Covid19
Conditions
Keywords
COVID-19, Diabetes Mellitus, SARS-CoV-2, Regulatory T Cell, Glucokinase
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.
Interventions
OTHERPlacebo
Matched placebo tablets
DRUGAZD1656
50mg film-coated tablets (at daily dose of 100mg BID)
Sponsors
St George Street Capital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
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
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Improvement by Day 14 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Glycaemic Control | 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 | 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 | Day 1 to Day 28 | Proportion of Serious Adverse Events (SAEs) in patients receiving AZD1656 compared with placebo |
| Clinical Improvement at Day 7, 14 and 21 | 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). |
| Mortality Rate | Day 1 to Day 28 | Mortality rate in patients receiving AZD1656 compared with placebo. |
| Intubation/Mechanical Ventilation | Day 1 to Day 21 | Number of Patients Receiving Intubation/Mechanical Ventilation |
| Duration of Hospitalisation | Day 1 to Day 21 | Time from hospital admission to hospital discharge (in hours) in patients receiving AZD1656 compared with placebo |
Countries
Czechia, Romania, United Kingdom
Participant flow
Recruitment details
170 subjects were screened for participation. 13 subjects were screening failures. 156 subjects were randomized of which 3 subjects withdrew consent prior to start of study medication. 153 subjects started with study treatment.
Participants by arm
| Arm | Count |
|---|---|
| AZD1656 (Plus Usual Hospital Care) 50mg film-coated tablets at a dose of 100mg BID
AZD1656: 50mg film-coated tablets (at daily dose of 100mg BID) | 80 |
| Matched Placebo (Plus Usual Hospital Care) Matched placebo tablets
Placebo: Matched placebo tablets | 73 |
| Total | 153 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Other | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | AZD1656 (Plus Usual Hospital Care) | Matched Placebo (Plus Usual Hospital Care) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 42 Participants | 42 Participants | 84 Participants |
| Age, Categorical Between 18 and 65 years | 38 Participants | 31 Participants | 69 Participants |
| Diabetes Type Type 1 | 1 Participants | 2 Participants | 3 Participants |
| Diabetes Type Type 2 | 79 Participants | 71 Participants | 150 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 77 Participants | 70 Participants | 147 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 6 Participants |
| Region of Enrollment Czechia | 27 Participants | 22 Participants | 49 Participants |
| Region of Enrollment Romania | 19 Participants | 14 Participants | 33 Participants |
| Region of Enrollment United Kingdom | 34 Participants | 37 Participants | 71 Participants |
| Sex: Female, Male Female | 30 Participants | 26 Participants | 56 Participants |
| Sex: Female, Male Male | 50 Participants | 47 Participants | 97 Participants |
| Vitamin D group < 25 nmol/l | 31 Participants | 27 Participants | 58 Participants |
| Vitamin D group >= 25 nmol/l | 46 Participants | 45 Participants | 91 Participants |
| Vitamin D group missing | 3 Participants | 1 Participants | 4 Participants |
| WHO OSCI rating 3 - Hospitalised, no oxygen | 19 Participants | 13 Participants | 32 Participants |
| WHO OSCI rating 4 - Hospitalised, oxygen | 52 Participants | 42 Participants | 94 Participants |
| WHO OSCI rating 5 - Non-invasive ventilation or high flow oxygen | 9 Participants | 18 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 80 | 9 / 73 |
| other Total, other adverse events | 43 / 84 | 17 / 69 |
| serious Total, serious adverse events | 10 / 84 | 19 / 69 |
Outcome results
Primary
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.
Time frame: Day 1 to Day 14
Population: Full Analysis Set: all participants who received at least one dose of treatment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement by Day 14 | Treatment failure | 18 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement by Day 14 | Missing | 1 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement by Day 14 | Treatment responder | 61 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement by Day 14 | Treatment responder | 51 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement by Day 14 | Treatment failure | 21 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement by Day 14 | Missing | 1 Participants |
p-value: 0.185495% CI: [0.9, 1.32]Chi-squared
Secondary
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).
