Clinical trial NCT04516759
Conditions: Covid19
Keywords: COVID-19 Diabetes Mellitus SARS-CoV-2 Regulatory T Cell Glucokinase
Sponsor: St George Street Capital
Start date: 2020-08-12; Completion date: 2021-05-12
Enrollment: 170 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 50mg film-coated tablets at a dose of 100mg BID arm 2: Matched placebo tablets
Interventions: intervention 1: AZD1656 intervention 2: Placebo
Intervention descriptions: intervention 1: 50mg film-coated tablets (at daily dose of 100mg BID) intervention 2: Matched placebo tablets

Protocol documents:
Prot_000.pdf: 
Investigational product:  
CONFIDENTIAL 
Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
Protocol No.: SGS.1656.201 
 FINAL 2.0 (Global) 
Page 1 of 65 
21 December 2020 
Form CL-201-01_Clinical Study Protocol Template 
V1 dated 04 April 2020 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
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 
 
 
EudraCT No: 2020-002211-21 
 
Protocol No.: SGS.1656.201 
 
Original Protocol 
Version No: 1.0, 03 July 2020 
Amendment 1 
Version No: 1.1 (CZ), 10 December 2020 
Amendment 2 
Version No: 1.2 (ROM), 17 December 2020 
Amendment 3 
Version No: 2.0 (Global), 21 December 2020 
 
Sponsor: St George Street Capital, 2a/2b Thrales End Business Centre, Thrales End Lane, 
Harpenden, AL5 3NS, UK 
 
 
Confidentiality Statement: 
This protocol contains information which is the property of St George Street Capital and therefore is 
provided to you in confidence for review by you, your staff, an applicable ethics 
committee/institutional review board and regulatory authorities.  It is understood that this 
information will not be disclosed to others without the written approval of St George Street Capital. 
 
This study will be conducted in compliance with Good Clinical Practice (GCP), the principles 
of the Declaration of Helsinki (with amendments), and in accordance with local legal and 
regulatory requirements 


Investigational product:  
CONFIDENTIAL 
Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
Protocol No.: SGS.1656.201 
 FINAL 2.0 (Global) 
Page 2 of 65 
21 December 2020 
 
 
 
1. 
PROTOCOL SYNOPSIS 
 
PROTOCOL 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. 
SHORT TITLE 
The ARCADIA Trial 
(Alleviation of cardioRespiratory complications in patients with 
COVID-19 And DIAbetes) 
PROTOCOL No. 
SGS.1656.201 
COORDINATING 
INVESTIGATOR 
Dr Kieran McCafferty 
SPONSOR 
St George Street Capital 
INVESTIGATIONAL 
PRODUCT  
AZD1656 
PHASE OF 
DEVELOPMENT 
II 
INDICATION AND 
RATIONALE 
Alleviation of cardiorespiratory complications in diabetic patients 
with suspected or confirmed COVID-19. 
 
AZD1656 is a glucokinase activator which has previously been 
shown to be well tolerated in patients with type 2 diabetes mellitus 
(T2DM).  Twenty-five clinical trials of up to 6 months’ treatment 
duration have been conducted, exposing approximately 960 subjects 
to AZD1656 with no safety concerns raised to date. 
 
A rapid and dose-dependent glucose-lowering effect (in the range 
0.8-2 mmol/L) has been demonstrated after dosing of AZD1656 in 
both healthy volunteers and in T2DM patients. The antidiabetic 
effects of AZD1656 did not persist beyond 4 months, thus limiting 
its long-term use for patients with diabetes (Kiyosue et al. (2013), 
Wilding et al. (2013)).  However, a shorter course of AZD1656 may 
be of benefit in controlling the abnormal glucose variability observed 


Investigational product:  
CONFIDENTIAL 
Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
Protocol No.: SGS.1656.201 
 FINAL 2.0 (Global) 
Page 3 of 65 
21 December 2020 
 
 
in diabetic patients with COVID-19, which may be an important 
contributing factor to disease development.  
 
Mortality rates are increased in diabetic patients with COVID-19 
(China CDC Weekly (2020)). Such patients are at particular risk of 
progressing rapidly with acute respiratory distress syndrome and 
sepsis and are more likely to require Intensive Care Unit (ICU) care 
than non-diabetic COVID-19 patients (22.2% vs 5.9%) (Wang D et 
al. (2020)). In a retrospective cohort study of 191 hospitalised 
patients examining risk factors for mortality associated with 
COVID-19, 31% of non-survivors had diabetes compared with 14% 
of survivors, p=0.0051 (Zhou et al. (2020)).  
 
Patients with diabetes who develop sepsis often develop 
hyperglycaemia and have to increase their diabetic therapy. 
Furthermore, compared with good glycaemic control those patients 
with poor glycaemic control on admission had poor control during 
their in-patient stay and had poorer outcomes including acute kidney 
injury, acute heart injury, acute respiratory distress syndrome and 
all-cause mortality (Zhu et al. (2020)).     
 
In addition to its glucose lowering effect, AZD1656 may have 
additional benefits to COVID-19 patients which involve its effects 
on immune function (Kishore et al. (2017)).  
 
In the immune response to infection, a delicate balance exists 
between T cell activation to fight infection and excessive 
inflammation with cytokine release which is known to cause damage 
to infected host cells. Regulatory T cells (Tregs) are important in 
maintaining this balance. 
 
Migration of activated Tregs to inflamed tissue is crucial for their 
immune-modulatory function, a process which is regulated by 
glucokinase-dependent glycolysis (Kishore et al. (2017)).  A 
glucokinase activator, such as 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).   
 
In-vivo studies using Tregs as an interventional treatment through 
adoptive transfer have shown benefit in an acute lung injury model 
through mediating the resolution of lung injury (D’Alessio et al. 
(2009)). This research shows that resolution in experimental lung 
injury is an active process in which Tregs play an essential role. The 


Investigational product:  
CONFIDENTIAL 
Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
Protocol No.: SGS.1656.201 
 FINAL 2.0 (Global) 
Page 4 of 65 
21 December 2020 
 
 
ability of Tregs to suppress the innate immune response is an 
important component of this (Pietropaoli et al. (2009)). 
  
In an IL-6-rich inflammatory microenvironment, which is known to 
be a feature of COVID-19 infection, inflammatory Th17 cells are 
enhanced while Tregs are suppressed (Chen et al. (2020)). A 
therapeutic agent which can shift the Th17/Treg balance towards 
Tregs might reduce the amplificatory inflammatory loop and 
therefore reduce the uncontrolled inflammation which occurs in 
ARDS.  In an observational study, Th17/Treg ratio was positively 
correlated with disease severity scores and 28-day mortality in a 
retrospective study of ARDS in 2015 (Yu et al. (2015)).  In addition, 
a recent study reported that 90-day survival for patients with ARDS 
was 83% for patients with Tregs/CD4+ percentage equal to or 
greater than 10.5%, but only 41% for patients with Tregs/CD4+ 
percentage less than 10.5% (P = 0.01) (Halter et al. (2020)). 
 
STUDY DESIGN 
This is a Phase II, randomised, placebo-controlled, double-blind 
clinical trial to assess the safety and efficacy of AZD1656 on the 
cardiorespiratory complications of COVID-19 in hospitalised 
diabetic patients with known or suspected COVID-19.  All patients 
will receive usual care plus either AZD1656 or placebo. 
The World Health Organization (WHO) 8-point Ordinal Scale for 
Clinical Improvement will be used as the standard methodology for 
measuring patient outcomes (Appendix 1). 
Safety Review Committee 
A Safety Review Committee (SRC) consisting of clinical and other 
experts will be established by the Sponsor to review safety findings 
during the study and to help ensure patient safety. 
 
STUDY OBJECTIVES 
 
Primary Objective:  
• To determine the effect of AZD1656 on the cardiorespiratory 
complications of COVID-19 in hospitalised diabetic patients 
with known or suspected COVID-19 disease, as measured using 
the WHO 8-point Ordinal Scale for Clinical Improvement (see 
Appendix 1) compared to placebo. 
Secondary Objectives:  
• To assess the extent to which AZD1656 supports maintainance 
of adequate glycaemic control in hospitalised diabetic patients 
with known or suspected COVID-19. 
• To assess the safety and tolerability of AZD1656 in the 
management of diabetes in hospitalised diabetic patients with 


Investigational product:  
CONFIDENTIAL 
Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
Protocol No.: SGS.1656.201 
 FINAL 2.0 (Global) 
Page 5 of 65 
21 December 2020 
 
 
known or suspected COVID-19.  
• To determine whether AZD1656 affects duration of hospital stay, 
requirement for mechanical ventilation or mortality in diabetic 
patients with known or suspected COVID-19. 
Exploratory Objectives: 
• To determine the pharmacokinetics (PK) of AZD1656 in diabetic 
patients with known or suspected COVID-19. 
• To explore the effects of AZD1656 on immunophenotyping 
characteristics during COVID-19 infection in hospitalised 
diabetic patients. 
• To explore the effects of AZD1656 on immunochemistry 
characteristics during COVID-19 infection in hospitalised 
diabetic patients. 
• To explore whether AZD1656 affects the extent of any cardiac 
injury related to COVID-19 in hospitalised diabetic patients. 
• To explore if ethnicity affects the clinical outcome of 
hospitalised diabetic patients with known or suspected COVID-
19 treated with AZD1656 versus placebo. 
• To explore if 25-hydroxyvitamin D levels at baseline affect the 
clinical outcome of hospitalised diabetic patients with known or 
suspected COVID-19 treated with AZD1656 versus placebo. 
 
STUDY ENDPOINTS 
 
Primary Endpoint: 
• 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. 
 
Secondary Endpoints: 
• 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. 
• 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. 
• Proportion of Treatment Emergent Adverse Events (TEAEs) 
leading to study drug discontinuation in patients receiving 
AZD1656 compared with placebo. 
• Proportion of Serious Adverse Events (SAEs) in patients 


Investigational product:  
CONFIDENTIAL 
Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
Protocol No.: SGS.1656.201 
 FINAL 2.0 (Global) 
Page 6 of 65 
21 December 2020 
 
 
receiving AZD1656 compared with placebo. 
• Time from hospital admission to hospital discharge (in hours) in 
patients receiving AZD1656 compared with placebo. 
• Time from hospital admission to receiving intubation/ 
mechanical ventilation in patients receiving AZD1656 compared 
with placebo. 
• Mortality Rate in patients receiving AZD1656 compared with 
placebo. 
 
Exploratory Endpoints: 
• Plasma AZD1656 levels during first 7 days of treatment in 
patients receiving AZD1656 compared with placebo. 
• Immunophenotyping panel to be conducted by Flow Cytometry:  
between group comparison (AZD1656 versus placebo) of levels 
of T, B and NK cells (including specific Treg and memory T cell 
populations); monocyte, neutrophil and eosinophil numeration to 
include activation markers for neutrophils (CD11b) and 
Monocytes subsets (CD14/CD16 identification including 6-Sulfo 
LacNAc (SLAN)). 
• Immunochemistry panel to be conducted using the MSD U-Plex 
multiplex assay for assessment of the following biomarkers: G-
CSF, GM-CSF, IL-1B, IL-4, IL-6, IL-8, IL-10, IL-12, and MIP-
1a.   
• Measurement of hsTroponin and NTproBNP to determine extent 
of cardiac injury in patients receiving AZD1656 compared with 
placebo. 
• Measurement of 25-hydroxyvitamin D levels before treatment to 
determine whether there is any correlation between Vitamin D 
level and clinical outcomes.    
• Correlation of clinical outcomes with patient ethnicity.   
 
PLANNED SAMPLE SIZE  
Approximately 165 patients will be screened to achieve 150 patients 
randomly assigned to AZD1656 or placebo. 
 
PATIENT POPULATION 
 
Inclusion Criteria 
1. Male or Female. 
2. Aged 18 and older. 
3. Have either type 1 diabetes mellitus (T1DM) or T2DM.  
4. Hospitalised with suspected or confirmed novel coronavirus 
(Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-


Investigational product:  
CONFIDENTIAL 
Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
Protocol No.: SGS.1656.201 
 FINAL 2.0 (Global) 
Page 7 of 65 
21 December 2020 
 
 
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 hospitalised. 
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 (see section 9.3). 
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 


Investigational product:  
CONFIDENTIAL 
Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
Protocol No.: SGS.1656.201 
 FINAL 2.0 (Global) 
Page 8 of 65 
21 December 2020 
 
 
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. 
AZD1656 
FORMULATION/DOSE 
50 mg film-coated tablets of AZD1656 or placebo to be dosed at 
100 mg BID 
ROUTE OF 
ADMINISTRATION 
Oral 
DURATION/FREQUENCY 
OF TREATMENT 
Two 50 mg tablets to be taken twice per day with food for up to 21 
days 
EFFICACY 
ASSESSMENTS 
The study will evaluate efficacy across a range of assessments 
evaluating clinical improvement, glycaemic control, time from 
hospital admission to hospital discharge and time from hospital 
admission to receiving intubation/mechanical ventilation. 
SAFETY ASSESSMENTS 
This study will compare the incidence of AEs, including SAEs, 
across the course of the 21-day treatment period and until the final 
visit.  The incidence of abnormal findings in objective assessments 
(e.g. clinical laboratory values, urinalysis, physical examination 
findings, vital signs, and ECG) during the course of the study will 
also be assessed. 
STATISTICAL METHODS 
The WHO 8-point Ordinal Scale will be used to assess the impact of 
treatment with AZD1656 in diabetic patients with COVID-19 versus 
those treated with placebo. The primary endpoint in this trial will be 
the proportion of patients treated with AZD1656 in WHO categories 
1-3 at Day 14 compared to placebo. 60-65% of patients treated with 
usual care alone are expected to meet this condition within the first 
14 days. (Zhou et al (2020), Chen et al (2020), Guan et al (2020), 
Guan et al [2] (2020)). A two group Chi-square (χ²) test with a 5% 
two-sided significance level will have 76.74% power to detect the 
difference between a placebo proportion of 0.6 and an AZD1656 
proportion of 0.8 when the sample size is 150 (75/group). In the case 
that the portion of placebo patients meeting WHO categories 1-3 at 
Day 14 is higher (0.65), then the power to find a similar 20 
percentage point increase would be 81.4%. 
 
The primary analysis will test the null hypothesis that the proportion 
of patients who respond to AZD1656 plus usual care is similar to 
that of those treated with placebo plus usual care at Day 14. The 
primary analysis will include all patients treated according to their 
randomised treatment (Intention To Treat (ITT) analysis set).  The 


Investigational product:  
CONFIDENTIAL 
Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
Protocol No.: SGS.1656.201 
 FINAL 2.0 (Global) 
Page 9 of 65 
21 December 2020 
 
 
difference in proportions (AZD1656 compared to placebo) of 
patients meeting the response criteria (WHO category 1-3 at Day 14) 
will be analysed using the χ² test for the difference of proportions 
with a 0.05 two-sided significance level.  Patients who are assigned 
to WHO category 1-3 at Day 14 will be considered responders.  In 
the unlikely event that a patient leaves the hospital without being 
formally discharged and is lost to follow-up, the last post-baseline 
observation carried forward will be used to impute results for this 
patient.  In the event that a patient is lost to follow-up without having 
recorded at least one post-baseline value, that patient will be 
considered a non-responder. 
PLANNED DATE OF 
FIRST PATIENT 
ENROLLED 
September 2020 
PLANNED DATE OF LAST 
PATIENT COMPLETED 
March 2021 
NUMBER OF STUDY 
CENTRES 
Approximately 35 sites in the UK, Czech Republic and Romania 


Investigational product:  
CONFIDENTIAL 
Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
Protocol No.: SGS.1656.201 
 FINAL 2.0 (Global) 
Page 10 of 65 
21 December 2020 
 
 
2. 
TABLE OF CONTENTS 
1. 
PROTOCOL SYNOPSIS .................................................................................................... 2 
2. 
TABLE OF CONTENTS .................................................................................................. 10 
3. 
LIST OF ABBREVIATIONS ........................................................................................... 13 
4. 
INVESTIGATORS AND ADMINISTRATIVE STRUCTURE ........................................ 15 
5. 
BACKGROUND INFORMATION .................................................................................. 17 
5.1 
COVID-19 ........................................................................................................................ 17 
5.2 
AZD1656 and Study Rationale ......................................................................................... 17 
5.3 
Pre-Clinical Research ........................................................................................................ 19 
5.4 
Clinical Experience ........................................................................................................... 19 
6. 
STUDY OBJECTIVES AND PURPOSE .......................................................................... 21 
6.1 
Primary Objective ............................................................................................................. 21 
6.2 
Secondary Objectives ........................................................................................................ 21 
6.3 
Exploratory Objectives ..................................................................................................... 21 
7. 
SELECTION AND WITHDRAWAL OF PATIENTS ...................................................... 23 
7.1 
Patient Numbers ............................................................................................................... 23 
7.2 
Inclusion Criteria .............................................................................................................. 23 
7.3 
Exclusion Criteria ............................................................................................................. 23 
7.4 
Participant Identification ................................................................................................... 24 
7.5 
Informed Consent ............................................................................................................. 25 
7.6 
Responsibility for the Informed Consent Process .............................................................. 25 
7.7 
Consent Considerations ..................................................................................................... 25 
7.8 
Vulnerable Participants’ Considerations ............................................................................ 25 
7.9 
Patient Withdrawal Criteria ............................................................................................... 25 
8. 
STUDY DESIGN ............................................................................................................. 27 
8.1 
Primary Endpoint .............................................................................................................. 27 
8.2 
Secondary Endpoints ........................................................................................................ 27 
8.3 
Exploratory Endpoints ...................................................................................................... 27 
8.4 
Study Design .................................................................................................................... 28 
8.5 
Safety Review Committee ................................................................................................. 29 
9. 
STUDY MEDICATION AND ADMINISTRATION........................................................ 30 
9.1 
Study Medication Manufacture and Supply ....................................................................... 30 
9.2 
Dispensing of IMP ............................................................................................................ 30 
9.3 
Selection of Doses in the Study ......................................................................................... 30 
9.4 
Allocation to Treatment .................................................................................................... 31 
9.5 
Study Treatment and Administration ................................................................................. 31 
9.6 
Duration of Patient Participation ....................................................................................... 31 
9.7 
Study Treatment Discontinuation Criteria ......................................................................... 32 
9.8 
Treatment Accountability and Compliance Checks ........................................................... 33 
9.9 
Treatment Blinding Code .................................................................................................. 33 
9.10 
Permitted Concomitant Medications ................................................................................. 33 
9.10.1 
Prohibited Concomitant Medication ................................................................................. 34 
10. 
STUDY SCHEDULE ....................................................................................................... 35 
10.1 
Efficacy Assessments ........................................................................................................ 38 
10.1.1 
WHO 8-Point Ordinal Scale ............................................................................................. 38 


Investigational product:  
CONFIDENTIAL 
Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
Protocol No.: SGS.1656.201 
 FINAL 2.0 (Global) 
Page 11 of 65 
21 December 2020 
 
 
10.1.2 
Glycaemic Control ........................................................................................................... 38 
10.1.3 
Time from Hospital Admission to Hospital Discharge ...................................................... 38 
10.1.4 
Time from Hospital Admission to Receiving Intubation/ Mechanical Ventilation ............. 38 
10.2 
Safety Assessments ........................................................................................................... 38 
10.2.1 
Medical History ............................................................................................................... 38 
10.2.2 
Adverse Events ................................................................................................................ 38 
10.2.3 
Physical Examination ....................................................................................................... 39 
10.2.4 
Vital Signs ....................................................................................................................... 39 
10.2.5 
Electrocardiograms .......................................................................................................... 39 
10.2.6 
Clinical Safety Laboratory Assessments ........................................................................... 39 
10.2.7 
Chest X-Ray or Chest CT Scan ........................................................................................ 41 
10.3 
Pharmacokinetic Assessments ........................................................................................... 41 
10.4 
Other Assessments ............................................................................................................ 41 
10.4.1 
hsTroponin (hs-CTNT) .................................................................................................... 41 
10.4.2 
NT-proBNP ..................................................................................................................... 41 
10.4.3 
SARs-CoV-2 PCR test ..................................................................................................... 41 
10.4.4 
Immunophenotyping ........................................................................................................ 42 
10.4.5 
Immunochemistry ............................................................................................................ 42 
10.4.6 
Demographics .................................................................................................................. 42 
10.4.7 
Clotting Factor Analysis................................................................................................... 42 
11. 
ADVERSE EVENTS ........................................................................................................ 43 
11.1.1 
Adverse Events that Do Not Require Reporting................................................................ 43 
11.1.2 
Definitions ....................................................................................................................... 43 
11.1.3 
Assessment of Severity and Causality .............................................................................. 45 
11.1.4 
Outcome Categorisation ................................................................................................... 46 
11.1.5 
Adverse Event Reporting ................................................................................................. 46 
11.1.6 
Notification of AEs of Special Interest ............................................................................. 48 
11.1.7 
Urgent Safety Measures ................................................................................................... 48 
12. 
STATISTICAL CONSIDERATIONS ............................................................................... 49 
12.1 
Estimated Sample Size ...................................................................................................... 49 
12.2 
Study Populations ............................................................................................................. 49 
12.3 
Demographics and Baseline Characteristics ...................................................................... 50 
12.4 
Statistical Methods for Efficacy Parameters ...................................................................... 50 
12.5 
Statistical Methods for Safety Parameters ......................................................................... 50 
12.6 
Handling Missing, Unused or Spurious Data ..................................................................... 50 
13. 
END OF THE STUDY ..................................................................................................... 51 
14. 
ETHICS COMMITTEE REVIEW .................................................................................... 52 
14.1 
Independent Ethics Committee (IEC) and Relevant Authorities......................................... 52 
14.2 
Ethical Conduct of the Study ............................................................................................. 52 
14.3 
Protocol Amendments ....................................................................................................... 52 
15. 
STUDY AND DATA MANAGEMENT ........................................................................... 53 
15.1 
Monitoring ........................................................................................................................ 53 
15.2 
Quality Assurance ............................................................................................................. 53 
15.3 
Data Recording ................................................................................................................. 53 
15.3.1 
Data to be Considered as Source Data .............................................................................. 53 
15.4 
Case Report Form ............................................................................................................. 54 


