Clinical trial NCT04539795
Conditions: Covid19
Sponsor: University of Alabama at Birmingham
Start date: 2021-01-25; Completion date: 2021-10-29
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the safety, tolerability and pharmacokinetics (PK), and explore the mechanistic and clinical effect of alvelestat (an oral neutrophil elastase inhibitor) orally twice per day for 10 days added to standard of care in adult patients (≥18 years) with COVID-19 respiratory disease.

Detailed description:

Arms: arm 1: placebo arm 2: MPH966 arm 3: MPH966 arm 4: MPH966
Interventions: intervention 1: Alvelestat intervention 2: Placebo
Intervention descriptions: intervention 1: oral tablet intervention 2: oral tablet

Protocol documents:
Prot_000.pdf: 
 
Protocol Version 2.0 
 
Page 1 of 70 
Protocol Title: 
A Phase Ib/II, single center, placebo-controlled, 
randomized, blinded study in adult patients (>18 years) 
with COVID-19 Respiratory Disease, to evaluate, Safety, 
Tolerability and mechanistic effect of Alvelestat on top of 
standard of care (COSTA) 
Protocol Title: 
Abbreviated: COVID-19 Phase Ib/II Study of Safety and 
Tolerability of Alvelestat (COSTA) 
Protocol Number: 
COSTA 
IND: 
151665 
NCT identifier: 
NCT04539795 
Compound Number: 
Alvelestat/MPH966 (formerly AZD9668) 
Principal Investigator: 
Dr Mike Wells 
Sponsor Name and Legal 
Registered Address: 
University of Alabama, Birmingham, 701 20th Street 
South, AB 1170, Birmingham, AL 35294-0111, USA 
 
 
 


 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ..............................................................................................................2 
LIST OF FIGURES .......................................................................................................................4 
1.0 
SYNOPSIS ..........................................................................................................................5 
2.0 
SCHEDULE OF ASSESSMENTS (SOA) .......................................................................9 
3.0 
INTRODUCTION............................................................................................................12 
3.1 
Background ............................................................................................................12 
3.2 
Study Rationale ......................................................................................................12 
4.0 
OBJECTIVES AND ENDPOINTS ................................................................................14 
5.0 
STUDY DESIGN ..............................................................................................................15 
5.1 
Overall Design and Purpose...................................................................................15 
5.2 
Number of Participants ..........................................................................................17 
5.3 
End of Study Definition .........................................................................................17 
5.4 
Scientific Rationale for Study Design....................................................................17 
5.5 
Justification for Dose .............................................................................................18 
5.6 
Preclinical Safety Studies ......................................................................................19 
5.7 
Clinical Safety Studies ...........................................................................................20 
5.8 
Benefit-Risk Assessment .......................................................................................22 
6.0 
STUDY POPULATION ..................................................................................................24 
6.1 
Inclusion Criteria ...................................................................................................24 
6.2 
Exclusion Criteria ..................................................................................................24 
6.3 
Lifestyle Restrictions .............................................................................................26 
6.3.1 
Meals and Dietary Restrictions .............................................................26 
6.3.2 
Alcohol and Tobacco ............................................................................26 
6.3.3 
Activity ..................................................................................................26 
6.4 
Screen Failures .......................................................................................................26 
7.0 
TREATMENTS................................................................................................................26 
7.1 
Treatments Administered .......................................................................................27 
7.2 
Method of Treatment Assignment .........................................................................27 
7.3 
Blinding..................................................................................................................27 
7.4 
Preparation/Handling/Storage/Accountability .......................................................27 
7.5 
Treatment Compliance ...........................................................................................28 
7.6 
Concomitant Therapy.............................................................................................28 
7.7 
Treatment After the End of the Study ....................................................................28 
8.0 
DISCONTINUATION CRITERIA ................................................................................29 
8.1 
Discontinuation of Study Treatment ......................................................................29 


 
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8.1.1 
Temporary Discontinuation ..................................................................31 
8.1.2 
Dose De-escalation due to Study Drug Intolerance ..............................32 
8.1.3 
Re-challenge ..........................................................................................32 
8.2 
Discontinuation from the Study .............................................................................33 
8.3 
Lost to Follow-up ...................................................................................................33 
9.0 
STUDY ASSESSMENTS AND PROCEDURES ..........................................................34 
9.1 
Key Screening Assessments ..................................................................................34 
9.2 
Efficacy Assessments.............................................................................................34 
9.2.1 
Blood Biomarkers .................................................................................34 
9.2.2 
SaO2/FiO2 (Oxygen saturation/fraction inspired oxygen ......................35 
9.3 
Clinical Outcome Efficacy Measurements ............................................................35 
9.3.1 
Effect on disease progression recorded as participant status ................36 
9.3.2 
WHO 9-Point Ordinal Scale .................................................................36 
9.4 
Safety Assessments ................................................................................................36 
9.4.1 
Physical Examinations ..........................................................................36 
9.4.2 
Vital Signs .............................................................................................37 
9.4.3 
Headache ...............................................................................................37 
9.4.4 
Clinical Safety Laboratory Assessments ...............................................37 
9.4.5 
Data Monitoring ....................................................................................38 
9.5 
Adverse Events ......................................................................................................38 
9.5.1 
Time Period and Frequency for Collecting AE and SAE 
Information ............................................................................................38 
9.5.2 
Follow-up of an AE and/or SAE ...........................................................38 
9.5.3 
Adverse Events of Special Interest .......................................................39 
9.5.4 
Regulatory Reporting Requirements for SAE.......................................40 
9.5.5 
Pregnancy ..............................................................................................40 
9.6 
Treatment of Overdose ..........................................................................................40 
9.7 
Pharmacokinetics ...................................................................................................41 
9.8 
Pharmacodynamics ................................................................................................41 
10.0 
STATISTICAL CONSIDERATIONS ...........................................................................41 
10.1 
Sample Size Determination....................................................................................41 
10.2 
Populations for Analyses .......................................................................................42 
10.3 
Statistical Analyses ................................................................................................42 
10.3.1 
Safety Analyses (Primary Endpoint) .....................................................44 
10.3.2 
Efficacy Analyses (Secondary Endpoints) ............................................45 
10.3.3 
PK Analyses ..........................................................................................46 


 
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10.3.4 
Interim Analyses ...................................................................................46 
11.0 
REFERENCES .................................................................................................................47 
12.0 
APPENDICES ..................................................................................................................50 
APPENDIX 1:  ABBREVIATIONS, TRADEMARKS & GLOSSARY .................................50 
APPENDIX 2:  CLINICAL LABORATORY TESTS .............................................................53 
APPENDIX 3:  STUDY GOVERNANCE CONSIDERATIONS ............................................54 
APPENDIX 4:  ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING .......................57 
APPENDIX 5:  CONTRACEPTIVE GUIDANCE AND COLLECTION OF 
PREGNANCY INFORMATION ...................................................................................62 
APPENDIX 6:  WORLD HEALTH ORGANISATION 9-POINT ORDINAL SCALE .......66 
APPENDIX 7:  COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS .....67 
APPENDIX 8:  STUDY ORGANIZATION ..............................................................................68 
APPENDIX 9:  SUMMARY OF VERSIONS AND CHANGES .............................................69 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic.....................................................................................................16 
 


 
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1.0 
SYNOPSIS 
Protocol Title: A Phase Ib/II, single center, placebo-controlled, randomized study in adult 
patients (>18 years) with COVID-19 Respiratory Disease, to evaluate, Safety, Tolerability and 
mechanistic effect of Alvelestat on top of standard of care (COSTA). 
Rationale: Neutrophils and neutrophil extracellular traps (NETs) have recently been established 
as a central feature of SARS-CoV-2 pathogenesis, and NET formation (NETosis) are associated 
with poor outcomes in patients hospitalized with COVID-19 (Zuo et al 2020; Barnes et al 2020). 
NETs are networks of extracellular DNA fibers, histones, myeloperoxidase (MPO) and 
neutrophil elastase (NE), released from neutrophils and involved physiologically in capturing 
bacteria. However, if uncontrolled, NETs are cytotoxic to endothelial and epithelial cells, acting 
as Damage Associated Molecular Pattern Molecules (DAMPs) and promoting cytokine release 
and thromboses (Kim et al 2019). Levels of NETs correlate with disease severity in ALI/ARDS 
(Li et al 2018) Neutrophil elastase is essential to NET formation (Papayannopoulos et al 2010) 
and remains active when decorating the NET fibers. The physiological inhibitor of NE is Alpha-
1 antitrypsin (AAT), but studies in COVID-19 have shown this to be overwhelmed  
(McElvaney et al 2020). Providing NE inhibition therefore has potential to reduce both NET 
formation and damaging activity of existing NETs. In experimental models of ARDS, alvelestat, 
the NE inhibitor proposed for this clinical trial, protected the lung from inflammation and injury 
through NET inhibition (Li et al 2018). There is also evidence from clinical efficacy studies 
using NE inhibitors in ALI/ARDs. Sivelestat (‘Elastpol’) is a selective human neutrophil elastase 
inhibitor that is approved in Japan and South Korea for the treatment of ALI/ARDS accompanied 
by Systemic Inflammatory Response Syndrome. A meta-analysis of 6 randomised controlled 
trials in patients with all forms of ALI/ARDS, did not demonstrate an effect on mortality, 
Intensive Care Unit (ICU) or ventilator days. However, a sensitivity analysis detected a 
significant improvement in oxygen deficit measured by PaO2/FiO2 (SMD: 0.87; 95% CI: 0.39 to 
1.35; P < 0.001, (Pu et al 2017) and oxygenation of Day 3 (Iwata et al 2010). Sivelestat appeared 
to have an effect on mortality in ARDS associated with disseminated intravascular coagulation 
(DIC) (Miyoshi et al 2014), a neutrophil-predominant disease, which is more closely aligned 
with COVID, and provides support for the NE mechanism. 
Alvelestat (MPH966, AZD9668) is an oral, specific, potent human NE inhibitor (Stevens et al 
2011). Alvelestat effectively inhibits neutrophil elastase activity in man, including during 
maximal neutrophil stimulation. It shows predictable systemic pharmacokinetic (PK) profile and 
therapeutically relevant concentrations in sputum (Gunawardena et al 2013). Clinical safety and 
efficacy experience has been gained in over 1000 healthy volunteers and patients with lung 
disease, including Chronic Obstructive Pulmonary Disease (COPD), cystic fibrosis and 
bronchiectasis (Kuna et al 2012; Elborn et al 2012; Stockley et al 2013). There has been 
evidence of mechanistic effect in clinical studies of neutrophil-driven diseases, with significant 
decrease in biomarkers of elastase activity in cystic fibrosis (Elborn et al 2012), and clinically 
significant improvement in lung function (Forced Expiratory Volume in 1 second [FEV1]) in 
bronchiectasis (Stockley et al 2013), with reduction in the pro-inflammatory biomarkers 


 
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Interleukin (IL)-6 and RANTES in sputum and blood observed in both these studies. Alvelestat 
is currently being investigated in ongoing clinical trials in alpha-1 antitrypsin deficiency lung 
disease (Clinical Trials.Gov NCT03636347; NCT03679598) and Bronchiolitis Obliterans 
Syndrome associated with chronic graft versus host disease (NCT02669251).  
The scientific rationale for NE inhibition in SARS-CoV-2 infection, the evidence for an effect in 
other inflammatory lung diseases and the safety profile for alvelestat, supports investigating 
alvelestat in COVID-19. Here, we propose a pilot randomized, placebo-controlled trial assessing 
the safety and tolerability and exploring mechanistic effect on NETosis and clinical outcomes of 
alvelestat given on top of standard of care, compared to standard of care alone in patients 
hospitalized with COVID-19.   
Overall Purpose and Design: 
The purpose of this study is to evaluate the safety, tolerability, PK and explore mechanism of 
action and clinical effect of alvelestat in patients hospitalized with proven COVID-19 lung 
disease.   
This is a Phase Ib/II single-center, 2:1 randomized, blinded, placebo-controlled, parallel group, 
first in disease study. The objectives are to determine the safety, tolerability and PK and to 
explore the mechanistic and clinical effect of the NE inhibitor alvelestat, 240mg orally twice per 
day for 5 or 10 days added to standard of care (SoC) versus placebo added to SoC, in adult 
patients (≥18 years) with COVID-19 respiratory disease. 