Time frame: Day 1 to Day 21
Population: Full Analysis Set: all participants who received at least one dose of treatment
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Baseline | Score 2: Ambulatory - limitation of activities | 0 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Baseline | Score 4: Hospitalized, oxygen by mask or nasal prongs | 52 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Baseline | Score 6: Hospitalized, intubation or mechanical ventilation | 0 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Baseline | Score 8: Death | 0 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Baseline | Missing | 0 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 7 | Score 2: Ambulatory - limitation of activities | 22 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 7 | Score 3: Hospitalized, no oxygen therapy | 15 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 7 | Score 6: Hospitalized, intubation or mechanical ventilation | 2 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 7 | Score 7: Hospitalized, ventilation + additional organ support - pressors, RTT, ECMO | 0 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 7 | Score 8: Death | 0 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 7 | Missing | 1 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 14 | Score 2: Ambulatory - limitation of activities | 37 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 14 | Score 3: Hospitalized, no oxygen therapy | 8 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 14 | Score 4: Hospitalized, oxygen by mask or nasal prongs | 9 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 14 | Score 7: Hospitalized, ventilation + additional organ support - pressors, RTT, ECMO | 0 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 14 | Score 8: Death | 1 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 14 | Missing | 1 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 21 | Score 2: Ambulatory - limitation of activities | 44 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 21 | Score 3: Hospitalized, no oxygen therapy | 4 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 21 | Score 5: Hospitalized, non-invasive ventilation or high-flow oxygen | 4 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 21 | Score 6: Hospitalized, intubation or mechanical ventilation | 4 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 21 | Score 7: Hospitalized, ventilation + additional organ support - pressors, RTT, ECMO | 0 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 21 | Score 8: Death | 1 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Study Drug Discontinuation (SDD) | Score 1: Ambulatory - no limitation of activities | 20 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Study Drug Discontinuation (SDD) | Score 2: Ambulatory - limitation of activities | 44 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Study Drug Discontinuation (SDD) | Score 3: Hospitalized, no oxygen therapy | 3 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Study Drug Discontinuation (SDD) | Score 4: Hospitalized, oxygen by mask or nasal prongs | 3 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Study Drug Discontinuation (SDD) | Score 5: Hospitalized, non-invasive ventilation or high-flow oxygen | 4 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Study Drug Discontinuation (SDD) | Score 6: Hospitalized, intubation or mechanical ventilation | 4 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Study Drug Discontinuation (SDD) | Score 7: Hospitalized, ventilation + additional organ support - pressors, RTT, ECMO | 0 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Study Drug Discontinuation (SDD) | Score 8: Death | 1 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Study Drug Discontinuation (SDD) | Missing | 1 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Baseline | Score 5: Hospitalized, non-invasive ventilation or high-flow oxygen | 9 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Baseline | Score 1: Ambulatory - no limitation of activities | 0 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Baseline | Score 3: Hospitalized, no oxygen therapy | 19 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Baseline | Score 7: Hospitalized, ventilation + additional organ support - pressors, RTT, ECMO | 0 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 7 | Score 1: Ambulatory - no limitation of activities | 7 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 7 | Score 4: Hospitalized, oxygen by mask or nasal prongs | 23 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 7 | Score 5: Hospitalized, non-invasive ventilation or high-flow oxygen | 10 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 14 | Score 1: Ambulatory - no limitation of activities | 16 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 14 | Score 5: Hospitalized, non-invasive ventilation or high-flow oxygen | 4 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 14 | Score 6: Hospitalized, intubation or mechanical ventilation | 4 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 21 | Score 1: Ambulatory - no limitation of activities | 20 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 21 | Score 4: Hospitalized, oxygen by mask or nasal prongs | 2 Participants |
