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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Covid19

Intervention / Treatment
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* Drug: AZD1656
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or Female. Aged 18 and older. Have either Type I or Type II Diabetes Mellitus. 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. Blood glucose level at or above 4 mmol/L. Able to take oral (tablet) formulation of medication. Patient is able to provide written informed consent prior to initiation of any study procedures. Exclusion Criteria: 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. Patients admitted with primary suspected or proven Mycoplasma pneumoniae, Chlamydia pneumoniae and bacterial pneumonia, who acquired COVID-19 while hospitalized. Treatment with immunomodulators or anti-rejection drugs within the last 3 months. Pregnant or breast feeding. 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. Anticipated transfer to another hospital which is not a study site within 72 hours. Known sensitivity to any of the study medication/placebo excipients. Prior dosing with AZD1656 on a previous clinical trial. Patients admitted as a result of and receiving immediate treatment for an acute asthmatic attack, acute myocardial infarction, acute cerebrovascular event. 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. Known history of drug or alcohol abuse within previous 12 months of screening. Known history of HIV, hepatitis C or unresolved hepatitis B or severe liver disease. Current or planned use of gemfibrozil or any other strong inhibitors of CYP2C8. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, Diabetes Mellitus, SARS-CoV-2, Regulatory T Cell, Glucokinase