Investigational product:  
CONFIDENTIAL 
Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
Protocol No.: SGS.1656.201 
 FINAL 2.0 (Global) 
Page 12 of 65 
21 December 2020 
 
 
15.5 
Confidentiality .................................................................................................................. 54 
15.6 
Retention of Study Data .................................................................................................... 54 
15.7 
Communication and Publication of Results ....................................................................... 55 
15.8 
Indemnification ................................................................................................................. 55 
15.9 
Study and Site Closure ...................................................................................................... 56 
16. 
STRUCTURED RISK BENEFIT ANALYSIS.................................................................. 57 
16.1 
Rationale for Dose and Treatment Period .......................................................................... 57 
16.2 
Previous Exposure in Humans........................................................................................... 57 
16.3 
Pharmacokinetic Considerations ....................................................................................... 57 
16.4 
Drug-Drug Interaction....................................................................................................... 58 
16.5 
Predictability of Effect in Patients with COVID-19 ........................................................... 58 
16.6 
Benefit Risk Assessment ................................................................................................... 58 
17. 
REFERENCES ................................................................................................................. 60 
18. 
SIGNATURES AND AGREEMENT WITH THE PROTOCOL ....................................... 62 
APPENDICES ................................................................................................................................... 65 
 
 


Investigational product:  
CONFIDENTIAL 
Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
Protocol No.: SGS.1656.201 
 FINAL 2.0 (Global) 
Page 13 of 65 
21 December 2020 
 
 
 
3. 
LIST OF ABBREVIATIONS 
 
ADR 
Adverse Drug Reaction 
AE 
Adverse event 
ALT 
Alanine amino transferase 
ARDS 
Acute Respiratory Distress Syndrome   
AST 
Aspartate amino transferase 
AUC 
Area under the plasma drug concentration-time curve 
BID 
Twice a day 
BAME 
Black, Asian and minority ethnic  
Cmax 
Maximum plasma concentration observed  
COVID-19 
Coronavirus Disease 2019 
CRO 
Contract Research Organisation 
CT 
Computed Tomography 
CTFG 
Clinical Trial Facilitation Group 
ECG 
Electro cardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GKA 
glucokinase activator 
HIV 
Human Immunodeficiency Virus 
ICH 
International Council for Harmonisation 
ICU 
Intensive Care Unit  
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 


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IRT 
Interactive Response Technology 
ITT 
Intention To Treat  
IUD 
Intrauterine Device 
IUS 
Intrauterine Hormone-Releasing System 
LDH 
Lactate dehydrogenase 
MAD 
Multiple Ascending Dose 
PCR 
Polymerase Chain Reaction  
PD 
Pharmacodynamic 
PI 
Principal Investigator  
PK 
Pharmacokinetic 
PPS 
Per Protocol Set  
RTSM 
Randomization and Trial Supply Management 
SAE 
Serious Adverse Event 
SAF 
Safety Set  
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SLAN  
6-Sulfo LacNAc 
SoA 
Schedule of Assessments 
SRC 
Safety Review Committee 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1DM 
Type 1 Diabetes Mellitus 
T2DM 
Type 2 Diabetes Mellitus 
TEAEs 
Treatment Emergent Adverse Events 
tmax 
Time to maximum plasma concentration  
Tregs 
Regulatory T cells 
TZD 
Thiazolidinedione 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 


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4. 
INVESTIGATORS AND ADMINISTRATIVE STRUCTURE 
 
Coordinating Investigator 
Dr Kieran McCafferty  
Dept of Nephrology 
Barts Health NHS Trust 
Royal London Hospital 
London 
E1 1BB 
Phone: 07980 620627  
Email: kieran.mccafferty4@nhs.net  
 
Medical Monitor (CRO) 
Dr Carmen Vizman 
Medical Monitor  
300724 Timisoara, Romania 
Calea Martirilor 1989, No. 1-3-5 
Corp B, Floor 3, Room 3-4 
Phone: +40 762 206 373  
Email: cvizman@clinipace.com 
 
Medical Director (Sponsor) 
Dr Donna Lockhart 
Consultant Medical Director 
2a/2b Thrales End Business Centre 
Thrales End Lane 
Harpenden  
AL5 3NS 
Phone: 07951 568520  
 
Project Leader (Sponsor) 
 
 
 
 
 
 
 
 
Statistical Consultant 
 
 
 
 
James Chorlton 
Head of Clinical Development 
2a/2b Thrales End Business Centre 
Thrales End Lane 
Harpenden AL5 3NS 
Phone: +44 (0)7901 119230 
Email: jamie@sgscapital.org 
 
 
Martin Dörr  
Senior Biostatistician 
Softwarecenter 3 
D-35037 Marburg 
Germany 
Phone: +49 6421 94849-41 
Email: MDoerr@clinipace.com 
 


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Clinical laboratories 
 
 
 
 
 
Pharmacokinetic & Immunochemistry 
analysis: 
York Bioanalytical Solutions 
Cedar House 
Northminster Business Park 
Upper Poppleton 
York YO26 6QR 
Tel. +44 (0)1904 686060 
 
Immunophenotyping analysis: 
Queen Mary University of London 
Mile End Road 
London E1 4NS 
Tel. +44 (0)20 7882 5555 
 


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5. 
BACKGROUND INFORMATION 
5.1 
COVID-19 
Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2). It was first identified in December 2019 in Wuhan, the 
capital of China's Hubei province, and has since spread globally, resulting in an ongoing pandemic. 
As of 19th June 2020, more than 8.3 million cases have been reported across 187 countries and 
territories, resulting in more than 450,000 deaths.  
 
Mortality rates are increased in diabetic patients with COVID-19 (China CDC Weekly (2020)). Such 
patients are at particular risk of progressing rapidly with acute respiratory distress syndrome and 
sepsis and are more likely to require intensive care unit (ICU) care than non-diabetic COVID-19 
patients (22.2% vs 5.9%) (Wang D et al. (2020)). In a retrospective cohort study of 191 hospitalised 
patients examining risk factors for mortality associated with COVID-19, 31% of non-survivors had 
diabetes compared with 14% of survivors, p=0.0051 (Zhou et al. (2020)). In Guan et al (European 
Respiratory Journal 2020) results for a subset of 130 diabetic patients (in a cohort of 1590) showed 
that 10% of diabetic patients died, 14.6% required treatment in an ICU setting and 8.5% required 
mechanical ventilation compared to 3.1%, 6.2% and 3.1% for the total cohort, respectively. 
 
5.2 
AZD1656 and Study Rationale 
AZD1656 is a glucokinase activator which has previously been shown to be well tolerated in patients 
with type 2 diabetes mellitus (T2DM). 
 
A rapid and dose-dependent glucose-lowering effect (in the range 0.8-2 mmol/L) has been 
demonstrated after dosing of AZD1656 in both healthy volunteers and in T2DM patients. The 
antidiabetic effects of AZD1656 did not persist beyond 4 months, thus limiting its long-term use for 
patients with diabetes (Kiyosue et al. (2013), Wilding et al. (2013)).  However, a shorter course of 
AZD1656 may be of benefit in controlling the abnormal glucose variability observed in diabetic 
patients with COVID-19, which may be an important contributing factor to disease development. 
 
Whilst AZD1656 has largely been tested in patients with type 2 diabetes with no safety concerns 
reported, there is some Phase I data from type 1 diabetics demonstrating the drug is also safe in this 
population. In addition, a large Ph II study was run in type 2 diabetic patients who were also insulin 
dependent and again no safety concerns were noted. The highest repeated doses in prior trials 
(300 mg per day) were given as an add on to insulin therapy. AZD1656 is anticipated to be beneficial 
to both type 1 and type 2 diabetic patients, with both diseases making patients more vulnerable to 
severe COVID-19. Recent reports from the UK showed people with type 1 diabetes are 3.5 times 
more likely to die and type 2 diabetes were 2 times as likely to die from COVID-19 compared with 
non-diabetics, hence both groups represent particularly vulnerable cohorts (Valabhji et al. (2020)). 
AZD1656 will reduce blood glucose levels and will thus provide additional glucose control in both 
diabetic populations, who typically present with hyperglycaemia when admitted with COVID-19. 
This trial will allow the effects of this additional glycaemic control to be elucidated in both 
populations. In addition, the hyperinflammatory process causing much of the damage in COVID-19 


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patients is not thought to be any different between type 1 and type 2 diabetics and so both 
populations could benefit from the potential immunomodulatory mechanism of action of AZD1656.   
 
Patients with diabetes who develop sepsis often develop hyperglycaemia and have to increase their 
diabetic therapy. Furthermore, compared with good glycaemic control those patients with poor 
glycaemic control on admission have poor control during their in-patient stay and have poorer 
outcomes including acute kidney injury, acute heart injury, acute respiratory diseases syndrome and 
all-cause mortality (Zhu et al. (2020)).     
 
In addition to its glucose lowering effect, AZD1656 may have additional benefits to COVID-19 
patients which involve its effects on immune function (Kishore et al. (2017)). In the immune 
response to infection, a delicate balance exists between T cell activation to fight infection and 
excessive inflammation with cytokine release which is known to cause damage to infected host cells. 
Regulatory T cells (Tregs) are important in maintaining this balance. 
 
Migration of activated Tregs to inflamed tissue is crucial for their immune-modulatory function, a 
process which is regulated by glucokinase-dependent glycolysis (Kishore et al. (2017)). A 
glucokinase activator, such as 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). 
 
In-vivo studies using Tregs as an interventional treatment through adoptive transfer have shown 
benefit in an acute lung injury model through mediating the resolution of lung injury (D’Alessio et 
al. (2009)). This research shows that resolution in experimental lung injury is an active process in 
which Tregs play an essential role. The ability of Tregs to suppress the innate immune response is an 
important component of this (Pietropaoli et al. (2009)).  
 
In an IL-6-rich inflammatory microenvironment, which is known to be a feature of COVID-19 
infection, inflammatory Th17 cells are enhanced while Tregs are suppressed (Chen et al. (2020)). A 
therapeutic agent which can shift the Th17/Treg balance towards Tregs might reduce the 
amplificatory inflammatory loop and therefore reduce the uncontrolled inflammation which occurs in 
ARDS.  In an observational study, Th17/Treg ratio was positively correlated with disease severity 
scores and 28-day mortality in a retrospective study of ARDS in 2015 (Yu et al. (2015)).  In 
addition, a recent study reported that 90-day survival for patients with ARDS was 83% for patients 
with Tregs/CD4+ percentage equal to or greater than 10.5%, but only 41% for patients with 
Tregs/CD4+ percentage less than 10.5% (P = 0.01) (Halter et al. (2020)). 
 
Dose 
AZD1656 is given twice daily. The dose of 200 mg per day of AZD1656 to be evaluated in this 
study has been defined based on data from T2DM patients in prior studies. 
 
Patient Population 
Hospitalised T1DM and T2DM patients with suspected or confirmed COVID-19, fulfilling the entry 
criteria set out in sections 7.2 and 7.3.    
 


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Pharmacokinetics 
Pharmacokinetic (PK) blood samples will be collected in order to characterise the PK properties of 
AZD1656 in diabetic patients with COVID-19. 
 
Safety 
Twenty-five clinical trials of up to 6 months’ treatment duration have been completed, exposing 
approximately 960 subjects to AZD1656 with no safety concerns raised to date. 
 
Duration 
A treatment duration of 21 days has been selected to explore the effects of AZD1656 on safety and 
efficacy.  Treatment durations of up to 6 months have been evaluated in previous trials, so the 
duration in this trial is considered safe and is appropriate for this patient population based on the 
expected duration of hospitalisation for diabetic patients requiring hospital treatment for COVID-19. 
 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and the 
applicable regulatory requirements. 
 
5.3 
Pre-Clinical Research 
A comprehensive International Council for Harmonisation (ICH)-compliant pre-clinical program has 
been conducted with AZD1656. Summary information is described in this section, with additional 
information on the non-clinical studies conducted to date contained within the current version of the 
Investigator’s Brochure. 
 
A strong and predictive PK/pharmacodynamic (PD) relationship has been established between 
AZD1656 levels and the magnitude and duration of glucose lowering in animal models. AZD1656 
induced hypoglycaemia (blood glucose <2.5 mM) at higher doses/exposures in normoglycaemic 
animals but not in diabetic animals. 
 
The safety and tolerability of AZD1656 has been investigated in toxicology studies of up to 6 months 
duration in rats and dogs. AZD1656 showed a potent glucose lowering effect and the results of these, 
and preceding toxicology studies, in healthy animals were confounded by severe hypoglycaemia at 
higher doses. Towards the end of the 6-month rat toxicology study, some animals in the high-dose 
group (20 mg/kg/day) were found dead with muscular wastage in their hind legs. Dose related 
increased incidence and severity of neuropathy (Wallerian type nerve degeneration) and myopathy 
(skeletal muscle fibre degeneration) were seen in rats at the mid and high-dose levels, but not in the 
low-dose group (5 mg/kg/day). These changes seen in the mid and high-dose groups were considered 
to be associated with hypoglycaemia. 
 
5.4 
Clinical Experience 
As of December 2019, 25 clinical trials of up to 6 months’ treatment duration have been completed 
in humans with no safety concerns raised to date. All the clinical studies were conducted in 
accordance with GCP regulations.  
 


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The clinical pharmacology (Phase I) programme consisted of 21 studies in 459 subjects, 397 of 
whom were dosed with AZD1656. The majority of subjects were diagnosed with T2DM, 67 were 
healthy male volunteers and 12 were patients with type 1 diabetes mellitus (T1DM). 
 
Based on previous experience with glucokinase activator (GKA) compounds and toxicology results, 
the glucose lowering effect of a GKA could be pronounced in non-diabetic subjects and therefore 
AZD1656 was evaluated on a euglycaemic clamp background in some Phase I studies in healthy 
volunteers. 
 
The Phase IIa and Phase IIb worldwide clinical program included 5 studies (including Part B of the 
28-day multiple ascending dose study D1020C00002) ranging from 4 weeks to 6 months duration 
and in which 566 patients were randomised to AZD1656 and whereof 117 provided data on 6 months 
treatment with AZD1656. 
 
One additional clinical trial of AZD1656 (in diabetic patients who have undergone renal transplant) 
was initiated in 2019 and was ongoing at the time of writing (the ADOPTION trial, EudraCT 
Number 2019-001587-30).  
 
In summary, approximately 1280 subjects have been randomised in the clinical programme, and of 
these 962 were exposed to AZD1656. Approximately 30% of the diabetic patients were females, all 
of whom were non-fertile. 
 
Overview of Safety & Efficacy 
 
Safety and tolerability data have been reported from 20 Phase I, 3 Phase IIa and 2 Phase IIb studies. 
An overview of the design and key results of completed clinical studies are presented in Appendix A 
(Table 12) of the AZD1656 Investigator’s Brochure. A full risk benefit assessment is presented in 
Section 16. 
 
AZD1656 has been well tolerated in clinical studies. Single oral doses of AZD1656 up to 180 mg 
have been given to healthy volunteers during euglycaemic clamp conditions. Patients with T2DM 
have been administered single oral doses up to 450 mg. Daily doses of 10 to 200 mg AZD1656 have 
been given to patients with T2DM for up to 6 months duration. No deaths have been reported.  
 
As with most diabetic medications there is a risk of hypoglycaemia. For AZD1656, in Phase I to IIa, 
few hypoglycaemic events have been reported and only rarely with a plasma glucose level below 3 
mmol/L (54 mg/dL). In Phase IIb, the proportion of patients reporting hypoglycaemic events was 
overall small. Fewer patients in the AZD1656 treatment groups reported hypoglycaemic events 
compared to the glipizide group. Low glucose levels were either asymptomatic (detected in 
scheduled measurement) or associated with mild symptoms, and in all cases manageable by the 
patients. All events with low plasma glucose have responded rapidly to carbohydrate intake.  
 
Although the Phase I and Phase IIa studies were not primarily designed to evaluate efficacy, 
AZD1656 showed a rapid glucose-lowering effect for a dose range from 7 to 10 mg once daily to the 
highest tested daily dose of 450 mg. The glucose-lowering effect of AZD1656 was observed when 


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AZD1656 was given alone and in combination with other antidiabetic drugs (metformin, insulin, 
Thiazolidinedione (TZD) or glipizide). 
 
In Phase IIb, statistically significant and clinically relevant improvements in glucose control were 
observed after 4 months in the global, but not the Japanese dose-finding study, with individually 
titrated doses of 10-200 mg of AZD1656 as compared to placebo. However, Japanese Phase IIb data 
up to 4 months and global extension study results up to 6 months indicate that glucose control 
deteriorated over time with AZD1656. 
 
6. 
STUDY OBJECTIVES AND PURPOSE 
6.1 
Primary Objective 
To determine the effect of AZD1656 on the cardiorespiratory complications of COVID-19 in 
hospitalised diabetic patients with known or suspected COVID-19 disease, as measured using the 
WHO 8-point Ordinal Scale for Clinical Improvement (see Appendix 1) compared to placebo. 
 
6.2 
Secondary Objectives 
Secondary objectives of this study are: 
 
• To assess the extent to which AZD1656 supports maintenance of adequate glycaemic control in 
hospitalised diabetic patients with known or suspected COVID-19. 
 
• To assess the safety and tolerability of AZD1656 in the management of diabetes in hospitalised 
diabetic patients with known or suspected COVID-19.  
 
• To determine whether AZD1656 affects duration of hospital stay, requirement for mechanical 
ventilation or mortality in diabetic patients with known or suspected COVID-19. 
 
6.3 
Exploratory Objectives 
Exploratory objectives of this study are: 
 
• To determine the pharmacokinetics (PK) of AZD1656 in diabetic patients with known or 
suspected COVID-19. 
 
• To explore the effects of AZD1656 on immunophenotyping characteristics during COVID-19 
infection in hospitalised diabetic patients. 
 
• To explore the effects of AZD1656 on immunochemistry characteristics during COVID-19 
infection in hospitalised diabetic patients. 
 
• To explore whether AZD1656 affects the extent of any cardiac injury related to COVID-19 in 
hospitalised diabetic patients. 


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• To explore if ethnicity affects the clinical outcome of hospitalised diabetic patients with known 
or suspected COVID-19 treated with AZD1656 versus placebo. 
 
• To explore if 25-hydroxyvitamin D levels at baseline affect the clinical outcome of hospitalised 
diabetic patients with known or suspected COVID-19 treated with AZD1656 versus placebo. 
 


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7. 
SELECTION AND WITHDRAWAL OF PATIENTS 
7.1 
Patient Numbers 
This is a double-blind, randomised, study of AZD1656 versus placebo across a 21-day treatment 
period. Up to 150 adult patients will be eligible to participate in the study. Subjects that withdraw 
from the study after receiving treatment will not be replaced.  
 
7.2 
Inclusion Criteria 
1. Male or Female. 
2. Aged 18 and older. 
3. Have either T1DM or T2DM.  
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. 
 
7.3 
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 (see section 9.3). 
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. 


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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. 
 
*Highly effective contraception is considered to be using one of the following birth control 
methods: 
• combined (estrogen and progestogen containing) hormonal contraception1 
o oral 
o intravaginal 
o transdermal 
• progestogen-only hormonal contraception associated with inhibition of ovulation1: 
o oral 
o injectable 
o implantable2 
• intrauterine device (IUD) 2 
• intrauterine hormone-releasing system (IUS) 2 
• bilateral tubal occlusion 2 
• vasectomised partner 2,3 
• sexual abstinence4 
1Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception 
2Contraception methods that in the context of the Clinical Trial Facilitation Group’s (CTFG) ‘Recommendations 
related to contraception and pregnancy testing in clinical trials’ guidance are considered to have low user 
dependency. 
3Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the 
WOCBP trial participant and that the vasectomised partner has received medical assessment of the surgical success. 
4In the context of the CTFG guidance sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred 
and usual lifestyle of the subject. 
7.4 
Participant Identification 
Potential participants will be identified by the clinical team from those patients admitted to hospital 
with suspected or confirmed COVID-19. 


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7.5 
Informed Consent 
For each study patient, written informed consent will be obtained prior to any protocol-related 
activities.  As part of this procedure, the Principal Investigator (PI) or one of his associates will 
explain orally and in writing the nature, duration, purpose of the study, and the action of the study 
drug in such a manner that the patient is aware of the potential risks, inconveniences, or adverse 
effects that may occur.  The patients will be provided ample time to review the information and ask 
questions.  They will be informed that their medical records may be reviewed by appropriately 
qualified monitors of the Sponsor or Sponsor Representative, and by auditors or regulatory 
authorities to ensure the accuracy of the details recorded as part of the study.  They will be informed 
that they may withdraw from the study at any time without prejudice to further treatment.  They will 
receive all information that is required by local regulations and ICH GCP guidelines.  The consent 
process must be fully documented in the patient’s source medical records.  A copy of the signed 
consent form must be provided to the patient and the original must be retained at site. 
 
7.6 
Responsibility for the Informed Consent Process 
The PI retains overall responsibility for the informed consent of participants at their site and must 
ensure that any person delegated responsibility to participate in the informed consent process is duly 
authorised, trained and competent to participate according to the ethically approved protocol, 
principles of GCP and the Declaration of Helsinki. If delegation of consent occurs, then details must 
be provided in the Site Delegation Log.  
 
7.7 
Consent Considerations 
The right of a patient to refuse participation without giving reasons will be respected. 
 
Where a patient is required to re-consent, for example if during the trial new Research Safety 
Information becomes available, or following an amendment that affects the patient, or new 
information needs to be provided to a patient, it is the responsibility of the PI to ensure this is done in 
a timely manner. 
 
7.8 
Vulnerable Participants’ Considerations  
The PI takes responsibility for ensuring that all subjects are protected and participate voluntarily in 
an environment free from coercion or undue influence. 
 
7.9 
Patient Withdrawal Criteria 
Patients may withdraw from the study at any time without stating a reason and without prejudice to 
further treatment.  The Investigator may withdraw a patient from the study and discontinue study 
treatment and assessments at any time.  If a patient is withdrawn at any time after entering the study 
the Investigator will make every effort to see the patient and complete the final visit assessments.  
 