| AZD1656 (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 21 | Missing | 1 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Study Drug Discontinuation (SDD) | Score 2: Ambulatory - limitation of activities | 40 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 21 | Missing | 1 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Baseline | Score 4: Hospitalized, oxygen by mask or nasal prongs | 42 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Baseline | Score 2: Ambulatory - limitation of activities | 0 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Baseline | Score 6: Hospitalized, intubation or mechanical ventilation | 0 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Study Drug Discontinuation (SDD) | Score 1: Ambulatory - no limitation of activities | 15 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Baseline | Score 8: Death | 0 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 21 | Score 4: Hospitalized, oxygen by mask or nasal prongs | 5 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Baseline | Missing | 0 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 7 | Score 1: Ambulatory - no limitation of activities | 7 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Baseline | Score 3: Hospitalized, no oxygen therapy | 13 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 7 | Score 2: Ambulatory - limitation of activities | 10 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Study Drug Discontinuation (SDD) | Score 3: Hospitalized, no oxygen therapy | 0 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 7 | Score 5: Hospitalized, non-invasive ventilation or high-flow oxygen | 5 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 21 | Score 6: Hospitalized, intubation or mechanical ventilation | 3 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 7 | Score 6: Hospitalized, intubation or mechanical ventilation | 3 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Study Drug Discontinuation (SDD) | Score 4: Hospitalized, oxygen by mask or nasal prongs | 5 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 7 | Score 7: Hospitalized, ventilation + additional organ support - pressors, RTT, ECMO | 0 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Baseline | Score 7: Hospitalized, ventilation + additional organ support - pressors, RTT, ECMO | 0 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 7 | Score 8: Death | 5 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Study Drug Discontinuation (SDD) | Score 5: Hospitalized, non-invasive ventilation or high-flow oxygen | 1 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 7 | Missing | 0 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 14 | Score 1: Ambulatory - no limitation of activities | 14 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 14 | Score 7: Hospitalized, ventilation + additional organ support - pressors, RTT, ECMO | 0 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 14 | Score 2: Ambulatory - limitation of activities | 30 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Study Drug Discontinuation (SDD) | Score 6: Hospitalized, intubation or mechanical ventilation | 3 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 14 | Score 3: Hospitalized, no oxygen therapy | 7 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 7 | Score 3: Hospitalized, no oxygen therapy | 17 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 14 | Score 4: Hospitalized, oxygen by mask or nasal prongs | 10 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 14 | Score 5: Hospitalized, non-invasive ventilation or high-flow oxygen | 2 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 14 | Score 6: Hospitalized, intubation or mechanical ventilation | 3 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Study Drug Discontinuation (SDD) | Score 7: Hospitalized, ventilation + additional organ support - pressors, RTT, ECMO | 0 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 21 | Score 8: Death | 6 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 14 | Score 8: Death | 6 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Study Drug Discontinuation (SDD) | Score 8: Death | 6 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 14 | Missing | 1 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 21 | Score 1: Ambulatory - no limitation of activities | 15 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 7 | Score 4: Hospitalized, oxygen by mask or nasal prongs | 26 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 21 | Score 2: Ambulatory - limitation of activities | 41 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Study Drug Discontinuation (SDD) | Missing | 3 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 21 | Score 3: Hospitalized, no oxygen therapy | 0 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 21 | Score 5: Hospitalized, non-invasive ventilation or high-flow oxygen | 2 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Baseline | Score 5: Hospitalized, non-invasive ventilation or high-flow oxygen | 18 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Baseline | Score 1: Ambulatory - no limitation of activities | 0 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Clinical Improvement at Day 7, 14 and 21 | Day 21 | Score 7: Hospitalized, ventilation + additional organ support - pressors, RTT, ECMO | 0 Participants |