 
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Objectives and Endpoints: 
Objective 
Endpoint 
Primary 
• To evaluate the safety and 
tolerability of alvelestat 
administered twice daily (bid) 
for 5 or 10 days 
By treatment group (alvelestat/placebo): 
• Numbers and % of subjects who experience at least 1 
treatment-emergent adverse event to Day 60 (Safety Outcome 
Assessment) 
• Adverse events of special interest (liver function 
abnormalities, corrected QT interval, infections, and 
neutropenia) and clinically significant safety monitoring labs 
tests to EoT  
• Number and % of subjects that discontinue alvelestat to Day 
5 or 10 
• Number and % of subjects requiring dose reduction to Day 5 
or 10 
• Number and % of subjects with AE of headache on 
prospective questioning and CTCAE severity Grade to Day 5 
or 10 
• Change in vital signs, EKG, safety laboratory measures to 
Day 5 or 10 or EOT 
Secondary 
• To evaluate the effect of 
alvelestat on blood 
pharmacodynamic markers of 
Neutrophil Extracellular Trap 
(NET) activation, elastase, 
inflammatory and 
coagulopathy activity 
By treatment group (alvelestat/placebo), change from baseline to 
Day 5 or 10 in: 
• Blood biomarkers of NETosis (cell-free DNA; citrullinated 
histone H3; Myeloperoxidase (MPO)-DNA complexes) 
• Blood biomarkers of inflammation (absolute neutrophil 
count; absolute lymphocyte count; neutrophil-lymphocyte 
ratio [NLR], C-Reactive protein, procalcitonin 
• Pro-inflammatory cytokines IL-1beta, IL-6, IL-8, TNF-alpha) 
• Coagulopathy as measured by D-Dimer 
• Plasma desmosine/isodesmosine 
• To explore the effect of 
alvelestat on pulmonary 
function 
By treatment group (alvelestat/placebo): 
• Change from baseline to Day 5 or 10 or EoT in SaO2/FiO2 
• The effect of alvelestat on 
disease progression 
By treatment group (alvelestat/placebo): 
• Proportion of subjects alive and free of respiratory failure 
(without need for non-invasive or invasive mechanical 
ventilation, high flow oxygen, or Extracorporeal Membrane 
Oxygenation (ECMO) at Day 29 


 
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Objective 
Endpoint 
• The effect of alvelestat on 
clinical outcomes  
By treatment group (alvelestat/placebo): 
• Mortality rate at Day 90 safety endpoint 
• Proportion of subjects alive and free of respiratory failure 
(without need for non-invasive or invasive mechanical 
ventilation, high flow oxygen, or ECMO) at Days 5, 10 
and 60 
• Length of hospital stay 
• Length of ICU stay 
• Time to room air (those on supplemental oxygen at Baseline) 
• The effect of alvelestat on 
disease severity 
By treatment group (alvelestat/placebo): 
• Percentage of patients deteriorating (>1 and >2 increase in 
WHO 9-point ordinal scale*) at Day 5, Day 10, Day 29 and 
Day 60 
• Percentage of patients improving (>1 and > 2 decrease in 
WHO 9-point ordinal scale) at Day 5, Day 10, Day 29 and 
Day 60 
• To explore Pharmacokinetics 
(PK) in patients with 
COVID-19 
• Plasma PK (sparse sampling taken pre or 1-2 hours post 
study drug dosing) in participants randomized to alvelestat. 
 
* WHO 9-point ordinal scale: 
0. Uninfected, no clinical or virological evidence of infection 
1. Ambulatory, no limitation of activities 
2. Ambulatory, limitation of activities 
3. Hospitalized – mild disease, no oxygen therapy 
4. Hospitalized – mild disease, oxygen by mask or nasal prongs 
5. Hospitalized – severe disease, noninvasive ventilation or high flow oxygen 
6. Hospitalized – severe disease, intubation and mechanical ventilation 
7. Hospitalized – severe disease, ventilation and additional organ support – vasopressors, renal replacement 
therapy, extracorporeal membrane oxygenation 
8. Death 
 


 
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2.0 
SCHEDULE OF ASSESSMENTS (SOA) 
a) For subjects completing treatment at Day 5 
Study period 
Screening Period 
Study Treatment Period (once daily assessment for safety, respiratory support 
requirement7, level of hospital care [ward/ICU] and adverse events during 
hospitalization)2 
Safety and Efficacy Follow Up Period2 
Visit Name 
Screening 
Baseline/ 
Randomize 
 
 
End of 
Treatment 
(EoT) 8 
Safety Follow 
Up (FU) 
Clinical Outcome 
Assessment 
(COA) 
Final Safety 
Follow Up 
(FU) 2 
Mortality 
Follow Up 
Study Day 
Day-2 to Day -1 
(screening and 
randomization can 
be on same day) 
Day 1 
Day 2 
Days 3 and 4 
Day 5 
Day 10 
(+/- 2 days) 
Day 29 
(+/- 2 days) 
Day 60 
(+/- 4 days) 
Day 90 
(+/- 7 days) 
Eligibility check 
X 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Physical exam (full at 
screening, limited thereafter) 
X 
X 
X 
X 
X 
X 
 
 
 
Study Drug dosing  
 
X 
X 
X 
X 
 
 
 
 
Interim history, concomitant 
med, and adverse event 
recording1, 2 
X 
X 
X 
X 
X 
X 
X5 
X5 
 
Prospective headache query 
 
X 
 
 
X 
 
 
 
 
Pregnancy test (high sensitivity 
serum at screening, urine 
thereafter) 9 
X 
 
 
 
 
X 
 
 
 
Blood draw (screening and in-
study safety monitoring)2, 9 
X 
X 
 
 
X 
X 
 
 
 
 
 


 
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Visit Name 
Screening 
Baseline/ 
Randomize 
 
 
End of 
Treatment 
(EoT) 
Safety 
Follow Up 
(FU) 
Clinical 
Outcome 
Assessment 
(COA) 
Final Safety 
Follow Up 
(FU) 2 
Mortality 
Follow Up 
Study Day 
Day-2 to Day -1 
(screening and 
randomization can 
be on same day) 
Day 1 
Day 2 
Days 3 and 4 
Day 5 
Day 10 
(+/- 2 days) 
Day 29 
(+/- 2 days) 
Day 60 
(+/- 4 days) 
Day 90 
(+/- 7 days) 
Blood draw (biomarkers) 
 
X 
 
 
X 
 
 
 
 
SaO2/FiO2 
 
X 
X 
X 
X 
 
 
 
 
Blood (PK)3 
 
X 
 
 
X6 
 
 
 
 
EKG2,4 
X 
X 
 
 
X6 
 
 
 
 
Progression Endpoint  
(alive and free of respiratory 
failure, respiratory support 
level7) 
 
 
 
 
X 
X 
 
X5 
 
Clinical outcomes 
assessments including WHO 
ordinal scale assessment 
 
X 
X 
X 
X 
X 
X5 
X5 
X5,10 
1 Only SAEs to be collected prior to randomization 
2 Investigations and examination performed as part of routine clinical assessment of COVID-19 may be used for eligibility and in study safety, adverse event and respiratory support requirement 
assessment 
3 Time of PK and last dose of study medication prior to PK to be recorded in CRF 
4 EKG to be taken 1-2 hours after study drug dosing when feasible 
5 Telehealth visit if hospital discharge occurs before scheduled visit  
6 PK and EKG can be taken on any one of Days 3-5 
7 Level of respiratory support determined by need for room air, supplemental oxygen, high flow oxygen, non-invasive ventilation, intubation, mechanical ventilation or ECMO 
8 Subjects who terminate study Before Day 5 should have EOT assessment and Safety Follow Up assessment 5 days +/- 2 days after last dose of study drug 
9 If Screening and baseline are within 24 hours the tests do not need to be repeated at Baseline 
10 Clinical outcome assessment of mortality only 


 
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b) For subjects extending study drug to Day 10 
Study period 
Treatment Period 
Safety and Efficacy Follow Up Period2 
Visit Name 
Extension Period
End of 
Treatment (EoT) Safety Follow Up 
Clinical Outcome 
Assessment (COA) 
Final Safety Follow 
Up (FU) 4 
Mortality Follow Up
Study Day 
Days 6 to 9 
Day 10 
Day 15 +/- 2 days 
Day 29 
(+/- 2 days) 
Day 60 
(+/- 4 days) 
Day 90 
(+/- 7 days) 
Limited Physical exam  
X 
X 
X 
 
 
 
Study Drug dosing  
X  
X  
 
 
 
 
Interim history, concomitant med, and adverse 
event recording1, 2 
X 
X 
X 
X5 
X5 
 
Prospective headache query  
 
X 
 
 
 
 
Pregnancy test (urine) 
 
 
X 
 
 
 
Blood draw  
(in-study safety monitoring)2 
X 
X 
X 
 
 
 
Blood draw (biomarkers) 
 
X 
 
 
 
 
SaO2/FiO2 
X 
X 
X 
 
 
 
EKG2,4 
 
X 
X6 
 
 
 
Progression Endpoint (alive and free of respiratory 
failure, respiratory support level7) 
 
X 
 
 
X5 
 
Clinical outcomes assessments including WHO 
ordinal scale assessment 
X 
X 
X 
X5 
X5 
X5,8 
1 Only SAEs to be collected prior to randomization 
2 Investigations and examination performed as part of routine clinical assessment of COVID-19 may be used for eligibility and in study safety, adverse event and respiratory support 
requirement assessment 
3 Time of PK and last dose of study medication prior to PK to be recorded in CRF 
4 EKG to be taken 1-2 hours after study drug dosing when feasible 
5 Telehealth visit if hospital discharge occurs before scheduled visit  
6 PK and EKG can be taken on any one of Days 3-5 
7 Level of respiratory support determined by need for room air, supplemental oxygen, high flow oxygen, non-invasive ventilation, intubation, mechanical ventilation or ECMO 
8 Clinical outcome assessment of mortality only 


 
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3.0 
INTRODUCTION 
3.1 
Background 
Infection with the SARS-CoV-2 virus has led to the coronavirus disease 2019 (COVID-19) 
pandemic, affecting global health and economies on an unprecedented scale (Zhu et al 2020; 
Holshue et al 2020; Goyal et al 2020). The spectrum of illness ranges from asymptomatic to 
critical, with mild symptoms in ~80% of cases. However, severe disease is characterized by 
dyspnea, hypoxemia, and respiratory failure with acute respiratory distress syndrome (ARDS), 
shock, and multi-organ failure. As of June 10, 2020, the World Health Organization reported that 
there are over 7.2 million cases of COVID-19 worldwide, accounting for nearly 413,000 deaths 
(World Health Organization | COVID-19 Situation Report 142, June 2020). While the use of 
stay-at-home orders, social distancing, and deployment of limited business models have resulted 
in a “flattening of the curve”, the number of new cases and deaths continue to rise and there are 
limited therapeutic options. To date there are no approved therapies for SARS-CoV-2 infection, 
though antiviral medications have shown the most promise (Grein et al 2020; Cao et al 2020). 
Other strategies have included targeting host inflammatory pathways or repurposing existing 
medications, but these have not been successful in early trials (Geleris et al 2020; Ingraham et al 
2020; Mercuro et al 2020). Emerging data demonstrated reduced mortality with use of 
dexamethasone from a placebo-controlled trial (Horby et al 2020). The evidence of 
immunopathogenesis of COVID-19 disease supports the potential of intervention with 
immunomodulators in addition to the efforts in anti-viral therapy. 
3.2 
Study Rationale 
The clinical course of COVID-19 is characterized by initial symptoms typical of viral infection. 
In some individuals, this is followed several days later by rapid deterioration, concurrent with the 
onset of the immune response (Ingraham et al 2020). An acute innate inflammatory response is 
typical, with elevated pro-inflammatory cytokines, marked elevation of acute phase reactants and 
cytokine storm. Available therapies consist of organ support, anti-coagulation to reduce risk of 
venous and arterial thrombosis, and as needed treatment of infection and sepsis. Repurposed’ 
existing immunomodulating therapies are being progressed through global ‘platform’ trials, 
including for anti-IL6, anti-IL1, dexamethasone and hydroxychloroquine, with results emerging. 
None are specifically targeting neutrophil-driven pathogenic mechanisms. 
Neutrophils and neutrophil extracellular traps (NETs) have recently been established as a central 
feature of SARS-CoV-2 pathogenesis, and NETosis is associated with poor outcomes in patients 
hospitalized with COVID-19 (Zuo et al 2020; Barnes et al 2020). Levels of NETs correlate with 
disease severity in ALI/ARDS outside of COVID-19. NETs are networks of extracellular DNA 
fibers, histones, myeloperoxidase (MPO) and neutrophil elastase (NE), released from neutrophils 
and involved physiologically in capturing bacteria. However, if uncontrolled, NETs are cytotoxic 
to endothelial and epithelial cells; acting as Damage Associated Molecular Pattern Molecules 
(DAMPs), promoting cytokine release and thromboses (Kim et al 2019). Neutrophil elastase is 
essential to NET formation (Papayannopoulos et al 2010) and remains active when decorating 