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Early withdrawal of any patient who has given informed consent to participate will be recorded 
including the reason for withdrawal. The primary reason for a patient withdrawing prematurely will be 
selected from the following standard categories: 
 
• Failed to meet enrolment criteria after providing informed consent 
• Withdrawal of Consent: The patient desired to withdraw from further participation in the study. 
The patient is not obliged to provide any reason for withdrawal of consent, but where a reason is 
given this will be recorded on the electronic Case Report Form (eCRF). 
• Lost to Follow-Up: The patient leaves hospital without being formally discharged and study 
personnel were unable to contact the patient. 
The trial may be terminated by the Sponsor at any time for any reason. This may include reasons 
related to the benefit/risk assessment of participating in the trial, practical reasons (including slow 
enrolment), or for regulatory, medical, scientific or ethical reasons. Should this be necessary, patients 
must be seen as soon as possible and treated as a prematurely discontinued patient. The Investigator 
may be informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The Independent Ethics Committees 
(IECs) must be informed of the early termination of the trial. 
 


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8. 
STUDY DESIGN 
8.1 
Primary Endpoint 
Clinical Improvement measured as the percentage of subjects at Day 14 who are in categories 1-3 
according to the World Health Organization (WHO) 8-point Ordinal Scale for Clinical Improvement, 
comparing AZD1656 treatment to placebo. 
 
8.2 
Secondary Endpoints 
• 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. 
• 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. 
• Proportion of Treatment Emergent Adverse Events (TEAEs) leading to study drug 
discontinuation in patients receiving AZD1656 compared with placebo. 
• Proportion of Serious Adverse Events (SAEs) in patients receiving AZD1656 compared with 
placebo. 
• Time from hospital admission to hospital discharge (in hours) in patients receiving AZD1656 
compared with placebo. 
• Time from hospital admission to receiving intubation/mechanical ventilation in patients receiving 
AZD1656 compared with placebo. 
• Mortality Rate in patients receiving AZD1656 compared with placebo. 
8.3 
Exploratory Endpoints 
• Plasma AZD1656 levels during first 7 days of treatment in patients receiving AZD1656 
compared with placebo. 
• Immunophenotyping panel to be conducted by Flow Cytometry: between group comparison 
(AZD1656 versus placebo) of levels of T, B and NK cells (including specific Treg and memory 
T cell populations); monocyte, neutrophil and eosinophil numeration to include activation 
markers for neutrophils (CD11b) and Monocytes subsets (CD14/CD16 identification including 6-
Sulfo LacNAc( SLAN)). 


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• Immunochemistry panel to be conducted using the MSD U-Plex multiplex assay for assessment 
of the following biomarkers: G-CSF, GM-CSF, IL-1B, IL-4, IL-6, IL-8, IL-10, IL-12, and  MIP-
1a.  
• Measurement of hsTroponin and NTproBNP to determine extent of cardiac injury in patients 
receiving AZD1656 compared with placebo. 
• Measurement of 25-hydroxyvitamin D levels before treatment to determine whether there is any 
correlation between Vitamin D level and clinical outcomes.    
• Correlation of clinical outcomes with patient ethnicity.  
8.4 
Study Design 
This is a Phase II, randomised, placebo-controlled, double blind clinical trial to assess the safety and 
efficacy of AZD1656 on the alleviation of cardiorespiratory complications in diabetic patients 
hospitalised with suspected or confirmed COVID-19.  All patients will receive usual care plus either 
AZD1656 or placebo. 
 
In consideration of the appropriate timing for assessment of the primary endpoint, Docherty et al. 
(2020) evaluated features and outcomes for 20,133 patients admitted to hospital in the UK and 
reported that the median duration of COVID-19-related symptoms prior to hospitalisation was 
4 days. Forty-one percent of patients were discharged, 26% died and the remainder were still 
receiving care at the timepoint cut off for the study, which was 14 days post admission. Docherty et 
al (2020) further reported that 80% of patients in the cohort w o died did so within 14 days. Guan et 
al (2020) further reported in a Chinese cohort of 1099 patients (7.5% diabetic) that the median 
duration of symptoms prior to admission was 4 days and that the median length of hospital stay was 
12 days (interquartile range 10-14 days). Based on these data, a 14 day timepoint to assess the 
primary endpoint appears appropriate since by this time the majority of patients will have either 
improved to be discharged or will have progressed to ICU admission, mechanical ventilation or 
death. Analyses of outcomes at other timepoints e.g. Day 7 and Day 21 will also be undertaken as 
secondary endpoints. 
 
It is expected that 165 patients will be screened to randomise 150 patients. 
 
The study will have 3 phases (see Figure 1, Study Design): 
 
• Screening/ Randomisation (Day -2 to 1, V1 to V2) 
o Patients will undergo a Screening Visit (V1) and Randomisation Visit (V2) to evaluate 
their eligibility to participate in the study and to commence study treatment (Day 1). 
• Double-Blind Treatment (Day 1 to Day 21, V2-V22) 
o Patients will receive study treatment for up to a maximum of 21 days, or until date of 
discharge from hospital, or date of mechanical ventilation or date of death, whichever 
comes first.  


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• Safety Follow-up Visit (7 days after completion of study treatment)   
o Patients will have a final visit 7 days after completion of study treatment to capture any 
new safety information or changes to concomitant medication. This will be at Day 28 for 
those completing the full treatment period of 21 days or 7 days after treatment 
discontinuation.  
o Following this visit the patients are discharged from the study. 
Procedures should be undertaken as listed in the schedule (see section 10) until study end criteria are 
met with a final assessment on that date (Visit 23). 
 
Figure 1, Study Design 
 
 
8.5 
Safety Review Committee 
A Safety Review Committee (SRC) consisting of clinical and other experts will be established by the 
Sponsor to review safety findings during the study and to help ensure subject safety. The SRC will 
form a Charter prior to their first data review; that Charter will include a description of the 
Committee, the Members and their responsibilities, the data to be reviewed, the timing of the 
reviews, and considerations for any statistical items (e.g. data displays) that may be required for the 
data reviews. Data included for SRC review will be subject to monitoring and/or Medical Monitor 
review to confirm data quality.      
 
The SRC will meet at intervals during the trial to review safety and tolerability data for the total 
study population (including frequency, severity and seriousness of adverse events; concomitant 
medication data; WHO Ordinal Scale data).  The SRC review of the study treatment assignments will 
be blinded. The Sponsor will also remain blinded to the treatment assignments. The SRC will make a 
recommendation to either proceed with the protocol with no modification or may suggest changes to 
the protocol.  Based on the results of their data reviews, the SRC will submit its recommendations in 
written form to the Sponsor who is responsible for responding to the recommendations of the SRC 
and to take appropriate action. 


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AZD1656 
 
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21 December 2020 
 
 
9. 
STUDY MEDICATION AND ADMINISTRATION 
9.1 
Study Medication Manufacture and Supply 
IMP: AZD1656 film-coated tablets for oral administration and matching placebo. 
 
The tablets were manufactured by Patheon.  
 
Patheon UK Limited. 
151 Brook Drive  
Milton Park  
Abingdon  
OX14 4SD  
United Kingdom 
 
The tablets will be packed and labelled by Fisher Clinical Services.  
 
Fisher Clinical Services UK Limited  
Langhurstwood Road  
Horsham  
RH12 4QD  
United Kingdom  
 
The packed and labelled tablets will be shipped securely from Fisher to the clinical trials pharmacy 
unit at each investigational site.  All medicinal products left over after study completion will be 
returned to Fisher for destruction.  
 
Note that a separate Pharmacy Manual will be produced to set out the requirements for the IMP 
management aspects of the trial. 
 
9.2 
Dispensing of IMP  
Dispensing guidelines will be provided in the Pharmacy Manual, which will be in place within each 
pharmacy. Each member of pharmacy staff involved in the study must be listed on the study specific 
trial delegation log.   When IMP is dispensed the pharmacy dispensing log will be signed and a 
patient accountability log completed to ensure appropriate IMP tracking and accountability.  
 
9.3 
Selection of Doses in the Study 
AZD1656 50 mg tablets will be supplied in plastic bottles.  Patients randomised to active treatment 
will receive 100 mg twice a day (BID) with food, resulting in a total daily dose of 200 mg.   
 
The selected dose of 200 mg/day has been shown to be well tolerated and effective at reducing 
glucose levels in diabetic patients in prior clinical studies. The selected dose is at the upper end of 
the range that has been previously studied but will be given for a shorter duration than previously 
studied. In prior trials, the highest repeated doses were 300 mg daily for 8 days and 200 mg daily for 


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21 December 2020 
 
 
up to 6 months. Single oral doses of AZD1656 have also been studied up to 450 mg. The 200 mg/day 
dose is also considered appropriate to test the hypothesis of an immune‐modulatory mode of action, 
since the enzymatic mechanism of action (via activation of glucokinase) is the same for both the  
glucose lowering effect and the Treg migratory effect of the drug. As such the pharmacodynamic 
effect of AZD1656 on Treg migration activity is expected to be the same as that required for glucose 
lowering (there is no evidence in humans to suggest otherwise). 
 
The film-coated tablet formulation contains AZD1656, cellulose microcrystalline, magnesium 
stearate, mannitol, sodium laurilsulphate, sodium starch glycolate, hydroxypropyl methylcellulose, 
macrogols and titanium dioxide. 
 
Matching placebo tablets contain cellulose microcrystalline, sodium stearyl fumarate, hydroxypropyl 
methylcellulose, macrogols and titanium dioxide. 
 
9.4 
Allocation to Treatment 
This is a double-blind placebo-controlled study: both the patient and the study team will be blinded 
to the treatment intervention.  
 
The treatment the patient is randomised to is determined by a randomisation scheme which will 
automatically be assigned by the Interactive Response Technology (IRT) (Medidata RAVE 
Randomization and Trial Supply Management (RTSM)).  
 
Subjects will be randomised in a 1:1 manner to either AZD1656 or placebo for a maximum dosing 
period of 21 days.    
 
9.5 
Study Treatment and Administration 
 
AZD1656 or placebo will be administered twice per day, at approximately the same time each day 
with or just after meals, by oral route. Due to the short tmax of AZD1656, the patient must not take 
their medication without food.  Patients will receive treatment for up to 21 consecutive days as in-
patients.   
 
Missed doses will be permitted: if a patient misses a dose they should take their next dose at the 
usual time.  Any missed doses must be recorded in the patient’s notes. 
 
9.6 
Duration of Patient Participation 
The maximum duration of patient participation in this study is 30 days, to comprise up to 2 days for 
Screening, 21 days of treatment and 7 days of follow-up (if patient is not discharged before Day 28). 
 
Once a decision has been made to discharge a patient from hospital, study medication should be 
stopped and their usual diabetes medication continued with any necessary adjustments as per usual 
care. If a patient is transferred to another hospital during the study, study medication should be 


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stopped and their usual diabetes medication continued with any necessary adjustments as per usual 
care. 
 
9.7 
Study Treatment Discontinuation Criteria 
Patients will receive study treatment for up to a maximum of 21 days, or until date of discharge from 
hospital, or date of mechanical ventilation or date of death, whichever comes first.  The primary 
reason for a patient discontinuing treatment prematurely will be selected from the following standard 
categories: 
 
• Adverse Event (Adverse Reaction): Clinical events occurred or laboratory results are reported 
that in the medical judgment of the Investigator are grounds for discontinuation in the best 
interests of the patient. 
• Intubation/Mechanical Ventilation: any patients who require intubation/mechanical ventilation 
will be discontinued at the point the intervention is required, since the patient will be unable to 
take study medication orally. 
 
• Protocol Violation: The patient failed to adhere to the protocol requirements, at the Investigator’s 
discretion e.g. the patient requires to start taking a medication from the prohibited medications list 
(section 9.10.1). 
• Pregnancy: The subject has either a positive urine or serum pregnancy test during the study. 
• Hypoglycaemia: that occurs despite removal of other glucose-lowering drugs: e.g. repeated 
events of minor hypoglycaemia defined as:  
− repeated episodes with symptoms and confirmed low glucose (<3.9 mmol/L) 
− repeated asymptomatic episodes with low glucose (<3.9 mmol/L)  
- repeated episodes with symptoms suggestive of hypoglycaemia when glucose was not 
measured.  
If a patient has any episodes of hypoglycaemia, their diabetic medications will be altered as per 
standard of clinical care. 
 
• One event of major hypoglycaemia regardless of any other diabetes drugs, as defined by the 
American Diabetes Association (ADA) as: Requires assistance of another person to actively 
administer carbohydrates, glucagon, or take other corrective actions. Plasma glucose 
concentrations may not be available during an event, but neurological recovery following the 
return of plasma glucose to normal is considered sufficient evidence that the event was induced 
by a low plasma glucose level  
• Introduction of gemfibrozil or other strong inhibitors of CYP2C8 (prohibited medication). 
 


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• Other: The patient was terminated for a reason other than those listed above, such as termination 
of study by Sponsor. 
9.8 
Treatment Accountability and Compliance Checks 
The Investigator has overall responsibility for accountability for study treatment that is received at 
site and dispensed to study patients.  In accordance with regulatory requirements, the Investigator or 
designated site staff must document the amount of IMP dispensed and/or administered to study 
subjects, the amount unused by study subjects, and the amount received from and returned to the 
Sponsor (or representative) when applicable. Product accountability records must be maintained 
throughout the course of the study and IMP must be stored in a locked, secure storage facility with 
access limited only to those individuals authorised to dispense the IMP. Clinical supplies not to be 
used for any other purpose than that stated in the protocol.  
 
Used study medication bottles to be retained at site for study treatment accountability until final 
reconciliation can be conducted. 
 
9.9 
Treatment Blinding Code 
All participants will be centrally assigned to randomised treatment using an IRT system. Before the 
study is initiated, the log in information & directions for the IRT will be provided to the site. Study 
treatment will be dispensed at the study visits as summarised in the Schedule of Assessments 
(section 10). Returned medication will not be re-dispensed to the participants. 
 
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
Investigator has the sole responsibility for determining if unblinding of a patient’s treatment 
assignment is warranted. Patient safety must always be the first consideration in making such a 
determination. If the Investigator decides that unblinding is warranted, the Investigator should make 
every effort to contact the Medical Monitor prior to unblinding a participant’s treatment assignment 
unless this could delay emergency treatment of the patient. If a patient’s treatment assignment is 
unblinded, the Medical Monitor must be notified within 24 hours after breaking the blind. The date 
and reason that the blind was broken must be recorded in the source documentation and case report 
form, as applicable. 
 
If the blinding is prematurely broken, it is the responsibility of the Investigator to promptly document 
and explain any unblinding to the Medical Monitor. 
 
9.10 
Permitted Concomitant Medications 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) that the participant is receiving at the time of enrolment or receives during the 
study must be recorded along with: 
 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 


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The Medical Monitor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
 
All treatments, including oxygen, which the patients are receiving as part of their usual care during 
their hospital admission will be recorded as concomitant medications. Note that the use of 
dexamethasone will not be contraindicated as part of usual care (if clinically indicated).  
 
 
9.10.1 
Prohibited Concomitant Medication 
Given the theoretical increase in AUC (but not Cmax) with gemfibrozil, any patient who is currently 
taking this agent or other strong inhibitors of CYP2C8 will be excluded from the study.  
 
 


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10. 
STUDY SCHEDULE 
Study procedures and their timing are summarised in the Schedule of Assessments (SoA). Protocol 
waivers or exemptions are not permitted. 
Immediate safety concerns should be discussed with the Medical Monitor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study treatment. 
Adherence to the study design requirements, including those specified in the SoA, is essential and 
required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
patients screened and to confirm eligibility or record reasons for screening failure, as applicable. 
Procedures conducted as part of the patient’s routine clinical management (e.g. SARs-CoV-2 PCR 
test, Chest X-ray, CT Scan, etc.) and obtained before signing of the ICF may be utilised for screening 
or randomisation purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA (i.e. within 2 days of randomisation).


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21 December 2020 
 
Schedule of Assessments 
 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
Visit Name 
Screening 
Randomis
ation 
Patient is on study treatment for up to 21 days, or date of discharge from hospital, or date of mechanical ventilation or date of death, whichever comes 
first. Procedures should be undertaken as listed in the schedule until study end criteria are met with a final assessment on that date (Visit 23) 
Safety 
Follow-
up5 
Day 
Day -2 
or -1 
Day 1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
Day 
8 
Day 
9 
Day 
10 
Day 
11 
Day 
12 
Day 
13 
Day 
14 
Day 
15 
Day 
16 
Day 
17 
Day 
18 
Day 
19 
Day 
20 
Day 
21  
or day 
study 
end 
criteri
a are 
met3 
Day 
28  
or 7 days 
after 
study 
end 
criteria 
are met 
Obtain written informed 
consent 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history1 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
(females) 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
+ 
 
Physical Examination  
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
 
12-Lead ECG2 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Chemistry2  
+ 
+ 
 
 
 
 
 
 
+ 
 
 
 
 
 
 
+ 
 
 
 
 
 
+ 
 
Haematology2 
+ 
+ 
 
 
 
 
 
 
+ 
 
 
 
 
 
 
+ 
 
 
 
 
 
+ 
 
Urinalysis2 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
hsTroponin (hs-CTNT) 
sample2 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
+ 
 
NT-proBNP sample2 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
+ 
 
SARs-CoV-2 PCR test2, 6 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c sample7 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
25-hydroxyvitamin D 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient WHO clinical status 
record 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
 
Immunophenotyping blood 
sample 7 
 
+ 
 
 
 
 
 
 
+ 
 
 
+ 
 
 
 
 
 
 
 
 
 
+ 
 
Immunochemistry blood 
sample7 
 
+ 
 
 
 
 
 
 
+ 
 
 
+ 
 
 
 
 
 
 
 
 
 
+ 
 
PK sample7 
 
 
+ 
 
+ 
 
 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clotting Factor Sample 7, 8 
 
+ 
 
 
 
 
 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug/placebo 
Administration 
 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
 
Adverse Events review 
 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 


Investigational product:  
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Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
Protocol No.: SGS.1656.201 
 FINAL 2.0 (Global) 
Page 37 of 65 
21 December 2020 
 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
Visit Name 
Screening 
Randomis
ation 
Patient is on study treatment for up to 21 days, or date of discharge from hospital, or date of mechanical ventilation or date of death, whichever comes 
first. Procedures should be undertaken as listed in the schedule until study end criteria are met with a final assessment on that date (Visit 23) 
Safety 
Follow-
up5 
Day 
Day -2 
or -1 
Day 1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
Day 
8 
Day 
9 
Day 
10 
Day 
11 
Day 
12 
Day 
13 
Day 
14 
Day 
15 
Day 
16 
Day 
17 
Day 
18 
Day 
19 
Day 
20 
Day 
21  
or day 
study 
end 
criteri
a are 
met3 
Day 
28  
or 7 days 
after 
study 
end 
criteria 
are met 
Concomitant /treatment 
record4 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Diabetic medication review 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
 
 
1 If clinically indicated, include record of X-ray/ CT scan if conducted at screening or at any point during the study. 
2 Frequency of testing to be clinically determined outside of specified timings in the schedule of events. If these tests are undertaken at more frequent intervals, only results that 
are out of range AND considered clinically significant are to be recorded in the eCRF. 
3 Visit timepoint will occur at death, discharge from hospital or up to 21 days after randomisation (whichever is sooner).  
4 To include usual care treatments including details of any respiratory support provision. 
5 To be conducted as in-patient if patient still hospitalised or via telephone call for those discharged. 
6 Patient can be randomised and start study treatment before SARs-CoV-2 PCR test result is available.  Please see section 10.4.3.  
7 Samples can be collected +/- 1 day of the scheduled day above. 
8 Clotting factor sample will be collected if patient provides additional consent and if the site is able to store the sample at -70°C.  
 
 
 
 


Investigational product:  
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Protocol No.: SGS.1656.201 
AZD1656 
 
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Protocol No.: SGS.1656.201 
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21 December 2020 
 
 
10.1 
Efficacy Assessments 
All assessments will be performed by the Investigator or appropriately delegated and trained 
personnel. Planned timepoints for all efficacy assessments are provided in the SoA. 
 
10.1.1 
WHO 8-Point Ordinal Scale 
The WHO 8-point Ordinal Scale (Appendix 1) will be used to assess the impact of treatment with 
AZD1656 of diabetic patients with COVID-19 versus those treated with placebo. The primary 
endpoint in this trial will be the proportion of patients treated with AZD1656 in WHO categories 1-3 
at Day 14 compared to placebo.  The highest score measured each day will be recorded for all 
patients from Visit 1 to the Final Visit inclusive. 
 
10.1.2 
Glycaemic Control 
The effectiveness of AZD1656 in reducing blood sugar over short durations of treatment has already 
been demonstrated. Given the short maximum treatment period of 21 days, the usual method of 
monitoring the level of diabetic control via HbA1c over time is not appropriate. However, a daily 
record of diabetic medication and doses throughout the study will be recorded in the eCRF. Blood 
sugars will also be measured, as determined by usual standard of care for a hospitalised diabetic 
patient with infection. By comparing the AZD1656 and control groups it will be possible to 
determine whether the requirement to increase diabetic medication to obtain control of glucose levels 
is reduced in the AZD1656 treated group compared to placebo.  
 
10.1.3 
Time from Hospital Admission to Hospital Discharge 
Hospital admission and hospital discharge times will be recorded in the eCRF for all applicable 
patients to assess time from hospital admission to hospital discharge. 
 
10.1.4 
Time from Hospital Admission to Receiving Intubation/ Mechanical Ventilation 
Hospital admission time and the time a patient receives intubation/mechanical ventilation will be 
recorded in the eCRF for all applicable patients. 
 
10.2 
Safety Assessments 
10.2.1 
Medical History 
Patients’ clinically relevant medical history will be collected and recorded in the eCRF.  The results 
of any clinically indicated test procedures, e.g. X-ray, CT scan, ultrasound, performed as part of 
usual care should be recorded at screening or at any point during the study. 
 
10.2.2 
Adverse Events 
Adverse events will be assessed and recorded in the eCRF for each patient during the trial.  See 
section 11 for further details. 
 


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10.2.3 
Physical Examination  
A full physical examination will be conducted at the Screening visit (V1).  Height and weight may be 
taken verbally from the patient if it is not possible for the patient to stand.  This will be completed by 
the Investigator or a delegated physician. 
 