p-value: 0.0286Wilcoxon (Mann-Whitney)
p-value: 0.0786Wilcoxon (Mann-Whitney)
p-value: 0.2169Wilcoxon (Mann-Whitney)
p-value: 0.186Wilcoxon (Mann-Whitney)
p-value: 0.2256Wilcoxon (Mann-Whitney)
Secondary
Duration of Hospitalisation
Time from hospital admission to hospital discharge (in hours) in patients receiving AZD1656 compared with placebo
Time frame: Day 1 to Day 21
Population: Full Analysis Set: all participant who at least received on dose of treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD1656 (Plus Usual Hospital Care) | Duration of Hospitalisation | 264.3 hours |
| Matched Placebo (Plus Usual Hospital Care) | Duration of Hospitalisation | 288.7 hours |
p-value: 0.1556Log Rank
Secondary
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
Time frame: Day 1 to Day 21
Population: Full Analysis Set: all participants who at least received one dose of treatment
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| AZD1656 (Plus Usual Hospital Care) | Glycaemic Control | Increase in Diabetic Medication Needed equal or More Than 3 Days | True | 12 Participants |
| AZD1656 (Plus Usual Hospital Care) | Glycaemic Control | Increase in Diabetic Medication Needed equal or More Than 3 Days | False | 68 Participants |
| AZD1656 (Plus Usual Hospital Care) | Glycaemic Control | Diabetic Medication is Stable/Reduced Equal or More Than 3 days | True | 61 Participants |
| AZD1656 (Plus Usual Hospital Care) | Glycaemic Control | Diabetic Medication is Stable/Reduced Equal or More Than 3 days | False | 19 Participants |
| AZD1656 (Plus Usual Hospital Care) | Glycaemic Control | Increase in Diabetic Medication Needed at Any Time During the Study | True | 25 Participants |
| AZD1656 (Plus Usual Hospital Care) | Glycaemic Control | Increase in Diabetic Medication Needed at Any Time During the Study | False | 55 Participants |
| AZD1656 (Plus Usual Hospital Care) | Glycaemic Control | Diabetic Medication is Stable/Reduced at Any Time During the Study | True | 74 Participants |
| AZD1656 (Plus Usual Hospital Care) | Glycaemic Control | Diabetic Medication is Stable/Reduced at Any Time During the Study | False | 6 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Glycaemic Control | Diabetic Medication is Stable/Reduced at Any Time During the Study | False | 6 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Glycaemic Control | Increase in Diabetic Medication Needed equal or More Than 3 Days | True | 13 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Glycaemic Control | Increase in Diabetic Medication Needed at Any Time During the Study | True | 21 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Glycaemic Control | Increase in Diabetic Medication Needed equal or More Than 3 Days | False | 60 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Glycaemic Control | Diabetic Medication is Stable/Reduced at Any Time During the Study | True | 67 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Glycaemic Control | Diabetic Medication is Stable/Reduced Equal or More Than 3 days | True | 58 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Glycaemic Control | Increase in Diabetic Medication Needed at Any Time During the Study | False | 52 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Glycaemic Control | Diabetic Medication is Stable/Reduced Equal or More Than 3 days | False | 15 Participants |
p-value: 0.4006Fisher Exact
p-value: 0.7482Fisher Exact
p-value: 0.6949Fisher Exact
p-value: 0.5521Fisher Exact
Secondary
Intubation/Mechanical Ventilation
Number of Patients Receiving Intubation/Mechanical Ventilation
Time frame: Day 1 to Day 21
Population: Full Analysis Set: all participants who at least received one dose of treatment
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AZD1656 (Plus Usual Hospital Care) | Intubation/Mechanical Ventilation | Receiving Intubation/Mechanical Ventilation | 3 Participants |
| AZD1656 (Plus Usual Hospital Care) | Intubation/Mechanical Ventilation | Not Receiving Intubation/Mechanical Ventilation | 76 Participants |
| AZD1656 (Plus Usual Hospital Care) | Intubation/Mechanical Ventilation | Missing | 1 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Intubation/Mechanical Ventilation | Receiving Intubation/Mechanical Ventilation | 3 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Intubation/Mechanical Ventilation | Not Receiving Intubation/Mechanical Ventilation | 69 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Intubation/Mechanical Ventilation | Missing | 1 Participants |
p-value: 0.6144Fisher Exact
Secondary
Mortality Rate
Mortality rate in patients receiving AZD1656 compared with placebo.