 
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the NET fibers. The physiological inhibitor of NE is Alpha-1 antitrypsin (AAT), but studies in 
COVID-19 have shown this to be overwhelmed (McElvaney et al 2020) and treatment with NE 
inhibitors have potential to impact the disease progression to ARDS through disruption of 
NETosis. In experimental models of ARDS, alvelestat, the NE inhibitor proposed for this clinical 
trial, protected the lung from inflammation and injury through NET inhibition (Li et al 2018). 
There is evidence from clinical efficacy studies using NE inhibitors in ALI/ARDs. Sivelestat 
(‘Elastpol’) is a selective human NE inhibitor that is approved in Japan and South Korea for the 
treatment of ALI/ARDS accompanied by Systemic Inflammatory Response Syndrome. A meta-
analysis of 6 randomized controlled trials in patients with all forms of ALI/ARDS, did not 
demonstrate an effect on mortality, Intensive Care Unit or ventilator days. However, a sensitivity 
analysis detected a significant improvement in oxygen deficit measured by PaO2/FiO2 
(Standardized Mean Difference (SMD): 0.87; 95% CI: 0.39 to 1.35; p <0.001 (Pu et al 2017) and 
oxygenation at Day 3 (Iwata et al 2010). Sivelestat appeared to have an effect on mortality in 
ARDS associated with disseminated intravascular coagulation (Miyoshi et al 2014), which is 
more closely aligned with pathogenic processes in COVID-19, and provides support for the NE 
mechanism.  
Alvelestat is an oral, specific, NE inhibitor, with experience in over 1000 healthy volunteers and 
patients with lung disease. There has been evidence of mechanistic effect in 4-week duration 
clinical studies of neutrophil-driven diseases (significant decrease in biomarkers of elastase 
activity and inflammation in cystic fibrosis (Elborn et al 2012), and clinically significant 
improvement in lung function and inflammation in bronchiectasis (Stockley et al 2013). 
A scientific rationale for NE inhibition in SARS-CoV-2 infection, plus the established safety 
profile for alvelestat supports investigating alvelestat in COVID-19. Here, we propose a pilot 
randomized control trial assessing the safety and tolerability and exploring biomarkers of 
efficacy and clinical outcomes, by comparing alvelestat on top of standard of care compared to 
placebo on top of standard of care in patients hospitalized with COVID-19.   
The specific objectives of this study are to evaluate the safety and tolerability of alvelestat in this 
first time in disease study, confirm PK and explore evidence for mechanistic effect on NETosis 
and clinical outcomes in patients with COVID-19 respiratory disease. The pathogenesis of 
COVID-19 is complex, where multiple pathogenic mechanisms are in play and this study will 
explore the potential role of NE inhibition. Positive data from this Phase Ib/II trial will support 
progression to a formal dose-ranging efficacy study, informed by safety, tolerability and PK in 
the COVID-19 population.  
Alvelestat is a potent and specific inhibitor of NE, has predicable PK and an established PK/PD 
relationship in ex vivo neutrophil elastase inhibition (Gunawardena et al 2013). This enables a 
dose to be chosen to fully test the mechanism in COVID-19 disease. Relevant blood biomarkers 
will be used to detect signals of effect. Blood biomarkers of NETosis, cell-free DNA (cf-DNA), 
citrullinated-H3 and MPO-DNA complexes are available. These are elevated in hospitalized 
COVID-19 patients and correlate with disease severity Cell-free -DNA and MPO-DNA 
complexes correlate with acute phase response, C-reactive protein, D-dimers, and neutrophil 


 
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count, whereas citrillunated-H3 with platelet count (Zuo et al 2020). Neutrophil elastase activity 
is measurable by the elastic breakdown product desmosine/isodesmosine, Effects on markers of 
inflammation, proinflammatory cytokines (IL-1beta, IL-6, IL-8 and TNF-alpha) and 
coagulopathy (d-dimer) will explore whether the inhibitory effect of alvelestat on neutrophil 
elastase/NETs delivers potential benefit on the downstream inflammatory and vascular 
processes. These mechanistic effects data in combination with safety and tolerability and 
predictability of PK, will be used to make progression decisions on alvelestat development in 
COVID-19 disease.  
4.0 
OBJECTIVES AND ENDPOINTS 
Objective 
Endpoint 
Primary 
• 
To evaluate the safety and tolerability 
of alvelestat administered twice daily 
(bid) for 5 or 10 days 
By treatment group (alvelestat/placebo): 
• 
Numbers and % of subjects who experience at least 1 
treatment-emergent adverse event to Day 60 (Safety 
Outcome Assessment) 
• 
Adverse events of special interest (liver function 
abnormalities, corrected QT interval, infections, and 
neutropenia) and clinically significant safety 
monitoring labs tests to Day 14 (acute treatment 
period) or EoT  
• 
Number and % of subjects that discontinue alvelestat 
to Day 5 or 10 
• 
Number and % of subjects requiring dose reduction 
to Day 5 or 10 
• 
Number and % of subjects with AE of headache on 
prospective questioning and CTCAE severity Grade 
to Day 5 or 10 
• 
Change in vital signs, EKG, safety laboratory 
measures to Day 5 or 10 or EOT 
Secondary 
• 
To evaluate the effect of alvelestat on 
blood pharmacodynamic markers of 
Neutrophil Extracellular Trap (NET) 
activation, elastase, inflammatory and 
coagulopathy activity 
By treatment group (alvelestat/placebo), change from 
baseline to Day 5 or 10 in: 
• 
Blood biomarkers of NETosis (cell-free DNA; 
citrullinated histone H3; Myeloperoxidase (MPO)-
DNA complexes) 
• 
Blood biomarkers of inflammation (absolute 
neutrophil count; absolute lymphocyte count; 
neutrophil-lymphocyte ratio [NLR], C-Reactive 
protein, procalcitonin 
• 
Pro-inflammatory cytokines IL-1beta, IL-6, IL-8, 
TNF-alpha) 
• 
Coagulopathy as measured by D-Dimer 
• 
Plasma desmosine/isodesmosine 


 
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Objective 
Endpoint 
• 
To explore the effect of alvelestat on 
pulmonary function 
By treatment group (alvelestat/placebo): 
• 
Change from baseline to Day 5 or 10, or EoT in 
SaO2/FiO2 
• 
The effect of alvelestat on disease 
progression 
By treatment group (alvelestat/placebo): 
• 
Proportion of subjects alive and free of respiratory 
failure (without need for non-invasive or invasive 
mechanical ventilation, high flow oxygen, or 
Extracorporeal Membrane Oxygenation (ECMO) at 
Day 29 
• 
The effect of alvelestat on clinical 
outcomes  
By treatment group (alvelestat/placebo): 
• 
Mortality rate to Day 90 safety endpoint 
• 
Proportion of subjects alive and free of respiratory 
failure (without need for non-invasive or invasive 
mechanical ventilation, high flow oxygen, or 
ECMO) at Days 5, 10 and 60 
• 
Length of hospital stay 
• 
Length of ICU stay 
• 
Time to room air (those on supplemental oxygen at 
Baseline) 
• 
The effect of alvelestat on disease 
severity 
By treatment group (alvelestat/placebo): 
• 
Percentage of patients deteriorating (>1 and >2 
increase in WHO 9-point ordinal scale*) at Day 5, 
Day 10, Day 29 and Day 60 
• 
Percentage of patients improving (>1 and >2 
decrease in WHO 9-point ordinal scale) at Day 5, 
Day 10, Day 29 and Day 60 
• 
To explore Pharmacokinetics (PK) in 
patients with COVID-19 
• 
Plasma PK (sparse sampling taken pre or 1-2 hours 
post study drug dosing) in participants randomized 
to alvelestat. 
 
5.0 
STUDY DESIGN  
5.1 
Overall Design and Purpose 
This is a Phase Ib/II single-center, 2:1 randomized, blinded, placebo-controlled, parallel group, 
first in disease study. The purpose is to determine the safety, tolerability and PK and explore the 
mechanistic and clinical effect of alvelestat 240mg orally twice per day for 5 or 10 days added to 
standard of care in adult patients (≥18 years) with COVID-19 respiratory disease. 
The study is divided into 3 periods:  a screening period, treatment period, and follow up period 
(Figure 1) 


 
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Figure 1: 
Study Schematic 
 
 
• 
A screening period from Day -2 to randomization.  Eligibility assessments and written 
informed consent will occur prior to randomization and treatment arm allocation. Serious 
Adverse Events will be collected during screening. 
• A treatment period consisting of alvelestat/matched placebo 240 mg/matched placebo bid 
Days 1 to 5 given on top of standard of care (SoC – per local clinical guidelines). Safety 
assessments including vital signs, liver and renal function, EKG, and hematology will be 
assessed at baseline, then as per the Schedule of Assessments (SoA) for the remainder of the 
5-day treatment period. Adverse events, vital signs, respiratory support and concomitant 
medications that may be part of routine clinical care will be collected daily during 
hospitalization. Blood will be collected at baseline and during study drug treatment to Day 5 
for secondary efficacy biomarkers, along with assessment of oxygen deficit assessments 
(SaO2/FiO2). PK sampling will be collected on 2 occasions, at initiation of dosing and at end 
of treatment (EoT) for steady state analysis. For patients that remain hospitalized at Day 5 
due to COVID-19, an optional extension period of treatment to Day 10 may be given and can 
be referred to on the separate SOA covering this extension. Clinical outcomes of disease 
progression (respiratory support requirements), disease severity (WHO ordinal scale), will be 
completed at Baseline (Day 1), during the treatment period to (Day 5 or 10), or EoT and to 
Day 60 (Clinical Outcome Assessments). Those subjects who are unable to complete the 
treatment period for any reason, including those discharged from hospital prior to completion 
of Day 5 or 10, will discontinue study drug and undergo an EoT assessment. Wherever 
possible they will continue to be followed up in the study.  
Including optional treatment 
extension to Day 10: 


 
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• A follow-up period from Day 5 or 10/EoT to Day 90. This is for safety testing to end of 
systemic drug exposure (Day 10 for 5-day study, Day 15 for 10-day study or 5 days after 
EoT), to Day 60 for longer term safety and to Day 90 for mortality data collection, for the 
Clinical Outcome Assessments (COA) to Day 60) and mortality (Day 90). Visits after 
Day 10 or Day 15 (or 5 days +/- 2 days after last dose), may be by telehealth visits. Adverse 
events, vital signs, respiratory support and concomitant medications that may be part of 
routine clinical care will be collected daily during hospitalization and to the Day 29 and 
Day 60 assessments (may be collected by telehealth call). 
 
5.2 
Number of Participants 
Approximately 20 subjects will be screened in order to recruit 15 (10 randomized to alvelestat + 
SoC; 5 randomized to SoC). Subjects who discontinue study drug or the study will not be 
replaced. 
5.3 
End of Study Definition 
The end of the study is defined as the date of all data being entered into the study database. The 
primary analysis of safety, biomarker and clinical outcomes efficacy will be performed when the 
last subject has completed Day 60 follow up, with the database being locked and ready for 
analysis. The Day 90 mortality data will continue to be collected and added to the database and 
reported separately. 
5.4 
Scientific Rationale for Study Design  
As the first study of alvelestat in the COVID-19 patient population, investigation of safety and 
tolerability are the primary objectives, and are appropriately investigated in a small 15 subject 
study. Given the severe nature of COVID-19, alvelestat or identical placebo will be dosed on top 
of full standard of care. A blinded, placebo-controlled design will support interpretation of 
safety, tolerability and efficacy biomarkers. Historic comparators were not considered as the 
evolution of the pandemic and changing management of COVID-19 means that a placebo arm 
recruited in parallel is a more robust approach.   
Neutrophils and NETosis play a critical role in the acute inflammatory response and the most 
appropriate time to intervene is early in its initiation, to reduce the risks of further progression. 
Therefore, the target population is those with proven SARS-CoV-2, requiring hospitalization, 
with evidence of pulmonary disease on chest radiograph or Computerised Tomography (CT) or 
other relevant imaging, but not progressed to severe disease (i.e. not requiring mechanical 
ventilation or with multi-organ failure) at the point of recruitment. This population is known to 
have an acute phase response and evidence for neutrophil activation (raised CRP and absolute 
neutrophilia, with activation of the NETosis pathway (Zuo et al 2020), therefore giving potential 
to detect a mechanistic signal in the study. At this stage neutrophil elastase may be a key 
pathogenic driver and its inhibition stand the greatest chance of success.   


 
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The duration of dosing will be for 5 days with optional extension to 10 days for subjects who 
remain hospitalized with SARS-Cov2 related disease per investigator decision. Deterioration in 
COVID-lung disease in hospitalized patients to intubation is rapid and bimodal with modes as 
3-4 days and 9 days from the date first symptoms recorded (Argenziano et al 2020) and even 
shorter period from date of hospital admission with the most patients worsening within the first 
3 days (Vultaggio et al 2020). With improvements in management of COVID-19 hospital stays 
have decreased to a mean of 5 days. Therefore, 5 days treatment will provide NE inhibition to 
cover the critical risk period during hospitalization, with the option to continue to 10 days for 
those who disease remains active requiring ongoing hospitalization by Day 5. 
An within-patient dose-escalation approach commencing at 120 mg bid Day 1, increasing to 
180 mg bid Day 2 and 240 mg bid Days 3 to 10, was previously used to address tolerability 
(headache) issues that have been identified for alvelestat. Experience to date is that study drug 
has been well tolerated, and in order to rapidly achieve drug levels during the acute phase of 
COVID-19, study drug will be initiated at 240 mg bid. Dose de-escalation, including to 120 mg 
bid, will be allowed in protocol-defined circumstances (Section 8.1.2) for toleration as 120 mg 
bid is still predicted to provide adequate NE inhibition. Dose de-escalation below 120 mg bid 
will not be permitted. 
5.5 
Justification for Dose  
Oral doses of alvelestat 2 mg to 150 mg have been evaluated in healthy participants. Following 
acceptable safety profile of repeat dosing of 60 mg bid in over 1000 individuals (patients with 
COPD, cystic fibrosis and bronchiectasis), doses of 120 mg to 240 mg bid have been progressed 
into clinical studies in Bronchiolitis Obliterans Syndrome (BOS) and alpha-1 antitrypsin 
deficiency (AATD) lung disease, dosing for up to 6 months duration with an acceptable safety 
profile. 
Alvelestat is rapidly absorbed (median time to reach peak concentration 0.5 to 1.5 h), with a 
dose-proportional increase in systemic exposure. The terminal half-life of between 
approximately 5 to 10 hours in patient studies, supports twice daily dosing and enable rapid wash 
out if any concerns on safety or tolerability for individuals in the study. Multiple dosing shows 
no clinically relevant accumulation, and the PK profile was generally similar between healthy 
participants and patients with COPD, bronchiectasis and cystic fibrosis, Caucasians and Japanese 
(Gunawardena et al 2013). It is not expected that PK will show meaningful difference in patients 
with COVID-19 lung disease. Pharmacologically relevant concentrations of alvelestat are present 
in induced and spontaneous sputum in patients with bronchiectasis and COPD (Gunawardena et 
al 2013; Stockley et al 2013). 
Alvelestat demonstrates dose-dependent pharmacodynamic (PD) profile in inhibition of 
zymosan-stimulated neutrophil elastase activity in ex vivo cells from studies in man. Although at 
plasma alvelestat concentrations of >100 nM, neutrophil elastase inhibition was differentiated 
from that observed on placebo, plasma concentrations >300 nM, were required to give 
meaningful effects achieving a mean neutrophil elastase inhibition of greater than 92%. 