A full physical examination is composed of a review of the following body systems: 
• General appearance 
• Skin 
• Head, eyes, ears, nose and throat 
• Respiratory 
• Cardiovascular 
• Abdomen (including liver and kidneys) 
• Musculoskeletal 
• Neurological 
 
10.2.4 
Vital Signs 
Vital signs will be measured as per the SoA with patients after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure, pulse, oxygen saturation using pulse oximeter and 
respiratory rate.  
 
10.2.5 
Electrocardiograms 
12-lead ECGs will be performed as outlined in the SoA according to local hospital standard practice.   
If ECGs are undertaken at more frequent intervals, only results that are out of range AND considered 
clinically significant are to be recorded in the eCRF.  
 
10.2.6 
Clinical Safety Laboratory Assessments 
All clinical safety laboratory assays will be performed according to the study site laboratory’s normal 
procedures. Reference ranges will be supplied by the study site laboratory and will be used to assess 
the laboratory data for clinical significance and out of range changes. 
Clinical Chemistry 
A clinical sample will be collected as outlined in the SoA. Clinical chemistry blood samples can be 
drawn with the subject in either a fasting or non-fasting state according to local practice. However, if 
a sample needs to be repeated, the subsequent sample should be drawn from the subject in the same 
fasting/non-fasting state. 
 
The clinical chemistry analysis will include, sodium, potassium, urea, creatinine, calcium, phosphate, 
total protein, bilirubin, alkaline phosphatase, LDH, ALT, AST, GGT and glucose.  


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Frequency of testing and those analytes tested are to be clinically determined outside of specified 
timings in the SoA. If these tests are undertaken at more frequent intervals or other parameters tested 
(e.g. blood gas monitoring), only results that are out of range AND considered clinically 
significant are to be recorded in the eCRF. 
 
25-hydroxyvitamin D  
Vitamin D is known to be important for immune function including increasing the number of Tregs 
(for example see meta-analysis by Fisher et al. (2019)), so vitamin D deficiency may reduce the 
efficacy of AZD1656. Measuring vitamin D status will allow any such correlation to be assessed, 
which would inform future protocols. It will also allow research into other effects that vitamin D 
deficiency has on immune parameters during COVID-19 as immunophenotyping and 
immunochemistry tests will be run as part of ARCADIA. Vitamin D deficiency is associated with 
worse COVID outcomes and Vitamin D deficiency is higher in Black, Asian and minority ethnic 
(BAME) patients in the UK. Hence measuring vitamin D status may additionally aid understanding 
of some of the disparities that have been observed with higher mortality rates from COVID-19 
amongst BAME patients. 
Vitamin D levels will be measured at the Randomisation visit (Day 1) to determine whether there is 
any correlation between Vitamin D level and clinical outcomes.    
Haematology 
A full blood count with differential should be collected as outlined in the SoA. This should include 
red blood cell count, platelets, white blood cell count (differential: eosinophils, basophils, 
neutrophils, lymphocytes, monocytes) haemoglobin and haematocrit.  Frequency of testing to be 
clinically determined outside of specified timings in the SoA. If these tests are undertaken at more 
frequent intervals, only results that are out of range AND considered clinically significant are to be 
recorded in the eCRF.. 
 
HbA1c 
An HbA1c sample should be obtained at Day 1 (V2) to determine the level of glycaemic control on 
entry to the study. 
Urinalysis 
Urinalysis will be performed by dipstick and documented in source documents as outlined in the 
SoA. Abnormal results should be investigated further, as clinically needed.  Frequency of testing to 
be clinically determined outside of specified timings in the SoA. If these tests are undertaken at more 
frequent intervals, only results that are out of range AND considered clinically significant are to be 
recorded in the eCRF. 
Pregnancy Test 


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For female patients of child-bearing potential a urine pregnancy test should be obtained at the 
Screening Visit (V1) and Final Visit (V22). 
 
10.2.7 
Chest X-Ray or Chest CT Scan 
If clinically indicated, a Chest X-Ray or Chest CT scan will be performed according to local hospital 
standard practice and details recorded in the eCRF.  
 
10.3 
Pharmacokinetic Assessments 
Whole blood samples will be collected for measurement of plasma concentrations of AZD1656 as 
specified in the SoA. Instructions for the collection and handling of samples will be provided by the 
Sponsor. The actual date and time (24-hour clock time) of each sample and the time of last study 
drug administration will be recorded. 
 
Drug concentration information that may unblind the study will not be reported to investigative sites 
or blinded personnel until the study has been unblinded. 
 
10.4 
Other Assessments 
10.4.1 
hsTroponin (hs-CTNT) 
A blood sample for analysis of hsTroponin (hs-CTNT) will be collected at Screening (V1) and the 
Final Visit to determine the extent of cardiac injury in patients receiving AZD1656 versus placebo. 
Frequency of testing to be clinically determined outside of specified timings in the SoA. If these tests 
are undertaken at more frequent intervals, only results that are out of range AND considered 
clinically significant are to be recorded in the eCRF. 
 
10.4.2 
NT-proBNP 
A blood sample for analysis of NT-proBNP will be collected at Screening (V1) and the Final Visit to 
determine the extent of cardiac injury in patients receiving AZD1656 versus placebo. Frequency of 
testing to be clinically determined outside of specified timings in the SoA. If these tests are 
undertaken at more frequent intervals, r only results that are out of range AND considered clinically 
significant are to be recorded in the eCRF. 
 
10.4.3 
SARs-CoV-2 PCR test 
Nasopharyngeal swabs will be taken for SARs-CoV-2 PCR testing at the Screening Visit (V1) to 
confirm SARs-CoV-2 infection unless a test has been conducted within the previous 48 hours whose 
results are available. If the SARs-CoV-2 PCR test is negative, but the Investigator believes that the 
patient’s clinical picture strongly supports SARs-CoV-2 infection, the patient will continue on study.  
If a SARs-CoV-2 PCR test was negative and the patient entered the study based on a clinical 
diagnosis but the clinical condition of the patient changes to such an extent that the Investigator no 
longer considers the symptoms to be COVID-19 related, the patient should be withdrawn from the 


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AZD1656 
 
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study.  The frequency of testing is to be clinically determined and the results of any additional SARs-
CoV-2 PCR tests are to be recorded in the eCRF. 
 
10.4.4 
Immunophenotyping 
A blood sample for Immunophenotyping analysis will be taken at Day 1 (V2), Day 8, Day 11 and 
Day 21 (or day study end criteria are met). An Immunophenotyping panel to be conducted by Flow 
Cytometry to perform a group comparison (AZD1656 versus placebo) of levels of T, B and NK cells 
(including specific Treg and memory T cell populations); monocyte, neutrophil and eosinophil 
numeration to include activation markers for neutrophils (CD11b) and Monocytes subsets 
(CD14/CD16 identification including SLAN). 
 
10.4.5 
Immunochemistry 
A blood sample for Immunochemistry analysis will be taken at Day 1 (V2) , Day 8, Day 11 and Day 
21 (or day study end criteria are met).  Samples will be prepared according to the study laboratory 
manual for central laboratory assessment of the following biomarkers: G-CSF, GM-CSF, IL-1B, IL-
4, IL-6, IL-8, IL-10, IL-12, and MIP-1a.  The MSD U-Plex multiplex assay will be used for this 
assessment. 
 
10.4.6 
Demographics 
Patients’ demographics details will be collected in the eCRF including ethnicity. 
 
10.4.7 
Clotting Factor Analysis  
In order in investigate the impact of clotting factors on patient outcome (such as von Willebrand’s 
factor antigen), a small blood sample will be taken on Day 1 (V2) and on Day 8 and frozen at -70°C 
on site for future analysis (only sites with the ability to store samples in a -70°C freezer should 
collect this sample).  Patients will be given the option to ‘opt-in’ to this additional assessment during 
the consent process.  
 


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11. 
ADVERSE EVENTS 
Adverse events may be volunteered spontaneously by the patient, or discovered as a result of 
general, non-leading questioning.  All adverse events should be recorded in the Case Report Form. 
 
11.1.1 
Adverse Events that Do Not Require Reporting  
Emergence or worsening of symptoms or test parameters clearly associated with the clinical course 
of the underlying COVID-19 infection do not need to be recorded as adverse events. General 
deterioration or improvement in clinical status will be recorded as part of the primary outcome 
measure of the study using the WHO Ordinal Scale. Examples that would not be considered adverse 
events include, but are not limited to, neutropenia, high alkaline phosphatase levels, abnormal 
appearance in Chest X-ray, increased requirements for oxygen, introduction of continuous positive 
airway pressure (CPAP), or worsening shortness of breath. 
 
Pre-existing conditions will be captured in the Medical History, and only clinically significant 
exacerbation or worsening of symptoms (other than those clearly associated with the clinical course 
of the underlying COVID-19 infection) will be reported as an AE/SAE.  
 
Planned hospital admissions and/or surgery for pre-existing conditions will not be considered 
AEs/SAEs. 
 
Death due to progression of disease (COVID-19) will not be reported as an SAE as it will be 
recorded as an outcome. 
 
11.1.2 
Definitions 
Adverse Event (AE) 
 
Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment.  An adverse 
event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. See section 11.1.1 for adverse 
events that do NOT need to be recorded.  
 
Adverse Drug Reaction (ADR) 
 
All events considered to be untoward and unintended responses to a medicinal product related to any 
dose should be considered adverse drug reactions. The definition covers also medication errors and 
uses outside what is foreseen in the protocol, including misuse and abuse of the product. The phrase 
“responses to a medicinal product” means that a causal relationship between a medicinal product and 
an adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled out. 
 
 


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Serious Adverse Event (SAE) 
 
The Investigator is responsible for reporting all SAEs to the Sponsor, or its designated representative, 
immediately (within 24 hours of awareness). Any immediate reports should be followed promptly by 
detailed, written reports.  An SAE is an adverse event that at any dose: 
 
• Results in death 
• Is life-threatening (i.e. the patient was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe) 
• Requires in-patient hospitalisation or prolongation of existing hospitalisation (see explanation 
below) 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is considered to be an important medical event 
 
Based upon medical and scientific judgment, important medical events that may not be immediately 
life-threatening, or result in death or hospitalisation, but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above may be considered a 
serious adverse event. 
 
Hospitalisations are defined as initial or prolonged admissions that include an overnight stay. Since 
all patients participating in this trial are hospitalised throughout the trial, only those events resulting 
in prolongation of hospitalisation not associated with the underlying COVID infection may be 
considered as SAEs.  
 
Pregnancy 
 
Pregnancy itself is not considered an AE.  However, any pregnancy complication, spontaneous or 
elective abortion (for medical reasons), still birth, neonatal death, or congenital anomaly will be 
recorded as an AE or SAE. 
 
Any pregnancy that occurs during the course of the study or the follow-up period to a female study 
participant or to the female partner of a male subject, will be documented and reported by the 
Investigator within 24 hours of awareness. The pregnancy should be followed up until term (by 
Investigators) and if any Adverse Event occurs in conjunction with the pregnancy, this will be 
documented, assessed for seriousness, severity and causal relationship, and reported accordingly. 
The anticipated date of birth or termination of the pregnancy should be provided at the time of the 
initial report. 
 
Unexpected Adverse Reaction 
 
An adverse reaction, the nature or severity of which is not consistent with applicable product 
information (e.g., Investigator’s Brochure for an unapproved investigational medicinal product). 
 


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AZD1656 
 
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Reports which add significant information on the specificity, increase of occurrence, or severity of a 
known, already documented serious adverse reaction constitute unexpected events. 
 
The term ‘severity’ is used to describe the intensity of a specific event. This has to be distinguished 
from the term ‘serious’. 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
 
A serious adverse event that is suspected to be related to the administered medicinal product and the 
nature or severity of which is not consistent with applicable product information. 
 
A serious adverse reaction, the nature or severity of which is not consistent with applicable product 
information (e.g., Investigator’s Brochure for an unapproved investigational medicinal product). 
 
11.1.3 
Assessment of Severity and Causality 
Severity 
 
The severity (intensity) of each adverse event will be classified as: 
 
• Mild  
Awareness of sign or symptom, but easily tolerated 
• Moderate 
Sign or symptom causes discomfort, but does not interfere with normal             
 
 
activities 
• Severe  
Sign or symptom of sufficient intensity to interfere with normal activities 
 
Causality 
 
The likely relationship of each adverse event to the medicinal product will be assessed according to 
the definitions below: 
 
Unrelated  
• Time to drug intake that makes a relationship improbable  
• Disease or other drugs provide more plausible explanations 
• There are no facts or arguments to suggest a causal relationship 
Related  
• Plausible time relationship to drug intake 
• Unlikely to be attributed to disease or other drugs 
• Response to study drug withdrawal/ rechallenge clinically reasonable (if data available) 
• There are facts or arguments to suggest a causal relationship 
 


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11.1.4 
Outcome Categorisation 
All AEs should have an outcome recorded, which should be updated if it changes during the 
reporting period. The possible outcomes should be: 
• Fatal 
• Recovered/Resolved 
• Recovering/Resolving 
• Recovered/Resolved with sequalae 
• Not recovered/not resolved 
For fatal outcomes, every effort should be made to ensure source documentation (e.g. autopsy report, 
death certificate) to confirm the cause of death. In case this is not possible, the Investigator will 
apply medical judgement to identify and report the most likely cause of death. Only one event should 
be reported as having a fatal outcome, reporting the event which is considered to be the immediate 
cause of death. 
 
11.1.5 
Adverse Event Reporting 
St George Street Capital is required to expedite reports to worldwide regulatory authorities of 
Serious Adverse Events, Serious Adverse Drug Reactions or Suspected Unexpected Serious Adverse 
Reactions (SUSARs) in line with the relevant legislation, including the European Commission 
Clinical Studies Directive (2001/20/EC). 
 
All AEs (serious and non-serious) and any reports of pregnancy (either in a female participant or the 
female partner or a male participant) must be recorded by the Investigator from the time when patient 
signs the Informed Consent until 7 days after treatment discontinuation. 
 
All AEs will be recorded on the eCRF and assessed by the Investigator for seriousness (Section 11), 
severity (Section 11.1.3), and causality (Section 11.1.3). 
 
Refer to Section 11.1.1 for adverse events that do not require reporting. 
 
Any Serious Adverse Event will be reported by the Investigator immediately (within 24h) by mail or 
fax to: 
Email: safetyreporting@syneoshealth.com 
Fax: +1 877 464 7787 
 
For each Serious Adverse Event the following information should be collected and reported via SAE 
form (no hospital or patients’ related original documents to be shared):  
• Detailed patient data including medical history and concomitant medications 
• Detailed information about study treatment including timing and the dosing regimen 
• Exact documentation of the event including time of onset, signs and symptoms, relevant 
investigations, treatments applied, event outcome 
• Action taken with study treatment and the effects of the dechallenge and rechallenge  


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• Details of the clinical course and the outcome of the event 
• Any data contributing for the causal relationship assessment of the SAE 
 
Each Adverse Event should be followed up until final outcome. Events that are not resolved by the 
end of the study or patient’s death will be recorded as ongoing. 
 
Assessment of event seriousness, severity and causality will be performed and reported by the 
Investigator with the initial notification.  The assessment should be based on the available 
information even if insufficient and can be updated when new information is available.  
 
Once the event is received by the Sponsor or Sponsor representative, the Sponsor or Sponsor 
representative’s physician will assess causality and expectedness based on the available information 
and the applicable reference safety information. The causality assessment given by the Investigator 
will not be downgraded by the Sponsor. If the Sponsor disagrees with the Investigator’s causality 
assessment, the opinion of both the Investigator and the Sponsor will be provided with the report. 
 
Abnormal findings from laboratory tests, ECG records, imaging investigations and patients’ vital 
signs will be assessed by the Investigator and if considered clinically significant and satisfying the 
definition for an Adverse Event, will be reported accordingly. If abnormal investigational findings 
are associated with clinical symptoms, then the diagnosis should be reported as an AE rather than 
reporting the abnormal finding. 
 
The Investigator will apply medical judgement and whenever possible will report a diagnosis as an 
event term, rather than individual signs and symptoms. However, if at the time of reporting the 
presented signs and symptoms cannot be medically characterised as a single diagnosis or medical 
concept, these can be recorded as Adverse Events. When the diagnosis is subsequently established, 
all previously reported AEs based on signs and symptoms will be nullified and replaced by a single 
AE report with onset date corresponding to the starting date of the first symptom. 
 
Occurrences that are secondary to other events (clinical sequelae) will not be reported separately but 
identified by their primary cause. As an exception, a severe or serious secondary event, or a 
medically significant secondary occurrence that is separated in time from the initiating event, will be 
reported as an independent Adverse Event. 
 
Any occurrence of overdose will be reported as an AE. Any signs or symptoms resulting from an 
overdose will also be recorded as AEs and assessed by the Investigator for seriousness, severity, and 
causality. 
 
Death is considered an outcome and is to be avoided as an event term. The Investigator will identify 
the event or condition that caused the patient’s death and will report accordingly as an event with 
fatal outcome. Only one AE will be reported as having fatal outcome. In case the death is attributed 
to progression of the baseline disease, the AE term should be reported as Disease Progression. 
 
All Investigators will receive a safety letter notifying them of relevant SUSAR reports.  In 
accordance with the European Commission Directive 2001/20/EC, St George Street Capital or their 


Investigational product:  
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Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
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 FINAL 2.0 (Global) 
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21 December 2020 
 
 
appropriately qualified designee will notify the relevant Ethics Committees in concerned Member 
states of applicable SUSARs as individual notifications or through a periodic line listing. 
 
St George Street Capital or their appropriately qualified designee will submit to the regulatory 
authorities all safety updates and periodic reports, as required by applicable regulatory requirements. 
  
11.1.6 
Notification of AEs of Special Interest 
There are no Adverse Events of Special Interest for this trial.  
 
11.1.7 
Urgent Safety Measures 
The PI may take urgent safety measures to ensure the safety and protection of the clinical trial 
subjects from any immediate hazard to their health and safety. The measures can be taken 
immediately, however, it is the responsibility of the PI to attempt, where possible, to discuss the 
proposed measures with the Sponsor and Medical Advisor at the MHRA (via telephone) prior to 
implementation.  If not possible to discuss prior to implementation, the Sponsor must be informed as 
soon as possible (same day) of the measures being taken in order that the Sponsor can inform both 
the MHRA and Independent Ethics Committee in writing within 3 days of the urgent safety measure 
being taken.  


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AZD1656 
 
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12. 
STATISTICAL CONSIDERATIONS 
Details of all planned analyses will be specified in a separate statistical analysis plan (SAP) which 
will be finalised prior to hard-lock of the study database. The SAP will contain details of all the 
analyses including specifications for all tables, listings and figures. The SAP will include the 
definition of major and minor protocol deviations and the link of major protocol deviations to the 
analysis sets. All statistical programming will be performed using SAS software version 9.4 or 
higher. 
 
12.1 
Estimated Sample Size 
Approximately 165 patients will be screened to achieve 150 randomly assigned patients to AZD1656 
or placebo for an estimated total of 75 evaluable patients per group.  Approximately 35 trials sites in 
the UK, Czech Republic and Romania will recruit the 150 randomised patients. 
 
A two group χ² test with a 5% two-sided significance level will have 76.74% power to detect the 
difference between a placebo proportion of 0.6 and an AZD1656 proportion of 0.8 when the sample 
size is 150 (75/group). In the case that the portion of placebo patients meeting WHO categories 1-3 
or live discharge at Day 14 is higher (0.65), then the power to find a similar 20 percentage point 
increase would be 81.4%. 
 
12.2 
Study Populations 
Full Analysis Set (FAS) 
The FAS or intention-to-treat population includes all randomised patients who receive at least one 
dose of assigned treatment. Following the intent-to-treat principle, patients will be analysed as 
randomised. This will be the primary analysis set for primary and key secondary endpoints. 
  
Per-Protocol Set (PPS) 
The PPS includes all patients of the FAS without major protocol deviations. Patients will be 
excluded from the PPS for the following reasons:  
• Any major deviation from exclusion / inclusion criteria. 
• Other major protocol deviations as identified at the blinded data review meeting. 
Patients to be excluded from the PPS will be identified and reviewed at the blinded data review 
meeting held before unblinding of the study. 
 
The PPS will be used for sensitivity analyses for primary and key secondary analyses. 
  
Safety Set (SAF) 
The SAF, also known as “treated population”, 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). The assignment of patients to the treatment 
groups will be as actually treated. 
  


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AZD1656 
 
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The SAF is the primary analysis set for all safety analyses. 
  
Pharmacokinetic Analysis Set 
The PK analysis set includes all patients who received a single dose of AZD1656 and have at least 
one post-dose PK measurement. 
  
The PK analysis set is the primary analysis set for pharmacokinetic analyses. 
 
12.3 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be analysed descriptively. Full details of the planned 
statistical analyses will be described in the trial SAP. 
 
12.4 
Statistical Methods for Efficacy Parameters 
Primary, key secondary and exploratory efficacy parameters will be displayed descriptively, and 
appropriate tests are conducted on the treatment impact. Full details of the planned statistical 
analyses will be described in the trial SAP.  
 
12.5 
Statistical Methods for Safety Parameters 
Safety parameters will be analysed descriptively. Full details of the planned statistical analyses will 
be described in the trial SAP 
 
12.6 
Handling Missing, Unused or Spurious Data 
 As enrolled patients will be hospitalised for the duration of the trial, it is not expected that any will 
be lost to follow up. However, should this occur, the Investigator will make every effort to rectify 
any missing or spurious data. If a patient leaves the hospital without being formally discharged and is 
lost to follow-up, the last post-baseline observation carried forward will be used to impute results for 
this patient.  In the event that a patient is lost to follow-up without having recorded at least one post-
baseline value, that patient will be considered a non-responder.   
  
For specific sensitivity and robustness analyses for the primary and key secondary efficacy variables, 
missing data are imputed. Full details of the planned routines will be described in the trial statistical 
analysis plan. 
  
Missing start and end date/times of adverse events will be imputed conservatively. Full details of the 
planned routines will be described in the trial SAP. 
 
Two blinded interim analyses will be conducted for the Safety Review Committee. Full details of the 
planned statistical analyses will be described in the trial SAP. 
 