Time frame: Day 1 to Day 28
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AZD1656 (Plus Usual Hospital Care) | Mortality Rate | Died | 4 Participants |
| AZD1656 (Plus Usual Hospital Care) | Mortality Rate | Did not die | 75 Participants |
| AZD1656 (Plus Usual Hospital Care) | Mortality Rate | Missing | 1 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Mortality Rate | Died | 9 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Mortality Rate | Did not die | 63 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Mortality Rate | Missing | 1 Participants |
p-value: 0.090395% CI: [0.13, 1.26]Fisher Exact
Secondary
Occurrence of Adverse Events
Proportion of Treatment Emergent Adverse Events (TEAEs) leading to study drug discontinuation in patients receiving AZD1656 compared with placebo
Time frame: Day 1 to Day 28
Population: This analysis includes all participants who received at least one dose of treatment and had at least one post-baseline safety assessment (where the statement that a patient had no AE on the AE eCRF constitutes a safety assessment). 4 patients from the placebo arm are moved to the AZD1656 arm due to having drug in their PK samples. The assignment of patients to the treatment groups are as actually treated.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AZD1656 (Plus Usual Hospital Care) | Occurrence of Adverse Events | Other TEAEs | 28 Events |
| AZD1656 (Plus Usual Hospital Care) | Occurrence of Adverse Events | TEAEs leading to study drug discontinuation | 2 Events |
| Matched Placebo (Plus Usual Hospital Care) | Occurrence of Adverse Events | Other TEAEs | 21 Events |
| Matched Placebo (Plus Usual Hospital Care) | Occurrence of Adverse Events | TEAEs leading to study drug discontinuation | 2 Events |
p-value: 0.5875Fisher Exact
Secondary
Occurrence of Serious Adverse Events
Proportion of Serious Adverse Events (SAEs) in patients receiving AZD1656 compared with placebo
Time frame: Day 1 to Day 28
Population: This analysis includes all patients who received at least one dose of IMP and had at least one post-baseline safety assessment (where the statement that a patient had no AE on the AE eCRF constitutes a safety assessment). 4 patients from the placebo arm are moved to the AZD1656 arm due to having drug in their PK samples. The assignment of patients to the treatment groups are as actually treated.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AZD1656 (Plus Usual Hospital Care) | Occurrence of Serious Adverse Events | Serious Adverse Events | 4 Events |
| AZD1656 (Plus Usual Hospital Care) | Occurrence of Serious Adverse Events | Other AEs | 28 Events |
| Matched Placebo (Plus Usual Hospital Care) | Occurrence of Serious Adverse Events | Serious Adverse Events | 7 Events |
| Matched Placebo (Plus Usual Hospital Care) | Occurrence of Serious Adverse Events | Other AEs | 17 Events |
p-value: 0.1129Fisher Exact
Post Hoc
Mortality Rate
Mortality rate from randomization up to and including 168 hours post randomization
Time frame: Randomization to 168 hours post randomization
Population: Full Analysis Set: all participant who received at least one dose of treatment; patients who withdrew consent are categorised as missing
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AZD1656 (Plus Usual Hospital Care) | Mortality Rate | Missing | 1 Participants |
| AZD1656 (Plus Usual Hospital Care) | Mortality Rate | Died | 0 Participants |
| AZD1656 (Plus Usual Hospital Care) | Mortality Rate | Did not die | 79 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Mortality Rate | Missing | 1 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Mortality Rate | Did not die | 66 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Mortality Rate | Died | 6 Participants |
p-value: 0.0105Fisher Exact
Post Hoc
Proportion of Patients Discharged up to and Including 168 Hours Having a WHO OSCI Rating of 1 or 2
Proportion of Patients Being Discharged From Hospital up to and Including 168 hrs Having WHO OSCI Rating of 1 or 2
Time frame: Day 1 up to and including 168 hours post randomization
Population: Full Analysis Set: all participants who had at least one dose of treatment
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AZD1656 (Plus Usual Hospital Care) | Proportion of Patients Discharged up to and Including 168 Hours Having a WHO OSCI Rating of 1 or 2 | Discharged from hospital (within 168 hrs with WHO 1 or 2) | 30 Participants |
| AZD1656 (Plus Usual Hospital Care) | Proportion of Patients Discharged up to and Including 168 Hours Having a WHO OSCI Rating of 1 or 2 | Not discharged from Hospital (within 168 hrs with WHO 1 or 2) | 49 Participants |
| AZD1656 (Plus Usual Hospital Care) | Proportion of Patients Discharged up to and Including 168 Hours Having a WHO OSCI Rating of 1 or 2 | Missing | 1 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Proportion of Patients Discharged up to and Including 168 Hours Having a WHO OSCI Rating of 1 or 2 | Discharged from hospital (within 168 hrs with WHO 1 or 2) | 18 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Proportion of Patients Discharged up to and Including 168 Hours Having a WHO OSCI Rating of 1 or 2 | Not discharged from Hospital (within 168 hrs with WHO 1 or 2) | 54 Participants |
| Matched Placebo (Plus Usual Hospital Care) | Proportion of Patients Discharged up to and Including 168 Hours Having a WHO OSCI Rating of 1 or 2 | Missing | 1 Participants |
p-value: 0.062Fisher Exact