 
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A Population PK model has been developed and used to simulate doses to meet the required 
exposure >300 nM at steady state trough levels over the full dosing period of bid dosing. A dose 
of 240 mg bid was selected as the target dose based on predicted trough PK levels >300 nM in 
approximately 90% of participants and within acceptable safety margins over the full 24-hour 
period. Simulations predict 120 mg bid to deliver trough PK levels >300 nM in approximately 
50% of participants and 240 mg in approximately 90% of participants. In an ongoing study of 
alvelestat in AATD, headache, a known adverse event associated with alvelestat, appears to be 
more frequent in those dosed with 240mg bid and impacts tolerability. Experience to date in this 
trial is that study drug has been well tolerated, and in order to rapidly achieve drug levels during 
the acute phase of COVID-19, study drug will be initiated at 240 mg bid. The allowance for dose 
de-escalation (including down to 120 mg bid) in protocol-defined circumstances (Section 8.1.2) 
if needed to maintain tolerance. 
As summarized below, the preclinical toxicology studies provide adequate safety margins for 
progressing to the 240 mg bid dose for 5 or 10 days in this study. The clinical safety experience 
with alvelestat to date, including to 240 mg bid, has shown no safety signals that prevent 
progression of the proposed dose in this study. A potential concern around transaminase 
elevation is monitorable and reversible, there have been no cases of drug induced liver injury. 
The safety of patients will be managed through the exclusion and inclusion criteria and safety 
monitoring approach, taking into account the preclinical toxicology data and clinical safety 
information.  
5.6 
Preclinical Safety Studies 
The safety margins for alvelestat have been evaluated in preclinical toxicology studies in two 
rodent and one non-rodent species (up to 6 months in rats, 12 months in dogs, and 3 months in 
mice), providing adequate cover for the 10-days dosing.   
In rats, the no adverse effect level (NOAEL) was 370 mg/kg/day (1-month gavage) and 
500 mg/kg/day (dietary 1 to 6-month studies). These were the highest doses studied, and no 
toxicity was observed. 
In dog, 1-, 3-, and 12-month toxicology studies at doses of 1.2, 12, and 122 mg/kg showed 
limited effect at the intermediate and high doses, including small decreases in body weight, small 
increases in plasma creatinine and triglycerides, and minor effects on electrocardiogram (EKG) 
with a transient increase of the QTc by Van de Water’s correction formula (QTcV) (<10%). The 
NOAEL was considered to be 122 mg/kg. In telemetered dogs at doses of 50 mg/kg 
(corresponding to a peak plasma concentration of 39.9 µM), a mean increase of 9% (individual 
increases of 8% to 14%) in QTcV was seen. 
In mice, alvelestat was well tolerated at doses up to 2000 mg/kg. Histopathology indicated slight 
focal hepatic necrosis above control. Additional effects in liver included minor increase in 
glycogen vacuolation at 2000 mg/kg, slight hypertrophy in males at 1000 mg/kg, and increased 
incidence above control of inflammatory foci in females at 1000 mg/kg. A recovery group 


 
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indicated possible reversibility, although the interpretation was difficult due to the low-grade 
change. Overall, focal necrosis is regarded as a non-specific response in mice, with no signs of 
progression or persistence and the relevance for humans is likely to be limited. 
Preclinical toxicology findings, with the exception of QTc change, would be expected to be 
driven by area under the curve (AUC). Based on preclinical data, a human exposure limit 
corresponding to the AUC at the NOAEL (500 mg/kg) in the rat 6-month study (free AUC of 
14.7 µM.h, corresponding to a total human AUC of 25.8 µM.h) is considered as acceptable in 
clinical studies. Significantly higher exposure levels have been evaluated in dogs for 12 months 
without any adverse effects.   
The maximum 240 mg bid dose in man is predicted to give an AUC of 23287 nm.h, 
approximately 27.2-fold lower than that at the NOAEL in the 12-month study in dogs and 
10.9-fold lower than NOAEL in the 6-month study in rats. The AUC is predicted to be 
approximately 9-fold below the level where liver findings in mice (increase in background 
pathology of likely limited relevance to man) were seen.  
The maximum observed concentration following 240 mg bid in man is predicted to be 3840 nM, 
approximately 10-fold lower than the concentration that resulted in small (<10%) changes in 
QTcV in telemetered dog.    
Alvelestat met criteria for phototoxicity in in vitro test systems and has a potential skin 
phototoxicity risk. Photo-safety precautions will be advised during the study. 
Alvelestat is considered not to represent a significant genotoxic risk. Reproductive toxicology 
studies in rats and rabbits do not indicate any effects of alvelestat on male or female fertility or 
embryofetal development. 
There is a potential for drug interactions. Drugs that are mainly metabolized by CYP2C9 and 
have a low therapeutic index, require drug levels to be monitored during the dosing period or 
drugs prohibited. Potential to interact with OATP1B1 has not been excluded and drugs that are 
substantially reliant on OATP1B1 for metabolism (e.g., enalapril and repaglinide), will be 
prohibited or clinical monitoring applied during the study drug dosing period. The potential to 
inhibit P-gp has also not been excluded with risk to reduce intestinal drug absorption. Therefore, 
concomitant oral therapies should not be administered within 1 hour of alvelestat administration. 
For more detailed information on the toxicology and nonclinical safety studies conducted to date, 
please refer to the current Investigator’s Brochure. 
5.7 
Clinical Safety Studies 
Clinical experience comes from 12 completed healthy volunteer and patient studies in which 
1149 subjects have received at least 1 dose of alvelestat. The highest single dose that has been 
given is 150 mg and the highest repeat dose is 240 mg bid (for 6 months). In clinical studies, 
540 COPD patients have received 60 mg bid for 3 months and 22 patients with bronchiectasis 


 
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and 26 patients with cystic fibrosis have received 60 mg bid for 28 days. Completed clinical 
studies to date have not revealed any adverse effects on blood pressure, EKG, hematology, or 
urinalysis that could be linked to any of the observations in toxicology studies. For clinical 
chemistry, there has been 1 patient with bronchiectasis with an instance of transient raised 
transaminases and 1 patient with cystic fibrosis with an increase in creatine kinase, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase. 
In the studies in COPD patients, there were 14 instances where patients experienced raised ALT 
or AST to ≥3 × upper limit of normal (ULN) across the studied doses (alvelestat 5, 20, and 60 
mg bid). Although definitive evidence of dose relationship was lacking, there was a suggestion 
of an increased incidence of liver transaminase elevations in patients on alvelestat for which 
there were no definitive alternative explanations. The highest transaminase elevations occurred 
in the highest alvelestat dose (60 mg bid). There have been no cases of Hy’s law related to 
alvelestat treatment reported in any of the studies to date (including up to 240 mg bid). The liver 
abnormalities noted to date with alvelestat, including from study in AATD-related lung disease 
dosed at up to 240 mg bid (Study MPH966-2-01, NCT03636347) have been infrequent 
(only 5 liver-related adverse events have been reported and no SAEs of liver abnormalities have 
been reported in study and values rarely above 3x ULN. Furthermore, all abnormal liver changes 
that have been observed have been reversible either with or without study drug interruption.  
The experience of alvelestat doses of 240 mg bid comes from 3 ongoing clinical studies. In a 
study in patients with bronchiolitis obliterans syndrome associated with chronic graft versus host 
disease following allogenic hematopoietic stem cell transplantation (NCT02669251), doses of up 
to 240 mg bid are being given. To date, 7 patients have received 240 mg bid dose for up to 
6 months. One patient underwent dose reduction to 180 mg bid following a SAE of severe 
gastroenteritis and renal failure that was considered unrelated to alvelestat. A second patient had 
elevation of transaminases with temporary treatment discontinuation on a dose of 60 mg bid. The 
event was considered related to alvelestat, and drug was restarted at the dose of 60 mg bid at 
recovery following a 2-week temporary discontinuation. 
In the ongoing blinded study in AATD-related lung disease (MPH966-2-01, NCT03636347) 
57 participants have been randomized to date to alvelestat (either 120 mg bid, 240 mg bid) or 
placebo (1:1:1) for 12 weeks duration. No safety signals have been identified. Of the 57 subjects 
the most common treatment emergent adverse events (TEAEs) to date are headache 31 events in 
24 subjects (42.1%), followed by nausea 8 events in 7 subjects (12.3%), exacerbation of COPD 6 
events in 5 subjects (8.8%), nasopharyngitis and respiratory tract infection, 4 events (7.0%) in 4 
subjects each, 3 events in 3 subjects each of dyspepsia, dyspnoea and arthralgia (5.3% for each). 
Tolerability issue of headache, (with migraneous characteristics), has been reported more 
frequently in the 240 mg bid/placebo arm than the 120 mg bid/placebo arm. The headaches 
respond to analgesics or study drug interruption. There have been no elevations in liver enzymes 
of clinical concern, none persisting, meeting protocol discontinuation criteria or Hy’s law. Any 
observed LFT elevations have been transient, reversible and generally return to baseline with 
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In an Investigator Initiated Study also in AATD-related lung disease [ATALANTa Study, 
NCT03679598], fourteen subjects have been treated in this blinded trial to date with 120 mg bid 
alvelestat/placebo.  There have been no SAEs reported in this study to date. There have been no 
deaths in any of the 3 studies doing with 120 mg or 240 mg bid. 
For more detailed information on clinical safety studies conducted to date, please refer to the 
current Investigator’s Brochure. 
5.8 
Benefit-Risk Assessment 
Patients hospitalized with COVID-19 lung disease have an extremely poor outcome. A study of 
1840 enrolees of Kaiser Permanente healthcare plans who were hospitalized with COVID-19 
documented a case fatality ratio of 23.5% among male inpatients and 14.9% amongst females, 
mortality risk increasing with age for both male and female patients (Lewnard et al 2020). Those 
over 65, with co-morbidities of obesity, hypertension, type 2 diabetes, as well as black and Asian 
ethnic groups, are particularly vulnerable. Outside organ support and modest effects of antivirals, 
there are limited therapeutic options currently available in this very high unmet need population. 
Efficacy for alvelestat has been demonstrated in animal models of lung inflammation and 
elastase-induced lung injury. Across clinical studies in COPD, cystic fibrosis, and bronchiectasis, 
there has been some evidence for effects on elastin breakdown, inflammatory biomarkers, and 
lung function. The extent of these effects was not consistent in all studies. This may be due to the 
heterogeneity of the pathogenesis and/or the doses used (maximum 60 mg bid) that would not be 
expected to adequately inhibit neutrophil elastase, allowing inflammatory “escape”. Greater 
efficacy and clinical benefit is expected by using a dose of alvelestat to maintain neutrophil 
elastase inhibition throughout the 24-hour period.  
Headache was the most frequently reported Adverse Event (AE) in 8 of the 12 completed studies 
to date. In healthy volunteer studies, headache was reported more commonly in the alvelestat 
group than the placebo group. Headache was generally mild in intensity (although 1 subject had 
severe headache), and there was no evidence of a dose–related relationship. In studies with cystic 
fibrosis and bronchiectasis, headache was also generally reported more commonly in the 
alvelestat group compared to placebo. In the COPD studies, headache remained one of the most 
common AEs reported and was the most commonly reported treatment-related AEs has also been 
the most frequently reported adverse event particularly in the 240 mg bid dose group in study 
MHP966-2-01 in AATD. The headache is manageable, resolving with analgesics or treatment 
cessation. 
In the Phase 2b COPD program, there were 14 reported events of raised ALT or AST to ≥3 × 
ULN across the studied doses (alvelestat) 5, 20, and 60 mg bid); there were no cases of Hy’s law 
during the treatment period. Although definitive evidence of dose relationship was lacking, there 
was a suggestion of an increased incidence of liver transaminase elevations in patients on 
alvelestat for which there were no definitive alternative explanations. The highest transaminase 
elevations occurred in the highest alvelestat dose (60 mg bid). Elevations in hepatic biochemistry 


 
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assessments (transaminases) observed in patients in the alvelestat studies were confounded by 
alcohol or by concomitant medication, but an effect of alvelestat cannot be excluded at this time. 
COVID-19 disease is frequently associated with mild elevations in transaminases with increases 
>ULN of 75% and 2XULN in 45% of hospitalized patients (Phipps et al 2020). Elevation in 
alkaline phosphatase and total bilirubin are uncommon, and severe liver damage/failure has not 
been reported to date (Tian & Ye 2020). However, patients may be on multiple medications with 
the possibility of drug-related hepatotoxicity and greater sensitivity to any potential effects of 
alvelestat. As mild elevations of transaminases are common, in order to assess for any hepatic 
effects in the target population, participants with transaminases up to 3X ULN will be eligible, 
but only if there is no elevation of bilirubin due to liver dysfunction. In summary, exclusion 
criteria for clinically relevant hepatic disease, close observation and frequent in-study 
monitoring, and study treatment discontinuation criteria are in place to protect the safety of the 
subjects and liver abnormalities are included as adverse events of special interest (AESI). 
There were no other clinically relevant changes in clinical chemistry data in the completed 
studies with alvelestat. There were also no clinically relevant changes in urinalysis were 
observed in the completed studies with alvelestat. There were no changes in EKG or vital signs 
data that indicated a clear treatment effect of alvelestat. However, in light of the minor changes 
in QTc in the dog toxicology, exclusion criteria and regular EKG monitoring at the time of peak 
concentrations of study treatment and discontinuation criteria will be applied in the study. 
Clinically significant changes in EKG are also included as an AESI. 
Defects in ELANE, the gene that encodes neutrophil elastase, are associated with neutropenia and 
susceptibility to infection. To date, no increases in rate or severity of infection or neutropenia 
have been reported with alvelestat. However, patients with COVID-19 are susceptible to sepsis 
and may be on immunosuppressive drugs, such as systemic corticosteroids that increase infection 
susceptibility. Patients with neutropenia will be excluded, new onset of neutropenia will 
constitute a patient stopping criterion, and infections will be an AESI to monitor the safety 
profile in this population. 
The potential phototoxicity risk will be managed by subject guidance on reducing intense sun 
exposure through covering exposed skin and use of sun block as needed. 
At present, based on the cumulative review of the data and with no new safety issues seen in the 
ongoing studies with dosing up to 240 mg bid of alvelestat, the benefit-risk balance supports the 
clinical development of alvelestat in COVID-19. The potential or theoretical safety concerns on 
liver function, QTc changes, and susceptibility to infection are manageable through exclusion 
criteria, monitoring, study treatment discontinuation criteria 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of alvelestat may be found in the current version of the alvelestat Investigator’s 
Brochure. 


