United Kingdom, M6 8HD
    • Penine Acute Hospitals NHS Trust (106)
  • Sheffield, United Kingdom, S10 2SB
    • Sheffield Hospitals NHS Foundation Trust (104)
  • Taunton, United Kingdom, TA1 5DA
    • Somerset NHS Foundation Trust (109)
  • Walsall, United Kingdom, WS2 9PS
    • Walsall Healthcare NHS Trust (113)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AZD1656 (plus Usual Hospital Care); 50mg film-coated tablets at a dose of 100mg BID	Drug: AZD1656; 50mg film-coated tablets (at daily dose of 100mg BID)
Placebo Comparator: Matched Placebo (plus Usual Hospital Care); Matched placebo tablets	Other: Placebo; Matched placebo tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Improvement by 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.	Day 1 to Day 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Improvement at Day 7, 14 and 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).	Day 1 to Day 21
Glycaemic Control	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	Day 1 to Day 21
Occurrence of Adverse Events	Proportion of Treatment Emergent Adverse Events (TEAEs) leading to study drug discontinuation in patients receiving AZD1656 compared with placebo	Day 1 to Day 28
Occurrence of Serious Adverse Events	Proportion of Serious Adverse Events (SAEs) in patients receiving AZD1656 compared with placebo	Day 1 to Day 28
Duration of Hospitalisation	Time from hospital admission to hospital discharge (in hours) in patients receiving AZD1656 compared with placebo	Day 1 to Day 21
Mortality Rate	Mortality rate in patients receiving AZD1656 compared with placebo.	Day 1 to Day 28
Intubation/Mechanical Ventilation	Number of Patients Receiving Intubation/Mechanical Ventilation	Day 1 to Day 21

Collaborators and Investigators

• Sponsor: St George Street Capital
• Investigators: Principal Investigator: Kieran McCafferty, MD, Barts & The London NHS Trust

Publications and helpful links

General Publications

• Chorlton J, Hollowood Z, Dyer C, Lockhart D, Boekman P, McCafferty K, Coffey P, Marelli-Berg F, Martin J. 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. EClinicalMedicine. 2022 Sep;51:101604. doi: 10.1016/j.eclinm.2022.101604. Epub 2022 Aug 18.
• 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.

Helpful Links

• Link to St George Street Capital's website

Study record dates

Study Major Dates

• Study Start (Actual): August 12, 2020
• Primary Completion (Actual): April 25, 2021
• Study Completion (Actual): May 12, 2021

Study Registration Dates

• First Submitted: August 14, 2020
• First Submitted That Met QC Criteria: August 16, 2020
• First Posted (Actual): August 18, 2020

Study Record Updates

• Last Update Posted (Actual): April 25, 2022
• Last Update Submitted That Met QC Criteria: April 21, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: SARS-CoV-2; Diabetes Mellitus; COVID-19; Regulatory T Cell; Glucokinase
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: SGS.1656.201; 2020-002211-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Qualified researchers can request access to deidentified individual participant data (IDP) that underlie the published clinical trial results.
• IPD Sharing 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.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Drug and device information, study documents

• 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