 


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13. 
END OF THE STUDY 
The end of the study is defined as the last subject’s last study assessment, which for this protocol is 
the final visit which will occur at death or 7 days after discontinuation of study treatment. 


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14. 
ETHICS COMMITTEE REVIEW 
 
14.1 
Independent Ethics Committee (IEC) and Relevant Authorities 
The final study protocol and the patient information and consent form will be approved by an 
appropriately constituted IEC.  Approval will be received in writing before initiation of the study. 
 
Clinical Study Authorisation will be obtained prior to initiation of the study from the relevant 
Regulatory Authority. 
 
14.2 
Ethical Conduct of the Study 
The study will be performed in accordance with the local regulations, the principals of GCP as 
described by the ICH, and the ethical principles that have their origins in the Declaration of Helsinki. 
 
The Investigator agrees to the terms and conditions relating to this study as defined in the protocol, 
eCRF and any other protocol-related documents ad agrees to conduct the trial in accordance with the 
protocol. The Investigator fully understands that any changes without previous agreement with the 
Sponsor would constitute a violation of the protocol, including any ancillary studies or procedures 
performed on study subjects/patients (other than those procedures necessary for the wellbeing of the 
subjects/patients). 
 
Any breach of the protocol which is likely to affect to a significant degree the safety and rights of a 
subject or the reliability and robustness of the data generated in the clinical trial will be reported by 
the Sponsor as a Serious Breach. 
 
14.3 
Protocol Amendments 
Any amendments to the protocol will require IEC and Regulatory Authority approval before 
implementation of changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study patients. 
  
 
 


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15. 
STUDY AND DATA MANAGEMENT 
 
15.1 
Monitoring 
The Investigator and institution will permit study-related monitoring, providing direct access to 
source data/documents (on-site and/or remotely), in compliance with local regulations and 
guidelines. 
 
Study monitors will perform ongoing source data verification to confirm that data entered into the 
eCRF by authorised site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of patients are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, ICH/GCP, and all 
applicable regulatory requirements. 
 
The Investigator and Co-investigators agree to cooperate with the monitor(s) to ensure that any 
issues detected in the course of monitoring visits are resolved.  
 
Monitoring will include both remote and on-site visits when this is permitted in line with national 
and local guidelines during the COVID-19 pandemic. An initiation visit will be performed at each 
site before the first subject is included. Initiation visits may be conducted remotely.  Monitoring 
visits and contacts will occur at regular intervals thereafter. A close-out visit will be performed after 
the database lock and resolution of all pending queries and follow-up of ongoing AEs/SAEs.  Full 
details of the study monitoring procedures to be employed in this trial will be detailed in the 
Monitoring Plan. 
 
15.2 
Quality Assurance 
The Sponsor may conduct audits of clinical research activities in accordance with its internal Quality 
System to evaluate compliance with the protocol and the principles of ICH GCP. Health Authorities 
may also wish to conduct an inspection (during the study or after its completion). Should an 
inspection be requested by Health Authorities, the Investigator must inform the Sponsor immediately 
that such request has been made.  The Investigator will permit such audits by St George Street 
Capital or Health Authorities and facilitate them by providing access to the relevant source 
documents. 
 
15.3 
Data Recording 
15.3.1 
Data to be Considered as Source Data 
The Investigator should maintain adequate and accurate source documents and trial records that 
include all pertinent observations on each of the site’s trial subjects.  Source data should be 
attributable, legible, contemporaneous, original, accurate, and complete (‘ALCOAC principles’).  
Changes to source data should be traceable, should not obscure the original entry and should be 
explained if necessary (e.g., via an audit trail). 


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For this study, source data can include, but is not limited to: medical records, study specific source 
sheets (as applicable), laboratory reports, laboratory sample collection forms, ECG traces and 
clinician correspondence. Source data can be recorded electronically or on paper. Electronic records 
must be in a validated system that allows ALCOAC principles to apply. Source documents are filed 
at the site. 
 
 
15.4 
Case Report Form 
An electronic Case Report Form (eCRF) using the Medidata Rave Electronic Data Capture (EDC) 
system will be used to capture subject data. Access to enter data in the eCRF will be limited to 
delegated and trained Investigator site staff only. 
 
Data in the eCRF will be verified by monitors according to a risk-appropriate monitoring strategy.  
Subject confidentiality will be maintained at all times during the monitoring process.  
 
 
15.5 
Confidentiality 
The Investigator must assure that the patient’s anonymity will be maintained.  On all study 
documentation, with the exception of the consent form and patient ID logs, patients will only be 
identified by their unique identification code and will not be referred to by name. Documents 
identifying the patients (e.g., signed informed consent forms) must not be sent to St George Street or its 
representatives and must be kept by the Investigator in strict confidence. 
 
The patient must be informed that his/her personal study-related data will be used by the Sponsor in 
accordance with local data protection law. The level of disclosure must also be explained to the 
patient. 
 
The Sponsor may transfer some data collected during the study to a different company or regulatory 
authority within/outside Europe for the purpose of processing, review, analysis or storage.  
Whenever the patient’s personal data is transferred, it will be kept confidential and secure, and will 
be used only for the purpose for which it was collected. 
 
15.6 
Retention of Study Data 
Following closure of the study, the Investigator must maintain all site study records, except for those 
required by local regulations to be maintained by someone else, in a safe and secure location. The 
records must be maintained to allow easy and timely retrieval, when needed (e.g., audit or 
inspection), and, whenever feasible, to allow any subsequent review of data in conjunction with 
assessment of the facility, supporting systems, and staff. Where permitted by local laws/ regulations 
or institutional policy, some or all of these records can be maintained in a format other than hard 
copy (e.g., microfiche, scanned, electronic); however, caution needs to be exercised before such 
action is taken. The Investigator must assure that all reproductions are legible and are a true and 
accurate copy of the originals, and meet accessibility and retrieval standards, including re-generating 
a hard copy, if required. Furthermore, the Investigator must ensure there is an acceptable back-up of 


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these reproductions and that an acceptable quality control process exists for making these 
reproductions. 
St George Street Capital will inform the Investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements. The minimum retention time will meet the 
strictest standard applicable to that site for the study, as dictated by any institutional requirements or 
local laws or regulations, or St George Street Capital or delegated CRO’s SOPs; otherwise, the 
retention period will default to 25 years. 
 
The Investigator must notify St George Street Capital of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership of the records in 
the event the Investigator leaves the site. The Investigator may not dispose of any records without 
prior approval from St George Street Capital. 
 
15.7 
Communication and Publication of Results 
This study will be registered in the EudraCT database and study results will be posted in accordance 
with the applicable laws and regulations. A clinical study report will be developed at completion of 
data analysis according to ICH E3 guidelines submitted to EudraCT in accordance with the required 
timelines according to The European Clinical Trials Directive 2001/20/EC. 
 
The Sponsor will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of multicentre 
studies only in their entirety and not as individual site data. Authorship will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
 
The Investigator has the right to publish study results from his/her specific site.  If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
However, any publication that includes St George Street Capital confidential information cannot be 
submitted for publication without St George Street Capital’s prior written approval. 
 
Both authors and publishers have ethical obligations. In publication of the results of research, the 
investigators are obliged to preserve the accuracy of the results. Negative as well as positive results 
should be published or otherwise publicly available. Sources of funding, institutional affiliations and 
any possible conflicts of interest should be declared in the publication. Reports of experimentation 
not in accordance with the principles laid down in this Declaration should not be accepted for 
publication. 
 
15.8 
Indemnification 
In the event of study-related damage or injuries, the public liability insurance of the Sponsor 
provides compensation for claims that arise in accordance with the regulatory requirements of the 
country involved, except for claims that arise from wilful misconduct or gross negligence. A copy of 
the insurance certificates will be held in the Trial Master File and in the Investigator Site File. 
 


Investigational product:  
CONFIDENTIAL 
Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
Protocol No.: SGS.1656.201 
 FINAL 2.0 (Global) 
Page 56 of 65 
21 December 2020 
 
 
15.9 
Study and Site Closure 
The Sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the Sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been collected 
and a study-site closure visit has been performed.  
 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.  
 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are not 
limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• Discontinuation of further study treatment development 
 


Investigational product:  
CONFIDENTIAL 
Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
Protocol No.: SGS.1656.201 
 FINAL 2.0 (Global) 
Page 57 of 65 
21 December 2020 
 
 
 
16. 
STRUCTURED RISK BENEFIT ANALYSIS 
This section provides a structured benefit risk assessment for AZD1656, categorised and summarised 
in an overall assessment of potential risks for study participants.  For AZD1656 effects discussed in 
the sections below, references were made to the Investigator’s Brochure. 
16.1 
Rationale for Dose and Treatment Period  
The total daily dose and treatment period in this study (100 mg BID for a maximum of 21 days) is 
within the higher dose range and lower treatment duration shown to be safe and effective at lowering 
blood glucose in prior clinical studies. Patients with type 2 diabetes have been administered single 
oral doses up to 450 mg; and daily doses of up to 200 mg have been given to patients with type 2 
diabetes for up to 6 months’ duration as an add-on to metformin.  
The selected dose was tested in previous clinical studies and hence this dose is considered 
scientifically and medically appropriate to investigate the immunomodulatory mode of action of 
AZD1656.  There is no evidence to suggest that the pharmacodynamic effect of AZD1656 on the 
immune system (and specifically on Treg migration) will be different to that for glucose lowering 
and so a dose with a good safety profile that is known to effectively lower glucose has been selected 
to test the hypothesis.   
We have chosen not to start at a lower dose and subsequently up-titrate the dose given the proposed 
immunomodulatory mechanism of action of AZD1656 whereby early mobilisation of regulatory T 
cells is required to prevent or ameliorate the cytokine storm that can occur in COVID-19 patients.   
 
16.2 
Previous Exposure in Humans 
Twenty-five clinical studies have been completed to evaluate the safety, tolerability, PK, PD and 
drug interactions with AZD1656. Approximately 960 subjects have been exposed to AZD1656 for 
up to 6 months’ duration, including in an out-patient setting.  In the completed clinical studies to 
date, AZD1656 has been well tolerated with some low risk of hypoglycaemia. The risk for 
hypoglycaemia was higher on AZD1656 as compared to placebo, but lower than for Sulfonylurea 
(glipizide). No other safety issues have been identified for AZD1656 from the completed Phase I to 
IIb programme. No safety signals have been identified regarding vital signs, ECG, weight, BMI and 
physical findings.  There have been no treatment related changes in safety laboratory variables 
including muscle biomarkers and liver function tests in Phase I to IIa. From the few cases with 
increased liver enzymes in Phase IIb, a minor increase from AZD1656 treatments could not be 
excluded. There was clinical improvement in fasting blood sugar and HbA1C levels in the first few 
months of treatment with AZD1656. 
 
16.3 
Pharmacokinetic Considerations 
Extensive PK analysis has been conducted to date, so in this trial only steady state PK will be 
assessed. 
 


Investigational product:  
CONFIDENTIAL 
Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
Protocol No.: SGS.1656.201 
 FINAL 2.0 (Global) 
Page 58 of 65 
21 December 2020 
 
 
 
16.4 
Drug-Drug Interaction 
AZD1656 is mainly metabolised via CYP2C8, therefore potent inhibitors of CYP2C8 (e.g. 
gemfibrozil) may increase exposure to this drug (AUC). Other than inhibitors of CYP2C8, no 
significant drug-drug interactions have been reported in phase I/II clinical trials; however there may 
be drug-drug interactions that are as yet unknown. 
 
16.5 
Predictability of Effect in Patients with COVID-19  
Across prior phase I and II clinical studies, AZD1656 has been well tolerated and no safety concerns 
have been raised to date. Except for reduced blood glucose, the pattern of reported adverse events 
(AEs) during treatment with AZD1656 is not clearly different to placebo. The most common AEs 
reported on AZD1656 treatment in Phase IIb were infections, gastrointestinal events and CNS related 
events.  
 
The risk for hypoglycaemia is low based on the data from the previous diabetes studies with 
AZD1656.  Few hypoglycaemic events have been reported and only rarely with a plasma glucose 
level below 3 mmol/L (54 mg/dL). Low glucose levels were either asymptomatic (detected in 
scheduled measurement) or associated with mild symptoms, and in all cases manageable by the 
patients. All events with low plasma glucose have responded rapidly to carbohydrate intake.  
 
In this study all those on study treatment will be in-patients, receiving hospital care.  If a patient’s 
blood glucose control is considered by their clinical team to be too high or low, then their regular 
diabetic medications will be altered to achieve diabetic control targets as per usual care. If recurrent 
hypoglycaemia occurs despite removal of other diabetic medications, then the study medication will 
be withdrawn as per the study withdrawal criteria.  
 
No safety signals have been identified in prior studies regarding vital signs, ECG, weight, BMI and 
physical findings.  There have been no treatment related changes in safety laboratory variables 
including muscle biomarkers and liver function tests in Phase I to IIa. From the few cases with 
increased liver enzymes in Phase IIb, a minor increase from AZD1656 treatments could not be 
excluded.  Any patient with any non-COVID-19, non-diabetes related, serious condition will be 
excluded from participation in the trial. 
 
16.6 
Benefit Risk Assessment 
Diabetes mellitus is estimated to affect almost 7% of all adults worldwide. Despite the range of 
treatment choices (including lifestyle interventions), many patients with T2DM fail to achieve 
adequate glycaemic control, even when multiple drugs are taken. AZD1656, being a selective 
glucokinase activator, has the potential to provide an effective glycaemic control in monotherapy as 
well as in combination with other anti-diabetic drug classes.  
 
In addition to its glucose lowering effect, AZD1656 may have additional benefits to COVID-19 
patients which involve its effects on immune function and may prevent the development of 
cardiorespiratory complications observed in hospitalised patients with COVID-19, leading to lower 


Investigational product:  
CONFIDENTIAL 
Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
Protocol No.: SGS.1656.201 
 FINAL 2.0 (Global) 
Page 59 of 65 
21 December 2020 
 
 
requirements for oxygen therapy and assisted ventilation, and reduced incidences of pneumonia and 
acute respiratory distress syndrome (ARDS). To date no safety risks have been identified in prior 
clinical studies with the exception of a low risk of hypoglycaemia.  
 
During the conduct of this trial every effort will be made to minimise potential risk(s) to patients 
participating in this study. Adequate minimisation measures have been put in place to ensure that 
participating patients will not be exposed to an unacceptable risk throughout the study. 
 
The risk of hypoglycaemia or hyperglycaemia will be mitigated by usual care for hospitalised 
diabetic patients including frequent blood glucose measurements and clinical monitoring including 
physical examination, laboratory tests, as well as clinical correlation to treatment and AE collection. 
 
The current risk analysis supports the initiation of a clinical trial in diabetic patients with COVID-19 
to investigate the safety, efficacy, immunological and pharmacokinetic effects of this novel IMP in 
order to further develop AZD1656 as a potential treatment option for this vulnerable patient group. 
 


Investigational product:  
CONFIDENTIAL 
Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
Protocol No.: SGS.1656.201 
 FINAL 2.0 (Global) 
Page 60 of 65 
21 December 2020 
 
 
 
17. 
REFERENCES 
Chen et al (2020) 
Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in 
Wuhan, China: a descriptive study. 
The Lancet 2020;395: 507-513 
 
The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team (2020) 
The Epidemiological Characteristics of an Outbreak of 2019 Novel Coronavirus Diseases (COVID-
19) — China.  
China CDC Weekly 2020;2 (8):113-22 
 
D’Alessio et al (2009) 
CD4+CD25+Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with 
acute lung injury. 
The Journal of Clinical Investigation 2009;119(10):2898-2913 
 
Docherty et al (2020) 
Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical 
Characterisation Protocol: prospective observational cohort study. 
BMJ 2020; 369:1-12 
 
Fisher et al (2019) 
The role of vitamin D in increasing circulating T regulatory cell numbers and modulating T 
regulatory cell phenotypes in patients with inflammatory disease or in healthy volunteers: A 
systematic review. 
PLoS One. 2019; 14(9): 1-18 
 
Guan et al (2020) 
Clinical Characteristics of Coronavirus Disease 2019 in China. 
The New England Journal of Medicine, Feb 28 2020; (https//DOI: 10.1056/NEJMoa2002032 
 
Guan W-jie, Liang W-hua, Zhao Y, et al (2020) [2] 
Comorbidity and its impact on 1590 patients with Covid-19 in China: A Nationwide Analysis. 
Eur Respir J 2020; in press (https://doi.org/10.1183/13993003.00547-2020) 
 
Halter et al (2020) 
T regulatory cells activation and distribution are modified in critically ill patients with acute 
respiratory distress syndrome: A prospective single-centre observational study. 
Anaesthesia Critical Care & Pain Medicine 2020;31(1):35-44 
 
M. Kishore, K. Cheung, H. Fu, V. De Rosa, G. Norata, F. Marelli-Berg (2017) 
Regulatory T Cell Migration Is Dependent on Glucokinase-Mediated Glycolysis. 
Immunity 2017;47(5):875-889 
 


Investigational product:  
CONFIDENTIAL 
Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
Protocol No.: SGS.1656.201 
 FINAL 2.0 (Global) 
Page 61 of 65 
21 December 2020 
 
 
A. Kiyosue, N. Hayashi, H. Komori, M. Leonsson-Zachrisson & E. Johnsson (2013) 
Dose-ranging study with the glucokinase activator AZD1656 as monotherapy in Japanese patients 
with type 2 diabetes mellitus. 
Diabetes, Obesity and Metabolism 2013;15(10):923-930 
 
A. Pietropaoli & S. Georas (2009) 
Resolving lung injury: a new role for Tregs in controlling the innate immune response. 
The Journal of clinical investigation 2009;119(10); 2891-2894 
 
Valabhji et al (2020) 
Type 1 and Type 2 diabetes and COVID-19 related mortality in England: a cohort study in people 
with diabetes. 
Pre-print, 19th May 2020. 
 
Wang D et al (2020) 
Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected 
Pneumonia in Wuhan, China. 
JAMA 2020;323(11):1061-1069 
 
J. P. H. Wilding, M. Leonsson-Zachrisson, C. Wessman & E. Johnsson (2013) 
Dose-ranging study with the glucokinase activator AZD1656 in patients with type 2 diabetes mellitus 
on metformin. 
Diabetes, Obesity and Metabolism 2013;15(8):750-759 
 
Yu et al (2015) 
The ratio of Th17/Treg cells as a risk indicator in early acute respiratory distress syndrome. 
Critical Care 2015;19(1): 82 
 
Zhou et al (2020) 
Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a 
retrospective cohort study. 
Lancet 2020;395: 1054–1062 
 
Zhu et al (2020) 
Association of Blood Glucose Control and Outcomes in Patients with COVID-19 and Pre-existing 
Type 2 Diabetes. 
Cell Metabolism 2020;31, 6: 1068–1077 
 


Investigational product:  
CONFIDENTIAL 
Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
Protocol No.: SGS.1656.201 
 FINAL 2.0 (Global) 
Page 62 of 65 
21 December 2020 
 
 
 
18. 
SIGNATURES AND AGREEMENT WITH THE PROTOCOL 
Sponsor Approval 
 
I have reviewed and approved the protocol and confirm that the protocol follows GCP. 
 
 
 
 
 
 
 
 
Signature: 
                                           
 
Date:                                          
 
 
James Chorlton 
 
 
Head of Clinical Development, St George Street Capital 
 
 
 
 
 
 
 
 
Signature: 
                                           
 
Date:                                          
 
 
Dr Kathryn Owen 
 
 
Consultant Physician, St George Street Capital 
 
22-Dec-2020 | 05:38 PST
21-Dec-2020 | 23:46 PST


Investigational product:  
CONFIDENTIAL 
Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
Protocol No.: SGS.1656.201 
 FINAL 2.0 (Global) 
Page 63 of 65 
21 December 2020 
 
 
Coordinating Investigator Approval 
 
I agree to conduct the study according to the terms and conditions of this protocol, current Good 
Clinical Practice and with applicable regulatory requirements. All information pertaining to the 
study shall be treated in a confidential manner. 
 
 
 
 
 
 
 
 
Signature: 
                                           
 
Date:                                          
 
 
Dr Kieran McCafferty 
 
 
Consultant Nephrologist, Bart’s Health NHS Trust 
 
 
 
 
 
 
 
22-Dec-2020 | 00:20 PST


Investigational product:  
CONFIDENTIAL 
Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
Protocol No.: SGS.1656.201 
 FINAL 2.0 (Global) 
Page 64 of 65 
21 December 2020 
 
 
Principal Investigator Approval 
 
 
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 
 
 
EudraCT No: 2020-002211-21 
 
Protocol No.: SGS.1656.201 
 
 
 
I agree to conduct the study according to the terms and conditions of this protocol, current Good 
Clinical Practice and with applicable regulatory requirements. All information pertaining to the 
study shall be treated in a confidential manner. 
 
 
 
 
 
 
 
Signature: 
                                           
 
Date:                                          
 
 
Name of Principal Investigator 
 
 
Title 
 
 


Investigational product:  
CONFIDENTIAL 
Protocol No.: SGS.1656.201 
AZD1656 
 
St George Street Capital 
 
 
Protocol No.: SGS.1656.201 
 FINAL 2.0 (Global) 
Page 65 of 65 
21 December 2020 
 
 
APPENDICES 
Appendix 1: WHO Ordinal Scale for Clinical Improvement (COVID-19 trials, February 18th 
2020) 
 
Patient State 
Descriptor 
Score 
Uninfected 
No clinical or virological evidence 
of infection 
0 
Ambulatory 
No limitation of activities 
1 
 
Limitation of activities 
2 
Hospitalised (Mild disease) 
Hospitalised, no oxygen therapy 
required 
3 
 
Hospitalised, oxygen therapy by 
mask or nasal prongs 
4 
Hospitalised (Severe disease) 
Non-invasive ventilation or high 
flow oxygen 
5 
 
Intubation 
and 
mechanical 
ventilation 
6 
 
Ventilation and additional organ 
support – pressors, RRT, ECMO 
7 
Dead 
Death 
8 
 


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SAP_001.pdf: 
 
 
QMS Document Name: Statistical Analysis Plan 
Page 1 of 34 
QMS No (include version ref): STF-015-GL.02 
Document date: 09JUL2019 
CONFIDENTIAL 
 
 
 
 
 
 
 
Protocol No: SGS.1656.201 
CP Project ID: SGS20201 
 
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. 
 