 
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6.0 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
6.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if ALL of the following criteria apply: 
Type of Participant and Disease Characteristics 
• Male or Female 
• Age ≥18 years 
• Proven SARS-Cov-2 infection (confirmed by PCR from a nasopharyngeal or lower 
respiratory tract sample or antigen testing from a nasal sample) 
• A score of Grade 3 to 5 on the WHO 9-point Ordinal Scale  
• Male participants must agree to use a highly effective contraception as detailed in 
Appendix 5 during the treatment period and for at least 4 days after the last dose of study 
treatment and refrain from donating sperm during this period 
• Female participants are eligible to participate if not pregnant; not breastfeeding; and at least 
one of the following conditions is met:   
• Not a woman of childbearing potential as defined in Appendix 5  
OR 
• A woman of childbearing potential who agrees to follow the contraceptive guidance 
in Appendix 5. During the treatment phase and for at least 4 days after the last dose of 
study medication 
• Capable of giving signed informed consent which includes a commitment to comply with the 
requirements and restrictions listed in the informed consent form (ICF) and within this 
protocol. 
6.2 
Exclusion Criteria 
Participants are excluded from the study if ANY of the following criteria apply: 
Exclusion Criteria: 
1) Patients who have previously had a score of 6 or 7 on the WHO 9-point Ordinal Scale  
2) Patients who require support with invasive mechanical ventilation at the time of inclusion, or 
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3) Alanine aminotransferase (ALT) OR aspartate aminotransferase (AST) >2 × the upper limit 
of normal (ULN) OR Total Bilirubin >ULN. In patients with a documented history of 
Gilbert’s Syndrome AND baseline total bilirubin elevation consistent with an exacerbation of 
Gilbert’s Syndrome (i.e. no other cause of total bilirubin elevation), subjects may enroll if 
total bilirubin is <5x ULN. 
4) Diagnosis of liver cirrhosis, esophageal varices, ascites or hepatic encephalopathy  
5) Chronic liver diseases such as autoimmune hepatitis, primary biliary cholangitis, primary 
sclerosing cholangitis, Wilson’s disease, haemochromatosis  
6) Significant renal disease or infection (as determined by the Investigator) including stage 4 
chronic kidney disease or estimated glomerular filtration rate <60mL/min  
7) Absolute neutrophil count ≤1000/µL at screening 
8) Myocardial infarction, transient ischemic attack or stroke within 3 months prior to the first 
dose 
9) Current unstable angina or congestive heart failure (New York Heart Association III/IV) 
10) Screening 12-lead EKG with a measurable QTc interval according to Fridericia correction 
(QTcF) >450 ms 
11) Anticipated transfer to another hospital that is not the study center within 24 hours 
12) Allergy to study medication or excipients 
13) Inability to swallow tablets 
14) Other documented comorbidities or laboratory abnormalities that in the opinion of the 
Investigator could affect the outcome of the study assessments, participant safety, or ability 
of the participant to comply with the requirements of the protocol 
15) Any patient whose interests are not best served by study participation, as determined by the 
Investigator 
Excluded Prior/Concomitant Therapy 
16) Requirement for medications mainly metabolized by CYP2C9 and with narrow therapeutic 
index (eg, warfarin, phenytoin) is prohibited unless therapeutic monitoring available for 
duration of alvelestat dosing  
17) Medicines that are potent CYP3A4 inhibitors including (but are not limited to) 
clarithromycin, diltiazem, erythromycin, itraconazole, ketoconazole, ritonavir, verapamil and 
potent inducers including but not limited to phenobarbital, phenytoin and rifampicin, will be 
exclusionary 
18) Requirement for medications substantially reliant on OATP1B1 for metabolism where 
discontinuation during study drug administration is not possible or where fluctuations in 
levels are considered clinically important (as per investigator judgement) and cannot be 
clinically monitored (e.g., statins, valsartan, olmesartan, enalapril, repaglinide) 


 
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Excluded Prior/Concurrent Clinical Study Experience 
19) Participation in any clinical investigation using investigational treatments within 4 weeks or 
5 half-lives of the drug (whichever is longer) prior to the initial dosing (or longer if required 
by local regulations) is prohibited. Use of remdesivir (Veklury) or other COVID-19 
therapies, including antibody treatment under the conditions of the authorization for 
emergency use in the US, and per manufacturer’s instructions, is permitted. 
6.3 
Lifestyle Restrictions 
6.3.1 
Meals and Dietary Restrictions 
There are no specific restrictions in respect of mealtimes and administration of study treatment. 
6.3.2 
Alcohol and Tobacco 
Participants should avoid alcohol during the 5 or 10 days of study drug dosing. 
6.3.3 
Activity 
Subjects should not participate in unaccustomed or more vigorous exercise than usual routine in 
the 48 hours before each blood sample for laboratory safety tests. 
6.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, available eligibility 
criteria, and any SAEs.  Individuals who do not meet the criteria for participation in this study 
(screen failures) may be rescreened after discussion with and approval of the Principal 
Investigator (PI). 
Additionally, individual laboratory parameters or screening tests may be repeated, within the 
screening period, if the result is considered aberrant or not clinically consistent with the patient’s 
health status. Decisions to re-test should be made in conjunction with the study PI. 
7.0 
TREATMENTS 
Study treatment is defined as the investigational treatment alvelestat (MPH966).  


 
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7.1 
Treatments Administered 
There are no bioavailability data to support administration of alvelestat given dissolved in fluid 
or as broken/crushed tablets for administration via nasogastric or other enteric feeding tube. If 
participants are unable to swallow tablets orally, study drug treatment needs to be discontinued 
(Section 8.1). 
Study Treatment Name: 
30mg alvelestat tablets 
Placebo 
Dosage Formulation: 
Tablet 
Tablet  
(identical in appearance to active) 
Unit Dose Strength(s) / Dosage 
Level(s): 
Days 1-5 (or 10): 240mg bid  
(8 x 30mg tablets bid) 
Days 1-5 (or 10):  8 x tablets bid 
Route of Administration  
Oral 
Oral 
Dosing Instructions: 
To be taken bid, 12 hours apart 
Packaging and Labeling: 
Study treatment will be provided in wallets and will be labeled as 
required per U.S. regulations. 
Manufacturer: 
Mereo BioPharma 4 Ltd., 1 Cavendish Place, London, W1G 0QF, 
UK 
 
7.2 
Method of Treatment Assignment  
All participants will be randomized via a random allocation to alvelestat or placebo arms to meet 
enrolment needs of the study. The randomization numbers will be linked to the 2 treatment 
regimens, and the randomization scheme will not be stratified 
7.3 
Blinding  
The placebo and alvelestat tablets are indistinguishable. This is double-blind study. The sponsor 
and principal investigator, will remain blinded to the study treatment allocation until the primary 
safety and efficacy assessment (based on Day 60 data). The site study team and participants will 
remain blinded until end of the study. The randomization list will be kept secure from the study 
team, Investigators, and participants throughout the conduct of the study and until unblinding is 
authorized by the PI. 
7.4 
Preparation/Handling/Storage/Accountability 
Only participants enrolled in the study may receive study treatment, and only authorized site 
staff may supply or administer study treatment. All study treatments must be stored in a secure, 


 
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environmentally controlled, and monitored (manual or automated) area in accordance with the 
labelled storage conditions with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study treatment are provided 
in the Manual of Procedures (MOP).  
7.5 
Treatment Compliance   
The per-protocol dosage, timing, and mode of administration of study treatment may not be 
changed apart from dose titration to manage toleration. Any departures from the intended 
regimen must be recorded in the CRF 
7.6 
Concomitant Therapy 
Treatment for COVID-19 disease, complications and co-morbidities 
Treatment required for medical management of COVID-19 and co-morbidities is allowed 
throughout the study, apart from protocol defined prohibited medications. Other investigational 
treatments should not be started during the period of study follow up. 
CYP2C9 Substrates 
Alvelestat has a weak potential to inhibit CYP2C9. Therefore, medications that are metabolized 
mainly by CYP2C9 and have a narrow therapeutic index are prohibited unless regular blood 
monitoring can be provided. Narrow therapeutic index CYP2C9 substrates include warfarin and 
phenytoin (a complete list is included in the MOP or online at 
http://medicine.iupui.edu/clinpharm/ddis/main-table). 
Enhanced clinical monitoring in patients receiving sensitive/moderate sensitive CYP2C9 for 
enhanced clinical effect should be considered. Moderate sensitive substrates include tolbutamide 
and glimepiride. 
7.7 
Treatment After the End of the Study  
Alvelestat will not be provided after the end of the study.  


 
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8.0 
DISCONTINUATION CRITERIA  
8.1 
Discontinuation of Study Treatment  
In considering discontinuation of the study treatment, the Investigator should give particular 
consideration of the following: 
Liver Test Abnormalities 
The following monitoring schedule is proposed when a case of acute liver function abnormalities 
or worsening of a liver function abnormality is reported: 
1) If ALT or AST increases to >3 × ULN but <5x ULN, in participants with normal 
transaminases at baseline, repeat testing within 48 to 72 hours including ALT, AST, ALP and 
Total Bilirubin [TB], should be performed and query for symptoms made. If repeat testing 
shows ALT or AST persists >3 x ULN (alternatively 2-fold increase above baseline for 
participants with abnormal values before study drug exposure), close observation is to be 
initiated as follows: 
• Regular monitoring (twice to three times a week) is required (AST, ALT, ALP and TB)  
• Initiate potential DILI evaluation for alternative etiologies. Testing for alternative 
etiologies can include serology tests (hepatitis A, hepatitis B, hepatitis C, 
Cytomegalovirus (CMV), Epstein-Barr Virus (EBV), Herpes Simplex Virus (HSV), 
varicella zoster virus (VZV), parvovirus, toxoplasmosis), imaging, and pathology 
assessments (creatine phosphokinase, clotting) as appropriate to the clinical situation. 
Consider a hepatology consult.  
• Follow the patient, if laboratory parameters stabilize or normalize the patient can 
continue on study treatment during this period.   
If the increase in ALT or AST to > 3 x ULN is also in association with abnormalities in TB 
or INR or with clinical hepatitis as specified below, study drug MUST be stopped. 
 
2) If AST or ALT are ≥5x ULN, a repeat value should be obtained within 24-48 hours. If the 
repeat ALT OR AST values is ≥5 x ULN, the drug should be discontinued and the patient 
followed until the laboratory values normalize or stabilize, in addition to initiating potential 
(Drug Induced Liver Injury) DILI evaluation. 
3) When the following abnormal liver test conditions are met, study treatment MUST be 
discontinued, the study PI be informed, and further steps discussed: 
• ALT or AST >3 × ULN and total bilirubin >2 × ULN OR 
• ALT or AST >3 × ULN and international normalized ratio (INR) >1.5 OR  


 
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• Any elevation in ALT or AST with clinical hepatitis: ALT or AST >ULN and the 
appearance of worsening fatigue, nausea, vomiting, right upper quadrant pain/tenderness, 
fever, rash, or eosinophilia 
• Alkaline phosphatase >2x ULN and direct bilirubin >2 x ULN 
4) When the following hepatic adverse events are met, study treatment MUST be discontinued, 
the study PI be informed, and further steps discussed: 
• Regardless of the magnitude of the transaminase elevation, if the bilirubin is elevated 
(any level) in addition to the presence of signs and symptom(s) such as rash, eosinophilia, 
nausea, vomiting, or right upper quadrant pain 
• INR ≥1.5 (unless due to therapeutic anti-coagulant use) and TB ≥2.5 x ULN, irrespective 
of the magnitude of ALT or AST elevation 
• TB elevation ≥2.5 x ULN, and ALP ≥2.5 x ULN for cholestatic liver injury. 
For each scenario, initiate potential DILI evaluation for alternative etiologies and consider a 
hepatology consult. Liver biopsy should be considered for DILI. The complete liver profile 
including PT/INR must be repeated within 48-72 hours after first abnormal value is obtained. 
Follow the patient until laboratory parameters stabilize or normalize. Study medication can be 
restarted only if an alternative etiology is “definitively” identified and liver tests have returned to 
baseline. Testing for alternative etiologies can include serology tests (hepatitis A, hepatitis B, 
hepatitis C, Cytomegalovirus (CMV), Epstein-Barr Virus (EBV), Herpes Simplex Virus (HSV), 
varicella zoster virus (VZV), parvovirus, toxoplasmosis), imaging, and pathology assessments 
(creatine phosphokinase, clotting) as appropriate to the clinical situation.  
Clinically significant liver function abnormalities should be reported as an AE/AESI. 
EKG Abnormalities 
If a clinically significant finding is identified (including but not limited to changes from baseline 
in QTcF after enrolment), the Investigator or qualified designee will determine if the participant 
can continue in the study and if any change in participant management is needed. This review of 
the EKG printed at the time of collection must be documented. Any new clinically relevant 
finding should be reported as an AE. 
When the following EKG change conditions are met, study treatment MUST be discontinued, 
the study PI informed, and further steps discussed: 
• Absolute QTcF >500 ms or >60 ms increase from baseline as confirmed with 3 consecutive 
EKGs taken in a 30-minute period with at least 5 minutes between each EKG. The mean of 
the 3 EKGs will be used for decision making. 


