Clinical trial NCT04516759: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Covid19
Keywords: COVID-19
Diabetes Mellitus
SARS-CoV-2
Regulatory T Cell
Glucokinase
Lead sponsor: St George Street Capital
Sponsor class: OTHER
First posted: 2020-08-18
Enrollment: 170
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Clinical Improvement by Day 14
timeFrame: Day 1 to Day 14
Secondary outcomes:
measure: Clinical Improvement at Day 7, 14 and 21
timeFrame: Day 1 to Day 21
measure: Glycaemic Control
timeFrame: Day 1 to Day 21
measure: Occurrence of Adverse Events
timeFrame: Day 1 to Day 28
measure: Occurrence of Serious Adverse Events
timeFrame: Day 1 to Day 28
measure: Duration of Hospitalisation
timeFrame: Day 1 to Day 21
measure: Mortality Rate
timeFrame: Day 1 to Day 28
measure: Intubation/Mechanical Ventilation
timeFrame: Day 1 to Day 21
Other outcomes:
Locations:
city: Brno
country: Czechia
facility: Masarykova Univerzita - Fakultni Nemocnice U SV Anny V Brne (308)
city: Hořovice
country: Czechia
facility: Nemocnice Hořovice (309)
city: Kolín
country: Czechia
facility: Oblastni Nemocnice Kolín (306)
city: Mladá Boleslav
country: Czechia
facility: Klaudianova Nemonice (302)
city: Prague
country: Czechia
facility: Fakultni Nemocnice V Motole (303)
city: Prague
country: Czechia
facility: Thomayerova Nemonice (310)
city: Třebíč
country: Czechia
facility: Nemocnice Třebíč (305)
city: Bucharest
country: Romania
facility: Colentina Clinical Hospital (204)
city: Cluj-Napoca
country: Romania
facility: Spitalul Clinic de Boli Infectioase Cluj-Napoca (203)
city: Cluj-Napoca
country: Romania
facility: Spitalul Clinic de Pneumoftiziologie "Leon Daniello" Cluj-Napoca (202)
city: Constanţa
country: Romania
facility: Spitalul Clinic de Boli Infectioase Constanţa (207)
city: Craiova
country: Romania
facility: Spitalul Clinic de Boli Infectioase si Pneumoftiziologie Dr Victor Babes Craiova (206)
city: Deva
country: Romania
facility: Spitalul Judetean de Urgenta Deva (208)
city: Iaşi
country: Romania
facility: Spitalul Clinic de Boli Infectioase "Sfanta Parascheva" Iaşi (205)
city: Timişoara
country: Romania
facility: Spitalul Clinic de Boli Infectioase si Pneumoftiziologie Dr Victor Babes Timişoara (201)
city: Barnsley
country: United Kingdom
facility: Barnsley Hospital NHS Foundation Trust (105)
city: Bolton
country: United Kingdom
facility: Bolton NHS Foundation Trust (122)
city: Bradford
country: United Kingdom
facility: Bradford Teaching Hospitals NHS Foundation Trust (103)
city: Bristol
country: United Kingdom
facility: North Bristol NHS Trust (116)
city: Darlington
country: United Kingdom
facility: County Durham and Darlington NHS Foundation Trust (121)
city: Dudley
country: United Kingdom
facility: The Dudley Group NHS Foundation Trust (107)
city: Gillingham
country: United Kingdom
facility: Medway NHS Foundation Trust (108)
city: Hull
country: United Kingdom
facility: Hull & East Yorkshire NHS Trust (102)
city: London
country: United Kingdom
facility: Barts Health NHS Trust (101 and 111)
city: London
country: United Kingdom
facility: Royal Free London NHS Foundation Trust (119)
city: London
country: United Kingdom
facility: St George's University Hospitals NHS Foundation Trust (114)
city: Salford
country: United Kingdom
facility: Penine Acute Hospitals NHS Trust (106)
city: Sheffield
country: United Kingdom
facility: Sheffield Hospitals NHS Foundation Trust (104)
city: Taunton
country: United Kingdom
facility: Somerset NHS Foundation Trust (109)
city: Walsall
country: United Kingdom
facility: Walsall Healthcare NHS Trust (113)
Study officials:
affiliation: Barts & The London NHS Trust
name: Kieran McCafferty, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.