 
 
 
Statistical Analysis Plan 
Safety analyses for SRC 
Final analysis 
Version: v5.0 
(Post Database Lock and Post Unblinding) 
Date: 27JUL2021 
 
 
 
 
 
 




 
Protocol No.: SGS.1656.201 
CP Project ID: SGS20201   
Version: v5.0 
Version Date: 27JUL2021 
Statistical Analysis Plan: Safety for SRC & Final  
 
 
QMS Document Name: Statistical Analysis Plan 
Page 3 of 34 
QMS No (include version ref): STF-015-GL.02 
Document date: 09JUL2019 
CONFIDENTIAL 
 
 
Table of Contents 
 
 
1 
Introduction .................................................................................................................................... 5 
1.1 
Preface ................................................................................................................................... 5 
1.2 
Timing of statistical analyses ................................................................................................. 5 
2 
Modification History ....................................................................................................................... 5 
2.1 
Changes to the study protocol .............................................................................................. 5 
2.2 
Changes to previous SAP versions ......................................................................................... 6 
3 
Study Design.................................................................................................................................... 8 
3.1 
Sample size estimation ........................................................................................................ 10 
3.2 
Randomisation, blinding and unblinding procedures ......................................................... 10 
4 
Analysis Sets .................................................................................................................................. 10 
5 
General Statistical Methods and Definitions ................................................................................ 12 
5.1 
General statistical methods ................................................................................................ 12 
5.2 
Covariates and strata .......................................................................................................... 13 
5.3 
Missing data ........................................................................................................................ 13 
5.4 
Observation and analysis times........................................................................................... 14 
5.5 
Multiple Comparison/Multiplicity ....................................................................................... 15 
6 
Patient Accounting and Disposition .............................................................................................. 15 
6.1 
Patient accounting .............................................................................................................. 15 
6.2 
Disposition and withdrawals ............................................................................................... 15 
6.3 
Minor and Major protocol deviations ................................................................................. 16 
7 
Demographics and Background Characteristics ........................................................................... 16 
7.1 
Demographics and baseline characteristics ........................................................................ 16 
7.2 
Medical history .................................................................................................................... 17 
7.3 
Previous and Concomitant Medications ............................................................................. 17 
8 
Exposure and Compliance ............................................................................................................. 18 
8.1 
Treatment groups ................................................................................................................ 18 
8.2 
Treatment duration ............................................................................................................. 18 
8.3 
Dosage ................................................................................................................................. 18 
8.4 
Compliance .......................................................................................................................... 18 
9 
Pharmacokinetics .......................................................................................................................... 18 


 
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10 Efficacy .......................................................................................................................................... 18 
10.1 Primary efficacy analysis ..................................................................................................... 18 
10.2 Secondary efficacy analyses ................................................................................................ 21 
10.3 Other efficacy analyses ....................................................................................................... 25 
11 Safety ............................................................................................................................................ 26 
11.1 Adverse events .................................................................................................................... 26 
11.2 Vital signs and oxygen saturation........................................................................................ 27 
11.3 Clinical safety laboratory ..................................................................................................... 28 
11.4 ECG ...................................................................................................................................... 28 
11.5 Chest X-Ray or Chest CT Scans ............................................................................................ 29 
11.6 Oxygen Therapy................................................................................................................... 29 
11.7 Physical examination ........................................................................................................... 29 
11.8 Childbearing potential and pregnancies ............................................................................. 29 
12 Interim analysis ............................................................................................................................. 29 
13 Statistical Analyses for Safety Monitoring .................................................................................... 29 
14 Statistical Analyses for Clinical Trial Registries ............................................................................. 29 
15 Data Exchange Procedures ........................................................................................................... 30 
16 Software ........................................................................................................................................ 30 
17 Abbreviations ................................................................................................................................ 30 
18 References .................................................................................................................................... 31 
Appendix I: Normal ranges for vital signs, oxygen saturation and body temperature for 
adults ............................................................................................................................... 32 
Appendix II: Multiple imputation for the longitudinal robustness analysis of the primary 
efficacy analysis ............................................................................................................... 33 
Appendix III: Alert ranges for selected laboratory values ............................................................. 34 
 
 
 


 
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1 
Introduction 
1.1 
Preface 
The objective of this document is to detail the statistical methodology to be used for the final 
statistical analysis of study ARCADIA. 
The statistical analysis plan is based on the following information and documents: 
Study Protocol 
03JUL2020 – Version 1.0 
21DEC2020 – Version 2.0 
Amendments to Study 
Protocol / Observational Plan 
none 
 
SRC Charter 
30JUL2020 – Version 1.0 
09FEB2021 – Version 2.0 
PD Plan 
06AUG2020 – Version 1.0 
05JAN2021 – Version 2.0 
Statistical Analysis Plan for the 
Interim Analyses 
not applicable 
1.2 
Timing of statistical analyses 
The following statistical analyses are planned for this study: 
▪ 
Safety analyses: as per SRC charter, two safety analyses for the SRC after 40 and 60 patients 
have completed the study, respectively. 
▪ 
Final analysis: one final analysis after the last patient has completed the study and the 
database is locked 
2 
Modification History 
2.1 
Changes to the study protocol 
The statistical analyses as specified in this statistical analysis plan (SAP) cover all statistical analyses 
as specified in the study protocol except the clotting factor analysis. 
In the exploratory endpoints of the protocol synopsis, the correlation of clinical outcomes with 
patient ethnicity or with vitamin D level is requested. As a correlation cannot be calculated for a 
nominal scaled variable (ethnicity), these analyses will be conducted as subgroup analyses of the 
primary analysis. 
This SAP further describes these new analyses: 
Primary efficacy endpoint  


 
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▪ 
Validity, sensitivity and robustness analyses 
Secondary efficacy endpoints 
▪ 
Proportion of patients being discharged alive from hospital 
▪ 
Proportion of patients receiving intubation/mechanical ventilation 
Exploratory efficacy endpoints 
▪ 
Subgroup analyses of the primary analysis for subgroups sex, age group, diabetes type and 
site. 
2.2 
Changes to previous SAP versions 
Due to the protocol version 2.0 update and due to the possibility of patients being discharged from 
hospital whilst still on oxygen, SAP version 2.0 has these modifications compared to SAP version 1.0: 
1. Disposition is additionally stratified by country, i.e. UK, Czech Republic, and Romania. 
2. Subgroup levels are specified in section 5.2 Covariates and strata. 
3. Primary efficacy endpoint ‘clinical improvement’: Patients who have been discharged alive 
from hospital with WHO OSCI rating of 4 due to triage are set to missing. 
4. Sensitivity analysis with the Bradley-Terry model: if a patient is discharged alive from hospital, 
requires intubation or mechanical ventilation, or dies earlier than Day 14, the last WHO OSCI 
observation will be carried forward (LOCF) until Day 14. This imputation is added as almost all 
patients have no Day 14 assessment. 
5. A tipping point sensitivity analysis is added for the unplanned scenario that ill patients are 
discharged from hospital to get capacity for worse patients. 
6. Secondary efficacy endpoint ‘proportion of patients being discharged from hospital’: Patients 
who have been discharged alive from hospital with WHO OSCI rating of 4 due to triage are set 
to missing. 
7. Secondary efficacy endpoint ‘time from hospital admission to hospital discharge’: Patients 
who have been discharged alive from hospital with WHO OSCI rating of 4 due to triage are 
censored at discharge day and time. 
8. Alert ranges for selected laboratory values have been defined. Values within sponsor-defined 
alert ranges will be presented in a new listing. 
SAP version 3.0 has these modifications compared to SAP version 2.0: 
1. Update of country and region analyses. 
2. Rewording of the follow-up period. 
3. Update of the treatment duration with date-time data. 
4. Update of exposure compliance categories, aligning them with inclusion criteria for the PPS 
set. 
5. The disposition and withdrawals table is rerun on the FAS. 


 
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6. The mapping, especially of missing values or censorings, has been updated/extended for these 
endpoints: 
a. Primary efficacy analysis variable clinical improvement 
b. Longitudinal sensitivity analysis 
c. Proportion of patients being discharged alive from hospital 
d. Time from hospital admission to alive hospital discharge during the study 
e. Proportion of patients receiving intubation/mechanical ventilation 
f. Time from hospital admission to receiving intubation/mechanical ventilation 
g. Mortality rate 
7. If a (quasi-) complete separation of data points is detected in the logistic regression sensitivity 
analysis, additional log-F(1,1) data priors are used to stabilize the fit. 
8. Mapping of data used for sensitivity analyses basing on worth parameters of a Bradley-Terry 
model have been extended. If SDD visits fall on the same day as a preceding regular visit, their 
WHO OSCI rating is used for LOCF imputation of succeeding days only but not as a datum in 
the time series of a patient. 
9. The tipping point analysis (sensitivity analysis for the primary efficacy endpoint) has been 
modified. A setting will show superiority of AZD1656 against placebo if the median χ2 test p-
value is lower or equal 0.025. And the number of multiple imputations has been increased to 
1000. 
10. Some glycaemic control endpoints  
11. If a patient is discharged alive from hospital, requires intubation or mechanical ventilation, or 
dies earlier than any of these timepoints, the last WHO OSCI observation will be carried 
forward (LOCF). If SDD visits fall on the same day with a regular visit, the WHO OSCI rating of 
the SDD visit is used for that day.  Drop-outs due to withdrawal of consent are kept missing. 
12. Urinalysis parameters have been corrected. 
13. The shift table for qualitative laboratory parameters has been removed as no post-baseline 
measures are collected. 
14. Tables for immunophenotyping, immunochemistry and cardiac injury have been moved from 
the safety to efficacy section. 
SAP version 4.0 has these modifications compared to SAP version 3.0: 
1. Definition of study treatment completion and study completion have been modified. 
SAP version 5.0 has these modifications compared to SAP version 4.0: 
1. The PK analysis has been defined more precisely. 
2. Mortality rate is additionally analysed at completion of study treatment. 
3. The immunochemistry analysis has been defined more precisely. 
4. Tables and Listings for immunochemistry, immunophenotyping and cardiac injury have been 
separated from each other. 


 
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5. The efficacy listing of plasma AZS1656 levels has been dropped as it has covered the same 
information as the PK listing. 
 
3 
Study Design 
Indication 
COVID-19 
Design 
Randomised, parallel group, double-blind, placebo-controlled 
Phase 
Phase II 
Primary Objective 
To determine the effect of AZD1656 on the cardiorespiratory 
complications of COVID-19 in hospitalized diabetic patients with known 
or suspected COVID-19 disease as measured using the WHO 8-point 
ordinal scale for Clinical Improvement compared to placebo. 
Secondary 
Objectives 
To assess the extent to which AZD1656 supports maintenance of 
adequate glycaemic control in hospitalised diabetic patients with known 
or suspected COVID-19. 
To assess the safety and tolerability of AZD1656 in the management of 
diabetes in hospitalised diabetic patients with known or suspected 
COVID-19. 
To determine whether AZD1656 affects duration of hospital stay, 
requirement for mechanical ventilation or mortality in diabetic patients 
with known or suspected COVID-19. 
Exploratory 
Objectives 
To determine the pharmacokinetics (PK) of AZD1656 in diabetic patients 
with known or suspected COVID-19. 
To explore the effects of AZD1656 on immunophenotyping characteristics 
during COVID-19 infection in hospitalised diabetic patients. 
To explore the effects of AZD1656 on immunochemistry characteristics 
during COVID-19 infection in hospitalised diabetic patients. 
To explore whether AZD1656 affects the extent of any cardiac injury 
related to COVID-19 in hospitalised diabetic patients. 
To explore if ethnicity affects the clinical outcome of hospitalised diabetic 
patients with known or suspected COVID-19 treated with AZD1656 versus 
placebo. 
To explore if 25-hydroxyvitamin D levels at Baseline affect the clinical 
outcome of hospitalised diabetic patients with known or suspected 
COVID-19 treated with AZD1656 versus placebo.   


 
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Endpoints 
Primary Endpoint: 
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. 
 
Secondary Endpoints: 
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. 
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. 
Proportion of Treatment Emergent Adverse Events (TEAEs) leading to 
study drug discontinuation in patients receiving AZD1656 compared with 
placebo. 
Proportion of Serious Adverse Events (SAEs) in patients receiving 
AZD1656 compared with placebo. 
Time from hospital admission to hospital discharge (in hours) in patients 
receiving AZD1656 compared with placebo. 
Time from hospital admission to receiving intubation/mechanical 
ventilation in patients receiving AZD1656 compared with placebo. 
Mortality Rate in patients receiving AZD1656 compared with placebo. 
 
Exploratory Endpoints: 
Plasma AZD1656 levels during first 7 days of treatment in patients 
receiving AZD1656 compared with placebo. 
Immunophenotyping panel to be conducted by Flow Cytometry: between 
group comparison (AZD1656 versus placebo) of levels of T, B and NK cells 
(including specific Treg and memory T cell populations); monocyte, 
neutrophil and eosinophil numeration to include activation markers for 
neutrophils (CD11b) and Monocytes subsets (CD14/CD16 identification 
including 6-Sulfo LacNAc (SLAN)). 
Immunochemistry panel to be conducted using the MSD U-Plex multiplex 
assay for assessment of the following biomarkers: GCSF, GM-CSF, IL-1B, 
IL-4, IL-6, IL-8, IL-10, IL-12, and MIP-1a. 
Measurement of hsTroponin and NTproBNP to determine extent of 
cardiac injury in patients receiving AZD1656 compared with placebo. 


 
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Measurement of 25-hydroxyvitamin D levels before treatment to 
determine whether there is any correlation between Vitamin D level and 
clinical outcomes. 
Correlation of clinical outcomes with patient ethnicity. 
Treatments 
AZD1656 and placebo 
Number of patients 
Approximately 165 patients will be screened to achieve 150 patients 
randomly assigned to AZD1656 or placebo. 
Safety analyses 
After 40 and 80 patients have completed the study. 
Planned enrolment 
3 countries, United Kingdom (UK), Czech Republic and Romania 
Approximately 30 sites 
3.1 
Sample size estimation 
Approximately 165 patients will be screened to achieve 150 randomly assigned patients to AZD1656 
or placebo for an estimated total of 75 evaluable patients per group.  Approximately 30 trial sites in 
the UK, Romania and CZ Republic will recruit the 150 randomised patients. 
A two group χ² test with a 5% two-sided significance level will have 76.74% power to detect the 
difference between a placebo proportion of 0.6 and an AZD1656 proportion of 0.8 when the sample 
size is 150 (75/group). In the case that the portion of placebo patients meeting world health 
organisation (WHO) categories 1-3 or live discharge at Day 14 is higher (0.65), then the power to find 
a similar 20 percentage point increase would be 81.4%. 
3.2 
Randomisation, blinding and unblinding procedures 
There will be a 1:1 allocation ratio of AZD1656 and placebo stratified by site. The full randomization 
design is covered in the randomization specifications. 
Randomization, blinding and unblinding will be done in the software package Medidata RTSM. 
Details on these procedures are documented in the online help [1]. 
4 
Analysis Sets 
Enrolled Analysis Set (ENR) 
The ENR includes all patients who provided informed consent. Patients will be analysed as 
randomised. 
This will be the primary analysis set for disposition and listings. 
Full Analysis Set (FAS) 
The FAS or intention-to-treat population includes all randomised patients who received at least one 
dose of IMP. Following the intent-to-treat principle, patients will be analysed as randomised. 


 
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This will be the primary analysis set for demographics and background characteristics, medical 
history, previous and concomitant therapies, exposure and compliance and primary, secondary and 
exploratory efficacy endpoints. 
Safety Set (SAF) 
The SAF, also known as “treated population”, 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). The assignment of patients to the treatment 
groups will be as actually treated. 
This will be the primary analysis set for safety analyses. 
Per-Protocol Set (PPS) 
The PPS includes all patients of the FAS without major protocol deviations. Patients will be excluded 
from the PPS for the following reasons: 
▪ 
Any major deviation from exclusion / inclusion criteria. 
▪ 
Other sets of minor and/or major protocol deviations as identified at the blinded data 
review meeting. 
Patients to be excluded from the PPS will be identified and reviewed at the blinded data review 
meeting held before unblinding of the study. 
The PPS will be used for sensitivity analyses for primary and secondary efficacy analyses as specified 
in section 10 Efficacy. 
Pharmacokinetic Analysis Set (PKS) 
The PKS includes all patients who received a single dose of IMP and have at least one post-dose PK 
measurement. 
The PKS is the primary analysis set for pharmacokinetic analyses. 
Usage overview of analysis sets 
If not otherwise stated in the respective section, the statistical analyses will be performed for the 
following analysis sets: 
Analyses 
ENR 
FAS 
PPS 
SAF 
PKS 
Disposition 
✓ 
✓ 
 
 
 
Demographics and background 
characteristics 
 
✓ 
(✓) 
(✓) 
 
Medical history 
 
✓ 
 
(✓) 
 
Previous and concomitant therapies 
 
✓ 
 
(✓) 
 
Exposure and compliance 
 
✓ 
(✓) 
(✓) 
 
Efficacy: Primary  
 
✓ 
 
 
 


 
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Efficacy: Secondary  
 
✓ 
 
 
 
Efficacy: Exploratory 
 
✓ 
 
 
 
Efficacy: Sensitivity analyses 
 
✓ 
✓ 
 
 
Pharmacokinetic 
 
 
 
 
✓ 
Safety 
 
 
 
✓ 
 
Listings 
✓ 
✓ 
 
✓ 
✓ 
The combinations of analysis and analysis set which are marked with “(✓)” become 
relevant only if there is a difference of at least one patient between the FAS and the PPS or 
SAF. 
5 
General Statistical Methods and Definitions 
5.1 
General statistical methods 
The statistical analyses will be presented by treatment group for the different analysis sets as 
defined in section 4 Analysis Sets. 
Summary tables will usually be structured with a column for each treatment in the order Placebo, 
AZD1656, All patients. 
In general, continuous variables will be summarised using descriptive statistics, i.e. generally 
displaying number of patients in the respective analysis population, number of patients with data, 
number of patients with missing values, mean, standard deviation, minimum, lower quartile, 
median, upper quartile, and maximum. 
Categorical variables will be summarised by using frequency counts and percentages. In addition, the 
number of patients with missing values will be displayed. The denominator for percentages will be 
the number of patients in the analysis set and treatment group under consideration. 
Means and medians will be presented by 1 additional decimal place and standard deviation will be 
presented by 2 additional decimal places than the standard presentation level of the respective 
patient data. Minimum, lower quartile, upper quartile and maximum values will be presented using 
the same number of decimal places as the patient data. Percentages will be presented to 1 decimal 
place if not otherwise stated. 
If the number of patients in a category is 0, then percentage will not be displayed, and only a count 
of 0 will be shown. 
P-values will be reported to 4 decimal places at least. Values less than 0.0001 will be displayed as 
<.0001. Values above 0.9999 will be displayed as 1.0000. 
In listings, data will be sorted by treatment, site, and patient, and when appropriate by visit or other 
identifiers for sequence or type of observation. 
If not otherwise specified, all statistical tests will be two-sided. The significance level of one-sided 
tests will be divided by two to ensure comparability with two-sided tests. 
The confidence level for calculation of confidence intervals will be chosen as (1-significance level) of 
the respective statistical test. 


 
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5.2 
Covariates and strata 
Randomization will be stratified by study site; it is not used as covariate in efficacy models. 
Primary, secondary and exploratory efficacy analyses do not use covariates. 
In sensitivity analyses these covariates are used: 
▪ 
Sex 
▪ 
Age group 
▪ 
Race 
▪ 
Diabetes type 
▪ 
Vitamin D group 
▪ 
Site 
Study sites, countries and regions 
Study sites will not be grouped in any analysis. Country and region analysis is only planned for the 
disposition table. 
Subgroups 
In subgroup analyses these covariates are used: 
▪ 
Sex (Male, Female) 
▪ 
Age group (>= 18 and < 65 years, >= 65 and < 85 years, >= 85 years) 
▪ 
Race (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or 
Other Pacific Islander, White, Unknown, Other) 
▪ 
Diabetes type (Type 1, Type 2) 
▪ 
Vitamin D group (<25 nmol/l, >=25 nmol/l) 
▪ 
Site 
Results for the different subgroups will be presented descriptively by presenting the results for the 
primary analysis separately for each subgroup. In addition, results will be displayed graphically using 
Forest plots. 
5.3 
Missing data 
In general, missing data are assumed to be missing completely at random (MCAR). Thus, they will 
not be imputed, and the data will be analysed as they are recorded. 
Sensitivity analyses of the primary and key secondary efficacy variables (see section 10.1 Primary 
efficacy analysis for details) might operate on imputed data, the imputation method will be 
described and discussed in these sections per analysis. 
Partial and missing dates will be imputed as specified below. 


 
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Partial or missing dates and times 
Missing start and end date/times will be imputed conservatively, i.e. missing values will be imputed 
in such a way that the duration of the adverse event or medication is considered with the longest 
possible duration and such that, whenever the adverse event or medication may potentially start 
after first IMP administration, the adverse event or medication will be handled as a treatment 
emergent adverse event (TEAE) or concomitant, respectively. 
If the partial start date of an adverse event (AE) or medication does not clearly occur before/after 
first dose of study drug and stop date does not clearly occur before first dose date, then impute first 
dose date. Otherwise impute first calendar day and/or first calendar month as well as first hour 
and/or first minute (if applicable). 
If the AE/medication stop date is completely missing, then keep it missing as this AE or medication is 
considered as ongoing. Otherwise impute last calendar day and/or last calendar month as well as 
last hour and/or last minute (if applicable). 
5.4 
Observation and analysis times 
Study days 
Study day is defined as the number of days since randomisation and, for a particular date, is 
calculated as: 
 
Study day = Assessment date – Date of randomisation + 1. 
Therefore, the date of randomisation will be Day 1. Days within the screening period will be 
numbered with negative numbers until Day -1 defined as the day before Visit 2 (Randomisation) on 
Day 1. 
In the situation where the assessment date is partial or missing, Study Day, and any corresponding 
durations, will appear partial or missing in the listings. 
Study periods 
The study consists of the periods 
▪ 
Screening period: screening period will run from screening visit (Visit 1 on Day -2 or -1) to 
study day -1, i.e. the day preceding Visit 2 on Day 1. 
▪ 
Double-blind treatment period: double-blind treatment period will run from randomisation 
visit (Visit 2 on Day 1) until Visit 22 on Day 21. 
▪ 
Follow-up period: follow up period will be the following 7 days from date of end of study 
treatment. There is no follow up period for patients who die. 
Definition of baseline values 
The baseline value is defined to be the last value which was assessed before randomisation at Visit 2. 
Definition of analysis timepoints or time windows 
The definition of analysis timepoints / time windows is specified in the respective sections where 
applicable. 