 
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Acute Kidney Injury (AKI) 
Alvelestat is predominantly renally excreted and the effect of acute kidney failure on PK is 
unknown. Participants who develop AKI requiring dialysis or hemofiltration must have study 
drug discontinued. 
Other Laboratory Parameters 
Study treatment MUST be discontinued if the following laboratory parameters criteria are met: 
• Absolute neutrophil count less than or equal to 0.5 x 109/L on 2 consecutive repeat tests 
within 48 to 72 hours. 
Other 
Study treatment MUST be discontinued if the following other criteria are met: 
• Significant safety issues (as judged by the Investigator). This includes AEs considered 
unacceptable by the patient and/or the Investigator 
• Any other protocol deviation that results in a significant risk to subject’s safety 
• Pregnancy as confirmed by positive urine test at any time during the study 
• Withdrawal of informed consent. 
• Progression to intubation/mechanical ventilation or other circumstance where continued 
administration of study drug tablets by the oral route is not possible. 
Participants may voluntarily discontinue investigational treatment for any reason at any time. 
Participant decision on discontinuation of study treatment does not imply an automatic 
withdrawal from the study.  
Refer to the Schedule of Assessments (SoA) for data to be collected at the time of treatment 
discontinuation (EoT) and follow-up and for any further evaluations that need to be completed. 
8.1.1 
Temporary Discontinuation  
Study treatment dosing may be temporarily suspended in the event of: 
• Clinically important laboratory abnormalities 
• Other intercurrent illnesses including acute new infection, major surgery, or gastrointestinal 
problems 
• Use of prohibited treatment 
• Any other protocol deviation that results in a significant risk to the participant’s safety. 


 
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After a laboratory abnormality leading to a delay of dosing normalizes sufficiently, study 
treatment may resume at the discretion of the Investigator in consultation with the PI as needed. 
Similarly, study treatment may resume after the medication leading to suspension of dosing is 
discontinued. A decision to discontinue study treatment and/or to reinstitute study treatment 
should be conveyed to the Study PI. The Investigator may suspend study treatment at any time, 
without consultation with the Study PI if the urgency of the situation requires immediate action 
and if this is determined to be in the participant’s best interest. However, the Study PI should be 
contacted as soon as possible in any case of study treatment discontinuation. 
8.1.2 
Dose De-escalation due to Study Drug Intolerance 
If a participant is unable to tolerate study drug at any time during the study due to symptoms of 
headache, nausea or vomiting despite use of appropriate symptomatic or prophylactic treatments, 
the study drug dose may be reduced for the remainder of the treatment period. This may only 
occur if the following criteria are met and the event is considered related to study drug as 
assessed by the investigator: 
• Adverse event of headache meeting Common Terminology Criteria for Adverse Events of > 
Grade 3 (Severe pain; limiting self-care activities of daily living). 
And/or 
• Adverse event of nausea meeting Common Terminology Criteria for Adverse Event of > 
Grade 3 (inadequate oral caloric or fluid intake). 
And/or 
• Adverse event of vomiting meeting Common Terminology Criteria for Adverse Event of > 
Grade 3 (requiring IV hydration or other medical intervention). 
The change needs to be recorded in the CRF. 
Refer to Appendix 7 for further details of Common Terminology Criteria for Adverse Events 
(CTCAE). 
8.1.3 
Re-challenge 
Resumption of study treatment after temporary discontinuation should always be discussed with 
the study PI or delegate. 
Re-challenge should be performed one time only if the study medication was held due to AST or 
ALT ≥5x ULN. Re-challenge should only occur after the ALT or AST return to pretreatment 
baseline value AND where there is a documented rationale that the elevation was not due to liver 
damage (e.g. technical error in blood test not compatible with the clinical picture and not present 


 
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on repeat testing, raised transaminase from muscle source supported by creatine phosphokinase 
results). 
In the specific case of liver tests meeting the study treatment discontinuation criteria in 
Section 8.1, no re-challenge is permitted. 
8.2 
Discontinuation from the Study 
The Investigator should consider the following when withdrawing a participant from the study: 
• A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, or 
administrative reasons. If a participant withdraws from study drug for any reason, they may 
remain within the study if they continue to consent to do so. 
• If the participant withdraws consent for disclosure of future information, UAB may retain 
and continue to use any data collected before such the withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
8.3 
Lost to Follow-up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in the 
study. 
• In cases in which the participant is deemed lost to follow-up, the Investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 telephone 
calls and mail a certified letter to the participant’s last known mailing address. These contact 
attempts should be documented in the participant’s file. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 


 
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9.0 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA.  
• 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 participants screened and to confirm eligibility or record reasons for screening 
failure, as applicable.  
• Sample handling: Routine bloodwork and laboratory measurements used for safety 
monitoring and eligibility assessment (CMP, coagulation measurements, CBC, pregnancy 
testing, etc.) will be processed and measured using local laboratory.  Samples (blood) used 
for PK or biomarker assessment will undergo initial processing at the local site but will be 
shipped to a central lab (Dr. Wells) at UAB for curation and analysis.  The procedure is 
detailed in the MOP. 
• Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples. 
• Biomarker samples (blood) will be stored for up to 60 months after the end of the study.  
9.1 
Key Screening Assessments 
• SARS-CoV-2 PCR testing or SARS-CoV-2 antigen testing (routine diagnostic test used for 
diagnosis of current illness to be used, no additional test required). It is recognized this may 
have been performed in the period prior to the screening period. 
• Laboratory testing performed for clinical management may be used for screening assessment 
if obtained within 3 days of planned randomization. 
• EKG performed for clinical management may be used for screening assessment if obtained 
within 7 days of planned randomization. 
9.2 
Efficacy Assessments 
9.2.1 
Blood Biomarkers 
Blood 
Blood will be collected as per the SoA, and samples will be collected and processed as described 
by the MOP. Samples may be stored for a maximum of 60 months following the end of study at 
a facility selected by the investigators to enable further analysis of biomarker responses to 
alvelestat.  
Blood Biomarkers of Efficacy Collected 
• NETosis  
o cell-free DNA 
o citrullinated histone H3 
o Myeloperoxidase (MPO)-DNA complexes) 


 
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• Neutrophil Elastase 
o Plasma desmosine/isodesmosine 
• Inflammation 
o Absolute and percentage neutrophil count 
o Absolute and percentage lymphocyte count 
o Neutrophil-lymphocyte ratio [NLR] derived 
o C-Reactive protein 
o IL-1beta 
o IL-6 
o IL-8 
o TNF-alpha) 
o Procalcitonin 
• Coagulopathy  
o D-dimer 
In addition, samples will be stored and analysis may be performed on additional biomarker 
variants thought to play a role in neutrophil elastase–induced damage to evaluate their 
association with observed neutrophil activation responses to alvelestat. 
9.2.2 
SaO2/FiO2 (Oxygen saturation/fraction inspired oxygen 
The ratio of O2 saturation to fraction inspired O2 (SaO2/FiO2) is a reliable, non-invasive 
surrogate for PaO2/FiO2 and predictive for 3-day worsening in patients with COVID-19 
infection (Vultaggio et al 2020). This will be collected at baseline and during the study as in the 
SoA, measured as per local standard operating procedures. 
9.3 
Clinical Outcome Efficacy Measurements 
The following information will be recorded for the Clinical Efficacy Endpoint Assessments, 
including those in 9.3.1 and 9.3.2: 
• Date of hospitalization and discharge 
• Dates of admission to and discharge from ICU 
• Date of death 
• Daily respiratory support requirements (room air, oxygen by mask or prongs, high flow 
oxygen, non-invasive ventilation, Extracorporeal Membrane Oxygenation (ECMO), invasive 
mechanical ventilation (to complete the Disease Progression Endpoint Assessment)) 
• Organ support, vasopressors, renal replacement 
• Limitation of activities of daily living (as required for the WHO 9-point ordinal scale) 


 
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9.3.1 
Effect on disease progression recorded as participant status 
• Alive and free of respiratory failure 
• Alive with respiratory failure (need for high-flow oxygen, Extracorporeal Membrane 
Oxygenation (ECMO), non-invasive or invasive mechanical ventilation 
9.3.2 
WHO 9-Point Ordinal Scale  
Each assessment will be recorded as a number in the CRF based on the status categories below. 
Where possible the timing of each assessment should be similar (i.e. morning or evening 
throughout) 
0. Uninfected, no clinical or virological evidence of infection 
1. Ambulatory, no limitation of activities 
2. Ambulatory, limitation of activities 
3. Hospitalized – mild disease, no oxygen therapy 
4. Hospitalized – mild disease, oxygen by mask or nasal prongs 
5. Hospitalized – severe disease, noninvasive ventilation or high flow oxygen 
6. Hospitalized – severe disease, intubation and mechanical ventilation 
7. Hospitalized – severe disease, ventilation and additional organ support – vasopressors, renal 
replacement therapy, extracorporeal membrane oxygenation 
8. Death 
9.4 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. Daily safety and adverse 
event assessments may include data acquired from routine clinical care. SAEs only to be 
collected during screening. SAEs/AEs to be collected from Randomization to Day 60. 
9.4.1 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, integumentary, and neurological systems. Height 
and weight will also be measured and recorded if possible, based on the clinical conditions. 
• A brief physical examination will include, at a minimum, assessments of the lungs, heart, 
abdomen, and skin. 
• Investigators should pay special attention to clinical signs related to COVID-19 disease. 


 
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9.4.2 
Vital Signs 
Vital signs will be measured in a semi-supine position after 5 minutes of rest and will include 
temperature, systolic and diastolic blood pressure, heart rate, respiratory rate, and pulse 
oximetry.  
• Oral or tympanic temperature. 
• Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for 
the participant in a quiet setting without distractions (e.g., television, cell phones). 
Electrocardiograms 
• 12-lead EKG will be obtained as outlined in the SoA using an EKG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals where 
possible. Refer to Section 8.1 for QTc withdrawal criteria and additional QTc readings that 
may be necessary. 
• Single EKGs will be performed at all scheduled time points, with the exception of when a 
change from baseline occurs that meets drug discontinuation criteria (Section 8.1). In this 
situation, a triplicate measurement is required to confirm the finding and for discontinuation 
decisions. 
• When a triplicate EKG is required, 3 consecutive EKG tracings should be taken in a 30-
minute period with at least 5 minutes between each EKG. 
• QTc value will be calculated using the Fridericia formula (QTc=QT/3√RR). Alternative may 
be used in discussion with PI. 
9.4.3 
Headache 
A proactive query for headache will be made at Baseline, and at end of treatment as per SoA and 
graded by CTCAE criteria (Grade 0- No headache, Grade 1 Mild pain Grade 2-Moderate pain; 
limiting instrumental activities of daily living, Grade 3 Severe pain; limiting self-care activities 
of daily living). 
9.4.4 
Clinical Safety Laboratory Assessments 
• Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SOA 
for the timing and frequency. 
• The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those that are not associated with the underlying disease, unless 
judged by the Investigator to be more severe than expected for the participant's condition. 


 
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• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline, 
with a frequency based on the judgement of the Investigator. If such values do not return to 
normal/baseline within a period of time judged reasonable by the Investigator, the etiology 
should be identified and recorded in the CRF. 
The monitoring schedule proposed for a case of acute liver function abnormalities or 
worsening of a liver function abnormality is reported is listed in Section 8.1 (Liver Test 
Abnormalities). 
• Clinically significant liver function abnormalities should be reported as an AE/AESI.  
• All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the SOA.  
9.4.5 
Data Monitoring 
Safety will be regularly reviewed by the Principal Investigator or delegate. 
9.5 
Adverse Events 
The definitions of an AE, SAE, SUSAR, and UP can be found in Appendix 4. 
An AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative).  
The Investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant 
to discontinue the study treatment (see Section 8.1). 
9.5.1 
Time Period and Frequency for Collecting AE and SAE Information  
All SAEs will be collected from the signing of the ICF until the follow-up visit at the time points 
specified in the SoA. SAEs/AEs will be collected from Baseline/Randomization to Day 60 and 
mortality to Day 90. 
All SAEs will be recorded and reported to safety reporting group within 24 hours, as indicated in 
Appendix 4.  
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 4. 
9.5.2 
Follow-up of an AE and/or SAE 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and non-serious AESIs (as defined in 


 
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Section 9.5.3), will be followed until resolution, until stabilization, until the event is otherwise 
explained, or until the participant is lost to follow-up (as defined in Section 8.3). Further 
information on follow-up procedures is given in Appendix 4. 
9.5.3 
Adverse Events of Special Interest 
Some AEs, regardless of their severity or outcome, will be expedited due to the relevance for 
subject safety or study treatment safety profile. These events should be reported to safety 
reporting group within 24 hours, as indicated in Appendix 4. The AESIs for alvelestat are: 
• Liver function abnormalities defined as: 
a) Any occurrence of (i) ALT or AST elevations >5 × ULN or (ii) ALT or AST >3 × ULN 
and total bilirubin >2 × ULN or INR >1.5 or the appearance of worsening fatigue, 
nausea, vomiting, RUQ pain/tenderness, fever, rash, or eosinophilia. 
b) Any occurrence of <5 × ULN or ALT or AST <3 × ULN and total bilirubin <2 × ULN 
where the tests have been repeated within 48 to 72 hours and the elevation confirmed on 
at least 2 separate occasions.  
For participant safety and to ensure that the hepatotoxic potential of the study treatment to be 
determined, a standardized procedure for identification, monitoring, and evaluation of liver 
events must be followed as outlined in Section 9.4.4 and Section 8.1.  
• EKG 
If a study subject experiences any of the following cardiovascular events, the event should be 
reported immediately as an AESI and the study treatment discontinued: 
a) Absolute QTcF >500 ms or >60 ms increase from baseline. 
b) Any clinically significant cardiac abnormality on EKG. 
• Infection 
Any new infection that requires the use of systemic antimicrobial treatment (antibiotics, anti-
viral, anti-fungal, or anti-mycobacterial) should be investigated with clinically relevant 
diagnostic tests. 
• Neutropenia 
Absolute neutrophil count less than or equal to 500 per µL on 2 consecutive repeat tests 
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9.5.4 
Regulatory Reporting Requirements for SAE 
• Prompt notification by the Investigator to safety reporting group of an SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study treatment under clinical investigation are met.  
• Mereo have a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and will be forwarded to 
Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (e.g. summary or listing of SAEs) will file it along with the 
Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements. 
9.5.5 
Pregnancy 
• Details of all pregnancies in female participants and female partners of male participants will 
be collected after the start of study treatment and until 5 half-lives (4 days) after the last dose. 
• If a pregnancy is reported, the Investigator should inform the safety reporting group within 
24 hours of learning of the pregnancy and should follow the procedures outlined in 
Appendix 5. 
• Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
Partner Pregnancies 
Pregnancy outcomes must be collected for the female partners of the subjects who took study 
treatment in this study. Pregnancy itself is not regarded as an AE unless there is suspicion that 
the study treatment may have interfered with the effectiveness of a contraceptive medication. If a 
pregnancy is reported for a subject’s partner, study treatment will be immediately discontinued. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) must be followed and documented. A follow-up report should be sent 
with any new information regarding the pregnancy and the outcome of the birth.  
9.6 
Treatment of Overdose 
For this study, any dose of alvelestat greater than 240 mg bid within a 24-hour time period will 
be considered an overdose. 
There is no specific treatment for an overdose. Any treatment should be supportive as indicated 
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In the event of an overdose, the Investigator/treating physician should: 
1) Contact the study PI immediately. 
2) Closely monitor the participant for AE/SAE and laboratory abnormalities until alvelestat can 
no longer be detected systemically (at least 3 days). 
3) Obtain a plasma sample for PK analysis within 3 days from the date of the last dose of study 
treatment if requested by the study PI (determined on a case-by-case basis). 
4) Document the quantity of the excess dose as well as the duration of the overdosing in the 
CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Study PI as necessary based on the clinical evaluation of the participant. 
9.7 
Pharmacokinetics 
Sparse PK sampling will be performed before and after study treatment dosing as detailed in the 
SoA and Study Manual. 
• Blood samples of approximately 3 mL will be collected for measurement of blood 
concentrations of alvelestat as specified in the SoA. Instructions for the collection and 
handling of biological samples are in the MOP. The actual date and time (24-hour clock 
time) of each sample will be recorded. 
9.8 
Pharmacodynamics  
Pharmacodynamic markers form the secondary efficacy endpoints in this study and are covered 
in Section 9.2.1. 
10.0 
STATISTICAL CONSIDERATIONS  
10.1 
Sample Size Determination  
Over the course of the study, 15 participants will be randomized in a 2:1 ratio to receive one of 
the following:  alvelestat or placebo on top of SoC or SoC alone .  
The primary objective of the study is safety and tolerability. All efficacy analyses are considered 
exploratory and hypothesis-generating. This is a pilot study and it is not formally powered based 
on any specific endpoint. Sample size has been set to minimize the number of patients exposed, 
but still large enough to give adequate safety and tolerability data to support progression of 
further development, to support estimates on the PK of alvelestat in the target population and to 
examine for signals on mechanistic and clinical outcome effect. 


 
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10.2 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Enrolled Set 
The Enrolled Set will include all participants who sign the ICF 
Full Analysis Set 
The Full Analysis Set will include all subjects who signed the ICF and 
were subsequently randomized into the study. Subjects will be analyzed 
according to randomized treatment (alvelestat or placebo). The FAS will 
be used for efficacy analyses. 
Safety Set 
All randomized participants who take at least 1 dose of study drug.  
Participants will be analyzed according to randomized treatment. The 
Safety Set will serve as the primary population for the analysis of safety 
and tolerability primary endpoint. Subjects will be analyzed according to 
randomized treatment (alvelestat or placebo) 
Per-Protocol Set 
Used for sensitivity testing and signal detection for efficacy analyses. The 
Per-Protocol Set includes all participants from the Full Analysis Set who 
have been treated according to the protocol and fulfil the following 
criteria: 
1) 
All inclusion/exclusion criteria affecting efficacy satisfied 
2) 
Absence of relevant protocol violations with respect to factors 
likely to affect the efficacy of alvelestat treatment. 
3) 
Adequate alvelestat compliance 
Subjects will be analyzed according to randomized treatment. 
PK Set  
The PK Set will include all participants randomized to the alvelestat arm 
in the Safety Set who have at least 1 evaluable serum concentration. 
 
10.3 
Statistical Analyses  
The main population for safety and tolerability analysis will be the Safety Set. The main 
population for efficacy analysis will be the Full Analysis Set; supportive analyses will also be 
performed using the Per-Protocol Set.  
Continuous data will be presented using descriptive summaries (e.g., mean, standard deviation, 
minimum, maximum, median, lower quartile, and upper quartile). Categorical variables will be 
presented by the number of observations and relative (%) frequency.   
Unless otherwise stated, baseline value for any variable will be the last value taken prior to the 
first dose of study medication. 


 
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Unless otherwise stated, all statistical tests will be 2-sided and conducted at the 5% level. All 
presented confidence intervals will be 2-sided 95% confidence intervals. 
Handling of Missing Data 
The study is designed to reduce the extent of missing data by alignment of assessments with 
routine clinical management where possible, by the use of clinical outcomes measures that are 
expected to be routinely collected for hospitalized patients with COVID-19 and use of telehealth 
assessments where appropriate to reduce the study burden on patients. However, missing data 
must be anticipated and handled as follows: 
When a patient drops out of a trial full reporting of all reasons for their discontinuation will be 
collected.  
For statistical analyzes missing values are considered a potential source of bias. A multiple 
imputation of missing data approach will be applied, using pattern mixture model methodology. 
Within each treatment, 4 proposed data patterns will be defined as follows: 
• Pattern 1: will include patients who completed treatment on study drug 
• Pattern 2: will include patients who discontinue treatment early due to AEs 
• Pattern 3: will include patients who discontinue treatment early due to lack of 
therapeutic efficacy (LOTE) 
• Pattern 4: will include patients who discontinue treatment early due to reasons other 
than AE event or LOTE. 
The strategy for dealing with missing values will be further detailed in the statistical analysis 
plan. If the pattern of missing data is different to that envisaged, including following blinded 
review of the data at the end of the trial the strategy and the Statistical Analysis Plan (SAP) will 
be updated. 
Descriptive statistical summaries will use Observed Case (OC) data and no missing data values 
will be imputed. 
The SAP will be developed and finalized before database lock and will describe the selection of 
participants to be included in the analyses and procedures for accounting for missing, unused, 
and spurious data. Below is a summary of planned statistical analyses of the primary and 
secondary endpoints. 


 
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10.3.1 
Safety Analyses (Primary Endpoint) 
All safety analyses will be performed on the Safety Set. Comparison of alvelestat and placebo 
will be performed using an analysis of covariance (ANCOVA) model for continuous variables. 
Endpoint 
Statistical Analysis Methods 
AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Summaries will be by system organ class and preferred term. 
Treatment-emergent AEs are defined as any AE occurring or worsening on or after 
the first dose of study medication. If a participant experiences the same preferred 
term multiple times, the event will be counted only once overall and by the greatest 
severity. 
The frequency and incidence of treatment-emergent AEs will be presented by 
system organ class and preferred term for each treatment group (number and 
percentage of participants experiencing at least 1 AE per preferred term as well as 
the number of observed events per preferred term). Separate tables will be 
presented by severity and by relationship. All AEs will be presented in full in a 
comprehensive listing including participant number, treatment regimen, severity, 
seriousness, action taken, outcome, relationship to treatment, onset/stop, and 
duration. Details of SAEs and AEs leading to withdrawal will be listed separately. 
Adverse Events of Special Interest 
AESIs, including liver function abnormalities, EKG events, infections, and 
neutropenia, will be tabulated and summarized by treatment group and overall. 
 
Headache 
AE of headache by CTCAE Grade will be summarized by the number and 
percentage within each category and change from baseline will be summarized by 
shift tables. 
Vital Signs 
Vital signs will be summarized as observed values and change from baseline by 
treatment group and overall. 
Physical Examination 
Physical examination results will be listed by subject ID and body system. 
EKG 
EKG parameters will be summarized as observed values and change from baseline 
by treatment group and study visit. 
Abnormal findings (“normal”, “abnormal, not clinically significant”, and 
“abnormal, clinically significant”) will be summarized by the number and 
percentage within each category and change from baseline will be summarized by 
shift tables. 
Clinical Laboratory 
Laboratory parameters will be summarized as observed values and change from 
baseline by treatment group and study visit. 


 
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Endpoint 
Statistical Analysis Methods 
Values outside the normal range will be summarized by the number and percentage 
within each category and change from baseline will be summarized by shift tables. 
Mortality 
The number and % of participants who have died by day 90. 
Safety and PK Relationships 
The safety correlation analysis with drug concentration may be done for the safety 
parameters shown to be sensitive to alvelestat exposure. The comparison of 
exposure will be done between groups with non-clinically significant changes and 
clinically significant changes in safety parameters using graphic and statistical 
methods where data allow.  
 
10.3.2 
Efficacy Analyses (Secondary Endpoints) 
Comparison of alvelestat and placebo will be performed using an analysis of covariance 
(ANCOVA) model for continuous variables, with Least Squared means for the difference 
between pairwise treatment regimens, standard errors, two-sided 95% CIs and P-value for the 
difference between pairwise treatment regimens.  
Categorical variable will be compared between treatments by Chi-square test (or Fisher’s exact 
test as appropriate). 
Endpoint 
Statistical Analysis Methods 
Biomarkers 
Within individual absolute and % change from baseline will be 
calculated. An analysis of covariance (ANCOVA) model with 
baseline levels as a covariate and treatment strata as factors will be 
used to generate least squared means and least squared mean 
differences between treatment groups.  Continuous measures will 
be log transformed where appropriate.  
The parameters during treatment will be compared to the baseline 
values for active and placebo patients separately to evaluate natural 
variability of the markers.  
The time-matched biomarker values will be compared between 
placebo and active groups to assess the differences outside natural 
variability and time to significant change for the responsive 
biomarkers. 
SaO2/FiO2 
Within individual absolute and % change from baseline will be 
calculated. 
Disease progression  
(alive and respiratory failure 
free) 
The proportion alive and respiratory failure free will be presented 
by the number of observations, absolute and relative (%) 
frequency. 


 
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Endpoint 
Statistical Analysis Methods 
Other clinical outcomes  
Continuous variables (e.g. duration of hospital/ICU stay) mean, 
standard deviation, minimum, maximum, median, lower quartile, 
and upper quartile). 
Change is level of respiratory support will be presented as shift 
tables. 
Time to event (e.g. time to room air, to death, to discharge), will be 
analysed using Kaplan-Meier methods, and quartiles for the 
median time to event will be presented together with their 95% 
confidence intervals. Comparisons between treatment regimens 
will be performed by means of the log-rank test. 
Disease severity  
(WHO 9-point ordinal scale) 
Change from baseline will be presented as mean, standard 
deviation, minimum, maximum, median, lower quartile, and upper 
quartile). 
Responder analyses (improvement and deterioration) will be 
presented as number of observations, absolute and relative (%) 
frequency. 
 
10.3.3 
PK Analyses  
Descriptive PK analyses will be provided and assessed within the existing Population PK model. 
10.3.4 
Interim Analyses  
No interim analysis is planned for this study.   