 
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Assessment timepoints and their corresponding time windows are defined in the protocol as follows: 
▪ 
Visit 1 (Screening), on Day -2 or Day -1 ± 0 days 
▪ 
Visit 2 (Randomisation), on Day 1 ± 0 days 
▪ 
Visit 3, on Day 2 ± 0 days 
▪ 
Visit 4, on Day 3 ± 0 days 
ongoing in the same pattern until 
▪ 
Visit 22, on Day 21 ± 0 days 
▪ 
Study drug discontinuation (SDD) visit 
▪ 
Visit 23 (Safety Follow-up), on Day 28 or 7 days after study end criteria are met ± 0 days 
If multiple measurements occur on the same day and only one measurement is expected, the worst 
measurement on that day will be taken for analyses. Two or more measures of WHO grade may be 
recorded on a single day: If the latest score in the day is higher, the higher score will be used. If the 
latest score in the day is lower, the lower score will be used.  
Cut-off points 
Following cut-off points are used for safety analyses for the SRC: 
▪ 
After 40 patients have completed the study. This will be the case after the 40th patient 
completed Visit 23 (Safety Follow-up). 
▪ 
After 60 patients have completed the study. This will be the case after the 60th patient 
completed Visit 23 (Safety Follow-up). 
5.5 
Multiple Comparison/Multiplicity 
No multiplicity adjustment is planned. 
6 
Patient Accounting and Disposition 
6.1 
Patient accounting 
The number and percentage of patients who failed screening will be presented overall. Additionally, 
the primary reason for screen failure will be described descriptively. 
The number and percentage of patients in each analysis set as defined in section 4 Analysis Sets will 
be presented overall and by randomised treatment (if applicable) and site. 
Furthermore, the number and percentage of patients in each analysis set will be presented overall 
and by treatment group including individual reasons of exclusion from the respective analysis set. 
A list of patients with all randomisation assignment information will be generated in order to confirm 
that the randomisation was performed according to the randomisation plan. 
6.2 
Disposition and withdrawals 
The number and relative frequency will be presented overall and by country for the ENR and FAS 
▪ 
patients performing the different visits, 


 
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▪ 
patients who complete the study treatment, patients who do not complete the study 
treatment and the reason for this, 
▪ 
patients who complete the study, patients who do not complete the study and the reason for 
this. 
Patients complete the study treatment if they complete Visit 22 (Day 21) or SDD visit according to 
the protocol. Patients complete the study/trial if they complete Visit 23 (Day 28) according to the 
protocol. 
A list of patients’ randomization date, date of study treatment (non-) completion, time to study 
treatment (non-) completion, reasons for not completing study treatment, trial end date, and 
reasons for trial withdrawal will be created. A list of patients’ allocation date to treatment, date of 
treatment end, treatment duration and reason for treatment discontinuation will be created. 
Treatment duration is the time difference of date of allocation to treatment and date of treatment 
end. Treatment end is the date when the study drug was dispensed for the last time. 
6.3 
Minor and Major protocol deviations 
Major protocol deviations leading to exclusion from the per-protocol set are specified in section 4 
Analysis Sets. 
The number and relative frequency of patients and the number and frequency of events with minor 
or major protocol deviations will be presented by treatment group and study site for the FAS. 
In addition, all deviations of the inclusion and exclusion criteria will be summarized by treatment 
group and study site for the FAS. 
Listings of all patients with protocol deviations as specified above as well as if the protocol deviation 
leads to exclusion from the PPS deviations of in- and exclusion criteria and allocation to trial 
populations will be created. 
7 
Demographics and Background Characteristics 
Demographic and baseline characteristics as specified in detail below will be presented descriptively 
by treatment group.   
7.1 
Demographics and baseline characteristics 
The following demographic characteristics will be presented descriptively and listed: 
▪ 
Sex (male, female) 
▪ 
Age (years) as derived in the clinical database 
▪ 
Age group (≥18 and <65, ≥65 and <85, ≥85 years) 
▪ 
Race (American Indian or Alaska Native, Asian (with subcategories: Asian Indian, Bangladeshi, 
Chinese, Pakistani, Other Asian), Black or African American, Native Hawaiian or Other Pacific 
Islander, White, Unknown, Other) 
▪ 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown) 
▪ 
Weight (kg) at baseline 
▪ 
Height (cm) at baseline 


 
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▪ 
BMI (kg/m2) at baseline = weight in kg / (height in cm / 100)^2 
▪ 
Diabetes type 
▪ 
HbA1c level at baseline (%) 
▪ 
Blood glucose group at baseline (4-8.5, >8.5) 
▪ 
Vitamin D level at baseline 
▪ 
Vitamin D group (<25 nmol/l, >=25 nmol/l) 
▪ 
WHO ordinal scale for clinical improvement (OSCI) rating at baseline 
Date of informed consent, protocol version, informed consent form (ICF) type and ICF version 
number will be listed. 
The date and time of hospital admission and discharge will be listed. The results of the SARs-CoV-2 
polymerase chain reaction (PCR) test will be listed. 
7.2 
Medical history 
The diseases are coded according to Medical Dictionary for Regulatory Activities (MedDRA® version 
23.0) and will be classified as follows: 
▪ 
Previous medical conditions, i.e. medical conditions that stopped prior to start of treatment 
▪ 
Ongoing (concomitant) medical conditions, i.e. medical conditions still present after start of 
treatment 
The frequency of diseases recorded from medical history will be presented after classification into 
previous and concomitant conditions by system organ class (SOC) as well as the frequencies of 
preferred terms (PTs) within each SOC. If patients have more than one disease within an SOC or PT 
they will be counted only once for the respective SOC or PT. 
A listing of medical history will also be created. 
7.3 
Previous and Concomitant Medications 
Previous and concomitant medications are coded according to the WHO drug dictionary (WHO-Drug 
version B3 March 2020) and stored with anatomical, pharmacological and chemical (ATC) codes and 
generic names. 
Therapies will be classified as previous if the stop date and/or time was before the first dose of study 
medication. All other medications are defined as concomitant. Missing or partly missing stop dates 
will be imputed using the rules defined in Section 5.3 Missing data. 
Note: Another way to define concomitant medications is “Other than the study drug, any 
medications or therapy present on or after the first dose of study medication but not starting after 
the last dose of study medication or with a start date prior to, and an end date on or after the date 
of the first dose of study drug or marked as ongoing will be considered concomitant medications.” 
The number and frequency of previous and concomitant medications will be given per ATC level 4 
and Preferred Names. If a patient has received more than 1 drug within an ATC class, he/she will be 
counted only once for this ATC class. 
A listing of previous and concomitant medication will also be created. 


 
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8 
Exposure and Compliance 
8.1 
Treatment groups 
The definition of treatment assignment, as specified in section 4 for each analysis set, will be used in 
this section, too. 
Deviations from the randomised treatment will be presented in the protocol deviation listing, see 
section 6.3 Minor and Major protocol deviations. 
8.2 
Treatment duration 
The treatment duration will be calculated in days as: 
Treatment duration (days) = date-time of last intake – date-time of first intake 
Descriptive statistics for the treatment duration will be presented. 
8.3 
Dosage 
50mg film-coated tablets of AZD1656 or placebo will be dosed at 100mg BID. 
Descriptive statistics for the total dose will be presented. 
8.4 
Compliance 
The number of tablets taken will be derived as the number of tablets dispensed minus the sum of 
the number of tablets returned and the number of tablets reported lost/missing. Percent 
compliance will be derived as the number of tablets taken divided by the number of tablets that 
should have been taken, expressed as a percent. The expected tablet intake is 4 tablets per full day 
and 2 tablets per part day (i.e. patients who start or end treatment during a day may not get the 
morning or evening dose, respectively). The percent compliance (categorized as <=70%, >70-100%)  
will be summarized. 
Study drug administration and the summary of exposure and compliance will be listed per patient, 
too. 
9 
Pharmacokinetics 
Plasma AZD1656 levels 
The pharmacokinetic evaluation of plasma AZD1656 and AZD5658 levels will be analysed 
descriptively on the PKS. The number of patients with levels below the lower level of quantification 
(LLOQ) will be added to the default statistics. Values below LLOQ are imputed with 0 and used in the 
analysis.Plasma AZD1656 levels will be listed, too. 
10 Efficacy 
10.1 Primary efficacy analysis 
The primary efficacy analysis variable clinical improvement is based on the rating of the WHO 8-
point Ordinal Scale for Clinical Improvement (WHO OSCI rating) at or before Visit 15 (Day 14). A 
patient is a clinical improvement responder if the WHO OSCI rating is 1 to 3 and a treatment failure if 
the WHO OSCI rating is 4 to 8. A patient discharged alive/recovered from hospital earlier than Day 14 


 
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is also a responder. Patients receiving intubation or who died before or who have been discharged 
alive from hospital with WHO OSCI rating of 4 (still on oxygen therapy) due to triage before Day 14 
are failures. Patients who have discontinued the treatment due to withdrawal of consent are set to 
missing.  
The primary alternative hypotheses (H1) is that the proportion of clinical improvement responders is 
higher with AZD1656 treatment than with placebo treatment. H1 will be tested against the null 
hypothesis (H0, one-sided) that the proportion of clinical improvement responders in the AZD1656 
arm is equal or lower than in the placebo arm: 
 
H0: rAZD1656 ≤ rplacebo 
 
H1: rAZD1656 > rplacebo 
where rTreatment denotes the proportion of clinical improvement responders in each treatment group. 
The primary hypothesis will be statistically assessed by means of a χ2 test on the one-sided 
significance level of 2.5% (corresponding to 5% two-sided). 
Descriptive analyses of relative risk (RR, AZD1656/placebo), odds ratio (OR, AZD1656/placebo) and 
absolute risk difference (ARD, AZD1656-placebo) with their two-sided 95% confidence intervals (CIs) 
will be added. In case of zero count in one of the cells of this four-field table, the Firth method is 
used to get results for relative risk and odds ratio, i.e. 0.5 is added to all cell counts. 
The primary analysis will be performed on the FAS. A statistical output documentation will be listed 
for the primary analysis. 
Handling of missing data 
Missing values for the primary endpoint are assumed to be missing at random and no imputation is 
planned. If a relevant proportion of missing data or data recorded after events interfering with the 
efficacy assessment are observed, additional sensitivity analyses will be performed (see section 
Sensitivity and Robustness Analyses below for details). 
Validity of Model Assumptions 
The simple design of the primary analysis variable makes it robust against misspecifications. 
Although low counts are not expected within the four-field table of the primary analysis, which 
would violate the constraints of the χ2 test, a rerun with the Fisher’s exact test is conducted. 
Sensitivity and Robustness Analyses 
In order to assess the clinical improvement using different assumptions from those in the FAS 
analysis, the primary efficacy analysis will also be performed using the PP set. Clinical improvement 
will be compared between both treatment groups using a logistic regression with the canonical logit-
link and including factors treatment, sex, age group, race, diabetes type, vitamin D group, and site. If 
a (quasi-) complete separation of data points is detected, additional log-F(1,1) data priors are used 
to stabilize the fit. Model fit statistics log likelihood and AIC and Type III test results of all covariables 
will be outputted. The contrast between both treatment groups, the associated Wald z-statistic, the 
one-sided p-value and the associated two-sided 95% Wald CI will be presented. The significance level 
will be set to 2.5% (one-sided, corresponding to 5% two-sided), the corresponding level of one-sided 
CI is 97.5% (corresponding to 95% two-sided). Furthermore, the marginal clinical improvement rate 
(back-transformed from logit(clinical improvement)) by treatment, the marginal relative risk 


 
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(AZD1656/placebo, back-transformed from ln(relative risk)), the marginal odds ratio 
(AZD1656/placebo, back-transformed from ln(odds ratio)), and the absolute risk difference 
(AZD1656-placebo) with their CIs will be shown as well as p-values for relative risk, odds ratio, and 
absolute risk difference; the marginalisation method is the delta method [1]. 
To check the robustness of the primary efficacy analysis, which focuses on a single timepoint, a 
longitudinal analysis basing on the WHO OSCI path from Day 1 to Day 14 will be conducted. If a 
patient is discharged alive from hospital, requires intubation or mechanical ventilation, or dies 
earlier than Day 14, the last WHO OSCI observation will be carried forward (LOCF) until Day 14. If 
SDD visits fall on the same day with a regular visit, the WHO OSCI rating of the SDD visit is used for 
that day. Drop-outs e.g. due to withdrawal of consent are kept missing. After that missing WHO OSCI 
ratings will be imputed with means of a multiple imputation (number of imputations M=20) 
assuming that patients will behave similarly to patients of the same treatment arm and on the same 
treatment day (for details see Appendix II: Multiple imputation for the longitudinal robustness 
analysis of the primary efficacy analysis). The completed WHO OSCI paths of patients will be 
converted into a single number (worth parameter) via pair comparisons on a daily basis with help of 
a Bradley Terry model with forced choice [3], ties are resolved with a fair coin flip. Higher values will 
dominate lower ones to preserve the direction of the WHO OSCI within the resulting worth 
parameters, i.e. the higher the worse. It is calculated via a binomial (grouped logit) regression with 
the canonical logit-link and having a specific design matrix [4]. 
The derived worth parameters are ratio scaled. An interpretation like “The mean of worth 
parameters of AZD1656 is 3 and of placebo is 6, so at the mean AZD1656 performs twice as well as 
placebo” is allowed. And the log worth parameters are approximately normal distributed. 
Resulting worth parameters (exponentiated parameter results of the logistic regression model 
described above) will be presented. 
The comparison of AZD1656 treatment with placebo will be tested via a Mann-Whitney U-test on 
the one-sided significance level of 2.5% (corresponding to 5% two-sided); average scores will be 
used for ties. An ANOVA with analysis variable log worth parameter (i.e. the parameter results of the 
logistic regression model described above) and factors treatment, sex, age group, race, diabetes 
type, vitamin D group, and site will be used to confirm the result of the primary efficacy analysis and 
to explore the impact of the other factors. Model fit statistics log likelihood and AIC and Type III test 
results of all covariables will be outputted. The contrast between both treatment groups, the 
associated Wald z-statistic, the one-sided p-value and the associated two-sided 95% Wald CI will be 
presented. The significance level will be set to 2.5% (one-sided, corresponding to 5% two-sided), the 
corresponding level of one-sided CI is 97.5% (corresponding to 95% two-sided). Furthermore, the 
marginal worth parameter (exponentiated log worth parameter) with their 95% CI will be presented 
for each factor level (subgroup); the marginalisation method is least squared (LS) means. A tipping 
point analysis of the primary efficacy analysis is conducted to see the impact of dropouts. Draws 
from a Bernoulli distribution looping through response probabilities from 0% to 100% by 1% steps 
independently for both arms will be done for dropouts. Each response probability setting will be 
repeated 1000 times; a setting will show superiority of AZD1656 against placebo if the median χ2 test 
p-value is lower or equal 0.025. The seed for the draws from the Bernoulli distribution per response 
probability configuration of AZD1656 and placebo is set to response probability of AZD1656 * 10000 
+ response probability of placebo * 100. This seed is used in one data step in which all 1000 
repetitions are imputed; this dataset is ordered ascendingly by the repetition ID of the response 
probability setting (1 to 100) and USUBJID.  


 
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10.2 Secondary efficacy analyses 
All secondary efficacy variables will be evaluated descriptively and exploratively. They will be 
analysed on the FAS. 
Clinical Improvement by WHO OSCI Rating 
The clinical improvement measured as the percentage of patients categorised at each severity rating 
on the WHO 8-point Ordinal Scale at or before Day 7, Day 14, Day 21 and SDD visit versus baseline, 
comparing AZD1656 treatment with placebo will be displayed descriptively. If a patient is discharged 
alive from hospital, requires intubation or mechanical ventilation, or dies earlier than any of these 
timepoints, the last WHO OSCI observation will be carried forward (LOCF). If SDD visits fall on the 
same day with a regular visit, the WHO OSCI rating of the SDD visit is used for that day. Drop-outs 
due to withdrawal of consent are kept missing. 
The clinical improvement within a treatment arm at or before Visit 8 (Day 7), Visit 15 (Day 14), Visit 
22 (Day 21) and SDD visit will be tested on the observed values via an exact Wilcoxon test on the 
one-sided significance level of 2.5% (corresponding to 5% two-sided); average scores will be used for 
ties. 
The comparison of AZD1656 treatment with placebo at Baseline, Visit 8, Visit 15, Visit 22 and SDD 
visit will be tested via a Mann-Whitney U-test on the one-sided significance level of 2.5% 
(corresponding to 5% two-sided); average scores will be used for ties. The daily outcome of the 
clinical improvement by the WHO OSCI rating per treatment arm will be displayed graphically in a 
stacked bar plot. 
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 will be described. 
An increase in overall diabetic medication (event) is present at a specific post-baseline study day if 
the total daily dose of at least one concomitant medication for the indication diabetes mellitus type I 
or II is higher at the specific study day compared to the dose of each concomitant medication for the 
indication diabetes mellitus type I or II at baseline. An increase in overall diabetic medication is also 
present if an additional concomitant medication is administered at any post-baseline study day 
which was not administered at baseline. 
A Fisher’s exact test on the one-sided significance level of 2.5% (corresponding to 5% two-sided) will 
be conducted to test on treatment differences. 
Descriptive analyses of relative risk (AZD1656/placebo), odds ratio (AZD1656/placebo) and absolute 
risk difference (AZD1656-placebo) with their two-sided 95% confidence intervals will be added. In 
case of zero count in one of the cells of this four-field table, the Firth method is used to get results 
for relative risk and odds ratio, i.e. 0.5 is added to all cell counts. 
The same analysis is conducted for type II diabetics controlled on oral medication on admission. An 
increase in diabetic medication (event) is present at a specific post-baseline study day if patients 
required the addition of insulin to their medication. 


 
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Furthermore, an analysis is conducted for type II diabetics controlled on oral medication on 
admission. An increase in diabetic medication (event) is present at a specific post-baseline study day 
if patients required an increased dose of their baseline medication or the addition of an additional 
orally administered drug to their medication. 
Also, an analysis is conducted for type I diabetics. An increase in diabetic medication (event) is 
present at a specific post-baseline study day if patients required an increase in total daily insulin 
dose, an increased dose of other baseline medication or the addition of an additional orally 
administered drug to their medication.  
Following analyses use the same setting as above, and they include all patients. Instead of 
concomitant medication they focus on blood sugar levels, i.e. glucose from laboratory chemistry, to 
define an event or failure. 
First, a notable glucose level (event) is present at a specific post-baseline study day if patients 
experience a glucose level of more than 17 mmol/l, i.e. twice the upper limit of normal 
(ULN).Second, a notable glucose level (event) is present at a specific post-baseline study day if 
patients experience a glucose level below 3.9 mmol/l, i.e. a hypoglycaemia. Third, a notable glucose 
level (event) is present at a specific post-baseline study day if patients experience a glucose level 
below 3.9 mmol/l, i.e. a hypoglycaemia, that requires an intervention (e.g. IV dextrose, additional 
orally administered sugar). 
Proportion of Patients Being Discharged from Hospital 
The proportion of patients being discharged alive from hospital in patients receiving AZD1656 
compared with placebo will be described. A patient will be categorised as responder for this analysis 
if the patient has been discharged alive from hospital during the treatment period, i.e. up to Day 21. 
Patients who withdrew consent are set to missing. All other patients are set to “Not Discharged from 
Hospital”. 
A Fisher’s exact test on the one-sided significance level of 2.5% (corresponding to 5% two-sided) will 
be conducted to test on treatment differences. 
Descriptive analyses of relative risk (AZD1656/placebo), odds ratio (AZD1656/placebo) and absolute 
risk difference (AZD1656-placebo) with their two-sided 95% confidence intervals will be added. In 
case of zero count in one of the cells of this four-field table, the Firth method is used to get results 
for relative risk and odds ratio, i.e. 0.5 is added to all cell counts. 
Time from Hospital Admission to Hospital Discharge 
Time from hospital admission to hospital discharge (in hours) in patients receiving AZD1656 
compared with placebo will be analysed with Kaplan-Meier estimates. All patients who have been 
discharged alive during the treatment period (up to Day 21), including triage patients, have an event 
at discharge date and time. Patients who have discontinued treatment for various reasons (e.g. 
intubation, death, withdrawal of consent, investigator decision, etc.) are censored at discontinuation 
day and time; if time is missing high noon 12:00pm is imputed. Patients without hospital discharge 
will be censored at the end of the double-blind treatment period, i.e. Visit 22 (Day 21). 
Time from hospital admission to hospital discharge in hours is calculated as the date and time of 
hospital discharge minus the date and time of hospital admission. 


 
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Beside Kaplan-Meier estimates and its pointwise two-sided 95%-CIs using the log-log transform, 
number of patients at risk, being censored or having an event as well as the event probability within 
a time interval will be presented by treatment. Additionally, quartiles of the survival times and their 
two-sided 95% CIs will be outputted. Patients without hospital discharge will be right censored at 
the end of the double-blind treatment period, i.e. SDD visit or Visit 22 on Day 21. 
The hypothesis that time to hospital discharge alive and well is shorter for AZD1656 patients than for 
placebo patients will be tested by means of a log-rank test on the one-sided significance level of 
2.5% (corresponding to 5% two-sided). 
Kaplan-Meier curves will be plotted, too. 
Proportion of Patients Receiving Intubation/Mechanical Ventilation 
The proportion of patients receiving intubation/mechanical ventilation in patients receiving 
AZD1656 compared with placebo will be described. A patient will be categorised as responder for 
this analysis if the patient will have a WHO OSCI rating of 6 or 7 (or similar data constellations, e.g. 
reason for study treatment discontinuation is intubation) at any timepoint during the study conduct. 
Patients who withdrew consent are set to missing. All other patients are set to “Not Receiving 
Intubation/Mechanical Ventilation”. 
A Fisher’s exact test on the one-sided significance level of 2.5% (corresponding to 5% two-sided) will 
be conducted to test on treatment differences. 
Descriptive analyses of relative risk (AZD1656/placebo), odds ratio (AZD1656/placebo) and absolute 
risk difference (AZD1656-placebo) with their two-sided 95% confidence intervals will be added. In 
case of zero count in one of the cells of this four-field table, the Firth method is used to get results 
for relative risk and odds ratio, i.e. 0.5 is added to all cell counts. 
Time from Hospital Admission to Receiving Intubation/Mechanical Ventilation 
Time from hospital admission to receiving intubation/mechanical ventilation in patients receiving 
AZD1656 compared with placebo will be analysed with Kaplan-Meier estimates. Patients who have 
discontinued the study for various reasons (e.g. withdrawal of consent, investigator decision, etc.) 
are censored at discontinuation day and time; if time is missing high noon 12:00pm is imputed. 
Patients who have been discharged alive from hospital with WHO OSCI rating of 4 due to triage are 
censored at discharge day and time. Patients will be censored at the end of the double-blind 
treatment period, i.e. either at Visit 22 (Day 21) or at SDD visit. 
Time from hospital admission to receiving intubation/mechanical ventilation is calculated as the date 
and time of receiving intubation/mechanical ventilation minus the date and time of hospital 
admission. 
Beside Kaplan-Meier estimates and its pointwise two-sided 95%-CIs using the log-log transform, 
number of patients at risk, being censored or having an event as well as the event probability within 
a time interval will be presented by treatment. Additionally, quartiles of the survival times and their 
two-sided 95% CIs will be outputted. Patients without receiving intubation/mechanical ventilation 
will be right censored at the end of the double-blind treatment period, i.e. SDD visit or Visit 22 on 
Day 21. 


 
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The hypothesis that time to receiving intubation/mechanical ventilation is longer for AZD1656 
patients than for placebo patients will be tested by means of a log-rank test on the one-sided 
significance level of 2.5% (corresponding to 5% two-sided). 
Kaplan-Meier curves will be plotted, too. 
Mortality Rate 
Mortality Rate in patients receiving AZD1656 compared with placebo will be described. Patients who 
have discontinued the treatment due to withdrawal of consent are set to missing. 
A Fisher’s exact test on the one-sided significance level of 2.5% (corresponding to 5% two-sided) will 
be conducted to test on treatment differences. 
Descriptive analyses of relative risk (AZD1656/placebo), odds ratio (AZD1656/placebo) and absolute 
risk difference (AZD1656-placebo) with their two-sided 95% confidence intervals will be added. In 
case of zero count in one of the cells of this four-field table, the Firth method is used to get results 
for relative risk and odds ratio, i.e. 0.5 is added to all cell counts. 
Furthermore, mortality rate is analysed at completion of study treatment, i.e., at Visit 22 (Day 21) or 
SDD visit. 
Immunophenotyping 
Immunophenotyping panel to be conducted by Flow Cytometry: between group comparison 
(AZD1656 versus placebo) of levels of T, B and NK cells (including specific Treg and memory T cell 
populations); monocyte, neutrophil and eosinophil numeration to include activation markers for 
neutrophils (CD11b) and Monocytes subsets (CD14/CD16 identification including 6-Sulfo LacNAc 
(SLAN)). 
Immunophenotyping parameters will be analysed on the observed values and on the change from 
baseline. 
The change from baseline within a treatment arm at Visit 9, Visit 12, Visit 22 and SDD visit will be 
tested on the observed values via an exact Wilcoxon test on the two-sided significance level of 5%; 
average scores will be used for ties. 
The comparison of AZD1656 treatment with placebo at Baseline, Visit 9, Visit 12, Visit 22 and SDD 
visit will be tested via a Mann-Whitney U-test on the two-sided significance level of 5%; average 
scores will be used for ties. 
Immunochemistry 
Immunochemistry panel to be conducted using the MSD U-Plex multiplex assay for assessment of 
the following biomarkers: G-CSF, GM-CSF, IL-1B, IL-4, IL-6, IL-8, IL-10, IL-12, and MIP-1a. 
Immunochemistry parameters will be analysed on the observed values and on the change from 
baseline. Values below LLOQ will be imputed with LLOQ/2 and will be used in the analysis. Values 
above upper limit of quantification (ULOQ) will be imputed with ULOQ and will be used in the 
analysis. 
The change from baseline within a treatment arm at Visit 9, Visit 12, Visit 22 and SDD visit will be 
tested on the observed values via an exact Wilcoxon test on the two-sided significance level of 5%; 
average scores will be used for ties. 


 
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The comparison of AZD1656 treatment with placebo at Baseline, Visit 22 and SDD visit will be tested 
via a Mann-Whitney U-test on the two-sided significance level of 5%; average scores will be used for 
ties. 
Cardiac Injury 
Measurement of hsTroponin (hs-CTNT) and NTproBNP to determine extent of cardiac injury in 
patients receiving AZD1656 compared with placebo will be analysed on the observed values and on 
the change from baseline. 
The change from baseline within a treatment arm at Visit 22 and SDD visit will be tested on the 
observed values via an exact Wilcoxon test on the two-sided significance level of 5%; average scores 
will be used for ties. 
The comparison of AZD1656 treatment with placebo at Baseline, Visit 22 and SDD visit will be tested 
via a Mann-Whitney U-test on the two-sided significance level of 5%; average scores will be used for 
ties. 
10.3 Other efficacy analyses 
All other efficacy variables will be evaluated descriptively and exploratively. If not stated otherwise, 
they will be analysed on the FAS. 
Clinical Improvement by Subgroup 
To explore if subgroups affect the clinical outcome of hospitalised diabetic patients treated with 
AZD1656 versus placebo, the primary efficacy analysis on clinical improvement will be repeated for 
subgroups of these variables: 
▪ 
Vitamin D group 
▪ 
Race 
▪ 
Sex 
▪ 
Age group 
▪ 
Diabetes type 
▪ 
Site 
Odds ratios and their two-sided 95% confidence intervals of the clinical improvement results of the 
primary efficacy analysis and all subgroup analyses will be displayed graphically in a forest plot. 
Efficacy Listings 
All efficacy listings will be provided for the FAS. 
Results of the 
▪ 
WHO OSCI rating and clinical improvement 
▪ 
Glycaemic control 
▪ 
Time-to-event endpoints 
▪ 
Immunophenotyping 
▪ 
Immunochemistry 


 
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▪ 
Cardiac injury 
will be listed. 
11 Safety 
11.1 Adverse events 
Adverse events (AE) will be coded using MedDRA version 23.0 and presented by System Organ Class 
(SOC) and Preferred Term (PT). 
The analysis will focus on the treatment-emergent AEs (TEAE), i.e., AEs which started or worsened 
on or after the first study medication intake and before the end of the follow up period, which will 
be 7 days after date of discharge, or 7 days after date of mechanical ventilation, or Visit 23 on Day 28 
for surviving patients. 
Number and frequencies of patients with TEAEs and the number and percentage of events will be 
given by SOC and by PT within each SOC as well as by treatment group for the following: 
▪ 
All TEAEs 
▪ 
Serious AEs on the ENR 
▪ 
Serious TEAEs 
▪ 
Non-serious TEAEs 
▪ 
TEAEs considered related 
▪ 
Serious TEAEs considered related 
▪ 
TEAEs leading to death (if occurring in more than 5 patients, otherwise a listing will be 
sufficient) 
▪ 
TEAEs leading to study discontinuation (if occurring in more than 5 patients, otherwise a 
listing will be sufficient) 
▪ 
TEAEs leading to discontinuation from IMP (if occurring in more than 5 patients, otherwise a 
listing will be sufficient) 
▪ 
All TEAEs by maximum intensity 
▪ 
TEAEs considered related by maximum intensity 
An overview table with total number and frequencies of patients with TEAEs of above listed 
analyses, excluding the stratification by intensity, will be done. 
Additionally, number and frequencies of patients with TEAEs and number and percentage of events 
will be presented by PT and by decreasing frequency for all TEAEs, serious TEAEs, non-serious TEAEs 
and TEAEs considered related. 
Furthermore, number and frequencies of patients with TEAEs and number and percentage of events 
will be presented by PT and by decreasing frequency for all TEAEs, serious TEAEsand non-serious 
TEAEswhich have an incidence rate of greater than 5% in All patients. 
Finally, number and frequencies of patients with TEAEs and number and percentage of events will be 
presented by PT and by decreasing frequency for all TEAEs, serious TEAEsand non-serious 


 
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TEAEswhich have an incidence rate of greater than 10% in AZD1656 patients and a incidence rate 
margin of greater than 5% between both treatment arms. 
Listings will be created for 
▪ 
All AEs 
▪ 
Serious AEs (SAEs) 
▪ 
AEs leading to discontinuation of study medication 
▪ 
AEs leading to discontinuation from study 
▪ 
AEs leading to death 
on the ENR and will thus also include patients enrolled but not randomised. 
Proportion of Treatment Emergent Adverse Events (TEAEs) Leading to Study Drug Discontinuation 
The proportion of Treatment Emergent Adverse Events (TEAEs) leading to study drug discontinuation 
in patients receiving AZD1656 compared with placebo will be described. 
A Fisher’s exact test on the one-sided significance level of 2.5% (corresponding to 5% two-sided) will 
be conducted to test on treatment differences. 
Descriptive analyses of relative risk (AZD1656/placebo), odds ratio (AZD1656/placebo) and absolute 
risk difference (AZD1656-placebo) with their two-sided 95% confidence intervals will be added. In 
case of zero count in one of the cells of this four-field table, the Firth method is used to get results 
for relative risk and odds ratio, i.e. 0.5 is added to all cell counts. 
Proportion of Serious Adverse Events (SAEs) 
The proportion of Serious Adverse Events (SAEs) in patients receiving AZD1656 compared with 
placebo will be described. 
A Fisher’s exact test on the one-sided significance level of 2.5% (corresponding to 5% two-sided) will 
be conducted to test on treatment differences. 
Descriptive analyses of relative risk (AZD1656/placebo), odds ratio (AZD1656/placebo) and absolute 
risk difference (AZD1656-placebo) with their two-sided 95% confidence intervals will be added. In 
case of zero count in one of the cells of this four-field table, the Firth method is used to get results 
for relative risk and odds ratio, i.e. 0.5 is added to all cell counts. 
11.2 Vital signs and oxygen saturation 
Actual values and changes from baseline in vital signs, i.e. temperature, systolic blood pressure, 
diastolic blood pressure, heart rate and respiratory rate, and oxygen saturation will be summarized 
descriptively over time. 
Furthermore, the number and percentage of patients based on reference ranges will be described 
according to the derived categories (i.e. Low, Normal, High) for vital signs and oxygen saturation. A 
listing of vital signs and oxygen saturation will be presented for all measurements and for abnormal 
findings, i.e. measurements outside of reference ranges. Vital signs that are outside of reference 
ranges will be flagged in the data listings, along with corresponding reference ranges. 


 
Protocol No.: SGS.1656.201 
CP Project ID: SGS20201   
Version: v5.0 
Version Date: 27JUL2021 
Statistical Analysis Plan: Safety for SRC & Final  
 
 
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QMS No (include version ref): STF-015-GL.02 
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11.3 Clinical safety laboratory  
Haematology, clinical chemistry and urinalysis 
The haematology analysis will include red blood cell (RBC) count, platelets, white blood cell (WBC) 
count, absolute eosinophils, eosinophils %, absolute basophils, basophils %, absolute neutrophil 
count, neutrophil %, absolute lymphocytes, lymphocytes %, absolute monocytes, monocytes %, 
haemoglobin, haematocrit and HbA1c (which will also be presented in the baseline characteristics). 
The clinical chemistry analysis will include sodium, potassium, urea, creatinine, calcium, phosphate, 
total protein, bilirubin, alkaline phosphatase (ALP), LDH, ALT, AST, GGT, glucose and 25-
hydroxyvitamin D (which will also be presented in the baseline characteristics). 
The urinalysis analysis will include glucose, protein, blood, ketones and pH. 
All haematology and clinical chemistry parameters, as well as urinalysis pH are quantitative 
parameters. All urinalysis parameters except pH are qualitative parameters. 
The following statistical analyses will be presented: 
▪ 
Quantitative data will be examined for trends using descriptive statistics of actual values and 
changes from baseline to each visit over time. 
▪ 
Quantitative data based on reference ranges will be described according to the derived 
categories (i.e. Low, clinically significant; Low, not clinically significant; Normal; High, not 
clinically significant; High, clinically significant). 
▪ 
Qualitative data will be described according to the categories (i.e. Normal; Abnormal, not 
clinically significant; Abnormal, clinically significant; Not done). 
▪ 
Shift tables of quantitative data showing changes with respect to the normal range and 
clinical significance between baseline and post-baseline visits as well as the worst value at 
any post-baseline visit (scheduled and unscheduled). 
Data from unplanned determinations, i.e. usually determinations where the investigator felt follow-
up was necessary, will be used for the number and frequency counts of overall post-baseline values. 
They will also be included in the data listings. 
A listing of laboratory values will be presented for all measurements and for abnormal findings, i.e. 
measurements outside of reference ranges or within sponsor defined alert ranges (Appendix III: 
Alert ranges for selected laboratory values). Laboratory values that are outside of reference ranges 
or within alert ranges will be flagged in the data listings, along with corresponding reference and 
alert ranges. Lastly, potential or suspected cases qualifying for Hy’s law criteria will be listed, too. 
They are all conducted on the ENR set. 
11.4  
 
ECG 
Baseline values of ventricular rate, RR, PR, QRS, QT, QTcB and QTcF, the interpretation and the 
clinical significance of the ECG will be summarized by treatment group using descriptive statistics. 
The Bazett’s Correction (QTcB) and Fridericia’s Correction (QTcF) are derived as follows:  


 
Protocol No.: SGS.1656.201 
CP Project ID: SGS20201   
Version: v5.0 
Version Date: 27JUL2021 
Statistical Analysis Plan: Safety for SRC & Final  
 
 
QMS Document Name: Statistical Analysis Plan 
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Bazett’s Correction (QTcB)  
RR
QT
QTcb =
 
Fridericia’s Correction (QTcF)  
3 RR
QT
QTcf =
 
where: RR = RR-interval measured in seconds. 
ECG results will be listed for both all data and clinically significant data only. 
11.5 Chest X-Ray or Chest CT Scans 
All available data will be listed. 
11.6 Oxygen Therapy 
All available data will be listed. 
11.7 Physical examination 
All available data will be listed. 
11.8 Childbearing potential and pregnancies 
The childbearing potential of women and reasons why a female patient is not considered to be of 
childbearing potential as well as the pregnancy test result will be presented in a listing. 
12 Interim analysis 
An interim analysis is not planned. 
13 Statistical Analyses for Safety Monitoring 
Safety analyses will be conducted after 40 and 80 patients have completed the study. This will be the 
case after the 40th and 80th patient completed Visit 23 (Safety Follow-up). 
The statistical analysis content for safety monitoring by the safety review committee (SRC) is 
specified in a separate SRC Charter. 
14 Statistical Analyses for Clinical Trial Registries 
The following additional analyses will be performed for the purpose of fulfilling the Clinical Trial 
Registry (CTR) requirements: 
Both Serious Adverse Events and ‘Non-Serious’ Adverse Events will be summarized by MedDRA 
preferred term. 
▪ 
An adverse event is considered ‘Serious’ whether or not it is a TEAE. 
▪ 
An adverse event is considered in the ‘Other’ category if it is both a TEAE and is not serious. 
For each Serious AE and ‘Other’ AE, for each term and treatment group, the following are provided: 
▪ 
the number of patients at risk of an event; 


 
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CP Project ID: SGS20201   
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Statistical Analysis Plan: Safety for SRC & Final  
 
 
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▪ 
the number of patients who experienced each event term; 
▪ 
the number of events experienced. 
15 Data Exchange Procedures 
Data exchange procedures will be specified in separate documents. 
16 Software 
If not stated otherwise, the data will be analysed using SAS Version 9.4 or higher. 
17 Abbreviations 
AE 
Adverse Event 
ARD 
Absolute risk difference 
ATC 
Anatomical, pharmacological and chemical 
ANOVA 
Analysis of VARIANCE 
CF 
Clotting factor analysis set 
CSR 
Clinical study report 
CTR 
Clinical trial registry 
DLT 
Dose limiting toxicity 
DMC 
Data monitoring committee 
DSUR 
Development safety update report 
ECG 
Electrocardiogram 
ENR 
Enrolled analysis set 
FAS 
Full analysis set 
ICH 
International conference on harmonization 
ICF 
Informed consent form 
ICU 
Intensive care unit 
MAR 
Missing at random 
MCAR 
Missing completely at random 
MedDRA 
Medical dictionary for regulatory activities 
LLN 
Lower limit of normal 
LLOQ 
Lower limit of quantification 
LOCF 
Last observation carried forward (imputation) 
LS 
Least squared 
OR 
Odds ratio 
OSCI 
Ordinary scale for clinical improvement 
PCT 
Polymerase chain reaction 
PK 
Pharmacokinetics 
PKS 
Pharmacokinetic analysis set 
PPS 
Per protocol set 
PT 
Preferred Term 
RR 
Relative risk 


 
Protocol No.: SGS.1656.201 
CP Project ID: SGS20201   
Version: v5.0 
Version Date: 27JUL2021 
Statistical Analysis Plan: Safety for SRC & Final  
 
 
QMS Document Name: Statistical Analysis Plan 
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SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SDD 
Study drug discontinuation 
SOC 
System organ class 
SRC 
Safety review committee 
TEAE 
Treatment emergent adverse event 
ULN 
Upper limit of normal 
ULOQ 
Upper limit of quantification 
WHO 
World health organisation 
18 References 
1. https://learn.mdsol.com/rave-rtsm/en/manage-subjects-125284904.html 
2. Cox, C. (1998): Delta Method, in P. Armitage and T. Colton, eds., Encyclopedia of Biostatistics, 
1125–1127, New York: John Wiley & Sons. 
3. Bradley, R. A. and Terry, Milton E. (1952): Rank Analysis of Incomplete Block Designs: I. The 
Method of Paired Comparisons. Biometrika, 39 (3/4): 324–45. doi:10.2307/2334029. 
4. Critchlow E. E. and Flinger M. A. (1991): Paired comparison, triple comparison, and ranking 
experiments as generalized linear models, and their implementation on GLIM. Psychometrika, 56 
(3), 517-33. 
5. Hassan T. et al. (2019): Vital signs in adults. National quality improvement project, national 
report 2018/19. The Royal College of Emergency Medicine. 
 
 


 
Protocol No.: SGS.1656.201 
CP Project ID: SGS20201   
Version: v5.0 
Version Date: 27JUL2021 
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Appendix I: Normal ranges for vital signs, oxygen saturation and body temperature for adults 
Parameter 
LLN 
ULN 
Blood pressure (diastolic) 
50 mmHg 
90 mmHg 
Blood pressure (systolic) 
90 mmHg 
140 mmHg 
Pulse rate 
60 bpm 
100 bpm 
Respiratory rate 
10 bpm 
20 bpm 
Oxygen saturation 
92 % 
100 % 
Body temperature 
35.0 °C 
37.5 °C 
LLN = lower limit of normal, ULN = upper limit of normal, bpm = beats per minute. LLNs and ULNs for 
pulse rate, respiratory rate and oxygen saturation are taken from [5]. 
 
 


 
Protocol No.: SGS.1656.201 
CP Project ID: SGS20201   
Version: v5.0 
Version Date: 27JUL2021 
Statistical Analysis Plan: Safety for SRC & Final  
 
 
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QMS No (include version ref): STF-015-GL.02 
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Appendix II: Multiple imputation for the longitudinal robustness analysis of the primary efficacy 
analysis 
It is assumed that patients having missing WHO OSCI ratings perform similarly as patients of the 
same treatment arm on the same day, i.e. missing at random (MAR). With this setting the three 
steps of a multiple imputation can be set up as follows: 
1. Impute: 
M=20 imputed datasets will be generated with help of this SAS code (dataset and 
variable names will be different): 
proc mi 
   data    = inData 
   out     = outData 
   seed    = 20201 
   nimpute = 20 
; 
   class trt day osci; 
   monotone logistic(osci = trt day/ details); 
   var trt day osci; 
run; 
 
The M completed datasets will be further prepared individually to get the grouped 
analysis variables “number or events” and “number of trials” for each pair 
comparison of two patients. Ties will be resolved with a fair coin flip with 
seed=20201: 
 
data x; 
   set y; 
   call streaminit(20201); 
   <...> 
   if <tie> then event = rand('Bernoulli', 0.5); 
run; 
2. Analyse: 
The M completed and prepared datasets will be analysed by a Bradley Terry model 
via a binomial (grouped logit) regression (PROC LOGISTIC) with canonical logit-link 
and using a specific design matrix. 
3. Combine: 
The M analysis results will be integrated into one final result (PROC MIANALYZE). 
This will be the basis for the descriptive analysis and ANOVA modelling. 
 
 


 
Protocol No.: SGS.1656.201 
CP Project ID: SGS20201   
Version: v5.0 
Version Date: 27JUL2021 
Statistical Analysis Plan: Safety for SRC & Final  
 
 
QMS Document Name: Statistical Analysis Plan 
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QMS No (include version ref): STF-015-GL.02 
Document date: 09JUL2019 
CONFIDENTIAL 
 
Appendix III: Alert ranges for selected laboratory values 
Parameter 
Unit 
LAR 
UAR 
Glucose 
mmol/L 
<3.9 
>13.9 
Alanine Aminotransferase (ALT) 
U/L 
- 
>160 
Aspartate Aminotransferase (AST) 
U/L 
- 
> 155 
hs-cTnT 
ng/L 
- 
>=30 
NT-proBNP 
pg/mL 
- 
>400 
LAR = lower alert range, UAR = upper alert range.