 
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11.0 
REFERENCES 
1. 
Argenziano, M., Bruce, S., Slater, C., et al. (2020) Characterization and clinical course of 
1000 patients with coronavirus disease 2019 in New York: retrospective case series. 
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2. 
Barnes, B.J., Adrover, J.M., Baxter-Stoltzfus, A. et al. (2020) Targeting potential drivers 
of COVID-19: Neutrophil extracellular traps. J Exp Med, 217(6). doi: 
10.1084/jem.20200652. 
3. 
Cao, B., Wang, Y., Wen, D. et al. (2020) A Trial of Lopinavir–Ritonavir in Adults 
Hospitalized with Severe Covid-19. N Engl J Med, 382(19), 1787-1799. doi: 
10.1056/nejmoa2001282. 
4. 
Elborn, J.S., Perrett, J., Forsman-Semb, K. et al. (2012) Efficacy, safety and effect on 
biomarkers of AZD9668 in cystic fibrosis. Eur Respir J, 40(4), 969-976. doi: 
10.1183/09031936.00194611. 
5. 
Geleris, J., Sun, Y., Platt, J. et al. (2020) Observational Study of Hydroxychloroquine in 
Hospitalized Patients with Covid-19. N Engl J Med, 382(25), 2411-2418. doi: 
10.1056/nejmoa2012410. 
6. 
Goyal, P., Choi, J.J., Pinheiro, L.C. et al. (2020) Clinical Characteristics of Covid-19 in 
New York City. N Engl J Med, 382(24), 2372-2374. doi: 10.1056/nejmc2010419. 
7. 
Grein, J., Ohmagari, N., Shin, D. et al. (2020) Compassionate Use of Remdesivir for 
Patients with Severe Covid-19. N Engl J Med, 382(24), 2327-2336. doi: 
10.1056/nejmoa2007016. 
8. 
Gunawardena, K., Gullstrand, H. & Perrett, J. (2013) Pharmacokinetics and safety of 
AZD9668, an oral neutrophil elastase inhibitor, in healthy volunteers and patients with 
COPD. Int J Clin Pharmacol Ther. 51(4), 288-304. doi: 10.5414/CP201674. 
9. 
Holshue, M.L., DeBolt, C., Lindquist, S. et al. (2020) First Case of 2019 Novel 
Coronavirus in the United States. N Engl J Med, 382(10), 929-936. doi: 
10.1056/nejmoa2001191. 
10. 
Horby P, Lim WS, et al. (2020) Dexamethasone in Hospitalized Patients with Covid-19 - 
Preliminary Report. N Engl J Med; 10.1056/NEJMoa2021436. 
doi:10.1056/NEJMoa2021436. 
11. 
Ingraham, N.E., Lotfi-Emran, S., Thielen, B.K. et al. (2020) Immunomodulation in 
COVID-19. Lancet Respir Med, 8(6), 544-546. doi: 10.1016/s2213-2600(20)30226-5. 
12. 
Iwata, K., Doi, A., Ohji, G. et al. (2010) Effect of Neutrophil Elastase Inhibitor 
(Sivelestat Sodium) in the Treatment of Acute Lung Injury (ALI) and Acute Respiratory 
Distress Syndrome (ARDS): A Systematic Review and Meta-Analysis. Intern Med, 
49(22), 2423-2432. doi: 10.2169/internalmedicine.49.4010. 


 
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13. 
Kim, E.H., Wong, S-W., & Martinez, J. (2019) Programmed Necrosis and Disease:We 
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Differ, 26(1), 25-40. doi: 10.1038/s41418-018-0179-3. 
14. 
Kuna, P., Jenkins, M., O’Brien, C.D. et al. (2012) AZD9668, a neutrophil elastase 
inhibitor, plus ongoing budesonide/formoterol in patients with COPD. Respir Med, 
106(4), 531-539. doi: 10.1016/j.rmed.2011.10.020. 
15. 
Lewnard, J.A., Liu, V.X., Jackson, M.L. et al. (2020) Incidence, clinical outcomes, and 
transmission dynamics of severe coronavirus disease 2019 in California and Washington: 
prospective cohort study. BMJ, p.m1923. doi: 10.1136/bmj.m1923. 
16. 
Li, H., Zhou, X., Tan, H. et al. (2018) Neutrophil extracellular traps contribute to the 
pathogenesis of acid-aspiration-induced ALI/ARDS. Oncotarget 9(2), 1772-1784. doi: 
10.18632/oncotarget.22744. 
17. 
McElvaney, O.J, McEvoy, N., McElvaney O.F. et al. (2020) Characterization of the 
Inflammatory Response to Severe COVID-19 Illness. AJRCCM Published June 25. 
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18. 
Mercuro, N.J., Yen, C.F., Shim, D.J. et al. (2020) Risk of QT Interval Prolongation 
Associated With Use of Hydroxychloroquine With or Without Concomitant 
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19. 
Miyoshi, S., Ito, R., Katayama, H. et al. (2014) Combination therapy with sivelestat and 
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Papayannopoulos, V., Metzler, K.D., Hakkim, A. et al. (2010) Neutrophil elastase and 
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21. 
Phipps MM, Barraza LH, LaSota PR, et al. (2020) Liver Injury in COVID-19: Prevalence 
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22. 
Pu, S., Wang, D., Liu, D. et al. (2017) Effect of sivelestat sodium in patients with acute 
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17:148. doi: 10.1186/s12890-017-0498-z. 
23. 
Stevens, T., Ekholm, K., Gränse, M., et al. (2011) AZD9668: Pharmacological 
Characterization of a Novel Oral Inhibitor of Neutrophil Elastase. J Pharmacol Exp Ther, 
339(1), 313-320. doi: 10.1124/jpet.111.182139. 
24. 
Stockley, R., De Soyza, A., Gunawardena, K., et al. (2013) Phase II study of a neutrophil 
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25. 
Vultaggio, A., Vivarelli E., Virgili, G, et al (2020) Prompt predicting of early clinical 
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27. 
Zhu, N., Zhang, D., Wang, W. et al. (2020) A Novel Coronavirus from Patients with 
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Zuo, Y., Yalavarthi, S., Shi, H. et al. (2020) Neutrophil extracellular traps in COVID-19. 
JCI Insight. 5(11), e138999. doi: 10.1172/jci. insight.138999. 
 


 
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12.0 
APPENDICES 
APPENDIX 1:  ABBREVIATIONS, TRADEMARKS & GLOSSARY 
Abbreviation 
Description 
AAT 
Alpha-1antitrypsin 
AATD 
Alpha-1 antitrypsin deficiency 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BAL 
Bronchoalveolar lavage 
bid 
Twice (2 times) a day 
cf-DNA 
cell-free DNA 
CFR 
United States Code of Federal Regulations 
CMV 
Cytomegalovirus 
COA 
Clinical Outcome Assessment 
CONSORT 
Consolidated Standards of Reporting Trials 
COPD 
Chronic obstructive pulmonary disease 
COVID-19 
Coronavirus disease 2019 
CRF 
Case report form 
CT 
Computerized or computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Event 
CYP2C9 
Cytochrome P450 2C9 
DAMPs 
Damage Associated Molecular Pattern Molecules 
DILI 
Drug Induced Liver Injury 
dL 
Deciliter 
EBV 
Epstein-Barr virus 
EKG 
Electrocardiogram 
ECMO 
Extracorporeal Membrane Oxygenation 
eCRF 
Electronic case report form 
EoS 
End of Study 
EoT 
End of Treatment 
FAS 
Final Analysis Set 
FEV1 
Forced expiratory volume in 1 second 
FU 
Follow-up 
g 
Gram 
GCP 
Good Clinical Practice 
h 
Hour 
hCG 
Human chorionic gonadotropin 
HRT 
Hormone replacement therapy 


 
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Abbreviation 
Description 
HSV 
Herpes simplex virus 
Hy’s Law 
A rule of thumb that a patient is at high risk of a fatal drug-induced liver injury 
(DILI) if given a medication that causes hepatocellular injury (not cholestatic injury) 
with jaundice 
IC50 
The concentration of an inhibitor where the response (or binding) is reduced by half 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
ICU 
Intensive Care Unit 
IL-1β 
Interleukin 1 beta 
IL-6 
interleukin-6 
IL-8 
interleukin-8 
IND 
Investigational new drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
Ki 
Inhibitory constant 
kPa 
kiloPascal, a unit of force 
LOTE 
Lack of therapeutic efficacy 
LTB4 
Leukotriene b4 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg/dL 
Milligrams per deciliter 
mIU 
Milli International Units 
MOP 
Methods of procedures 
MPO 
Myeloperoxidase 
MS 
Millisecond 
NE 
Neutrophil elastase 
NET 
Neutrophil extracellular trap 
NOAEL 
No observed adverse effect level 
Pa 
Pascal 
PD 
Pharmacodynamics 
PI 
Principal investigator 
PK 
Pharmacokinetics 
PR 
time from the onset of the P wave to the start of the QRS complex on EKG 
QRS 
Represents ventricular depolarization on EKG 
QT 
The duration of ventricular depolarization and repolarization on EKG 
QTc 
Corrected QT interval 
QTcF 
QTc by Fridericia’s correction method 
QTcV 
QTc by Van de Water’s correction formula 
RANTES 
Regulated on activation, normal T cell expressed and secreted 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SaO2/FiO2 
Ratio oxygen saturation to fraction inspired oxygen 
SAP 
Statistical Analysis Plan 


 
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Abbreviation 
Description 
SARS-CoV-2 
Severe Acute Respiratory Syndrome coronavirus-2 
SoA 
Schedule of Assessments 
SoC 
Standard of Care 
SOP 
Standard operating procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
Total bilirubin 
TEAE 
Treatment emergent adverse event 
ug 
Microgram 
ULN 
Upper limit of normal 
uM 
Micromolar 
UPs 
Unanticipated problems 
VZV 
Varicella zoster virus 
WBC 
White blood cell 
 
 


 
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P a ge 5 3  of 7 0  
A P P E N DI X  2:  C LI NI C A L L A B O R A T O R Y T E S T S  
•  T he tests detaile d i n t he t a ble bel o w will be perf or me d b y t he l ocal la b orat or y.  
•  Pr ot oc ol-s pecific r e q uire me nts f or i ncl usi o n or e x cl usi o n of partici pa nts are detaile d i n 
Secti o n  6. 1  or Secti o n  6. 2 , res pecti vel y. 
•  A d diti o nal tests ma y be perf or me d at a n y ti me d uri n g t he st u d y as deter mi ne d necessar y b y 
t he I n v esti gat or or r e q uir e d b y l ocal re g ul ati o ns. 
Pr ot oc ol- R e q uire d S a fet y a n d Effic ac y L a b or at or y Assess me nts 
L a b or at or y 
Assess me nts  
P ar a meters  
He mat ol o g y  
Platelet C o u nt  
R B C C o u nt  
He m o gl o bi n  
M ea n C ell V ol u me  
M ea n C ell 
H e m o gl o bi n 
W B C c o u nt wit h 
differe ntial ( % a n d 
a bs ol ute c o u nts): 
Ne utr o p hils 
L y m p h oc ytes 
M o n oc ytes 
E osi n o p hils 
Bas o p hil s 
I nter nati o nal 
n or malize d rati o 
(I N R) 
Cli nical 
C he mistr y 1 
Bl o o d urea nitr o ge n  
P otassi u m  
A S T/ Ser u m gl uta mic -
o xal oacetic 
tra nsa mi nase  
T otal bilir u bi n  
 
Creati ni ne  
S o di u m  
A L T/ Ser u m gl uta mic -
p yr u vic tra nsa mi nase  
T otal pr otei n  
 
Al kali ne p h os p hatase  
C P K  
 
 
Efficac y 
Bi o mar kers  
C ell-free D N A 
C itr ulli nate d hist o ne 
H 3 
M yel o per o xi dase 
( M P O)-D N A 
c o m ple xes 
I L-1  beta  
I L- 6 
I L- 8 
T N F -al p ha 
De s m osi ne 
 
C- Reacti ve Pr otei n  
D -Di mer  
Fi bri n o ge n 
Pr ocalcit o ni n  
 
P K  
Pre or 1 -2 hrs  P ost d ose   
 
 
Ot her Scree ni n g 
a n d i n St u d y 
Tests  
•  Uri ne pre g na nc y test d uri n g t he st u d y (as nee de d f or w o me n of c hil d beari n g p ote ntial) 
•  Ser u m  h u ma n  c h ori o nic  g o na d otr o pi n  pre g na nc y  test  (as  nee de d  f or  w o me n  of 
c hil d beari n g p ote ntial)  
•  All st u d y -re q uire d la b orat or y assess me nts will be perf or me d at t he l ocal la b orat or y, 
wit h t he e xce pti o ns of t he bi o mar ker efficac y (see Secti o n 9. 2 ) an d P K sa m ples w hic h 
will be se nt t o a ce ntral la b orat or y f or c urati o n a n d a nal ysis.  
•  T he res ults of eac h test m ust be e ntere d i nt o t he C R F  
1 Details of li ver c he mistr y st o p pi n g criteria a n d re q uire d acti o ns a n d f oll o w -u p assess me nts after li ver st o p pi n g or  
m o nit ori n g e ve nt are gi ve n i n Secti o n 8. 1 . All e ve nts of A L T 3 × U L N a n d bilir u bi n 2 × U L N ( > 3 5 % direct 
bilir u bi n) or A L T 3 × U L N a n d I N R > 1. 5, if I N R is meas ure d, w hic h ma y i n dicate se vere li ver i nj ur y ( p ossi ble 
H y’s La w), m ust be re p orte d as a n S A E. 2 L ocal uri ne testi n g will be sta n dar d.  
 
I n v esti gat ors m ust d oc u me nt t heir re vie w of eac h la b orat or y safet y re p ort. 


 
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APPENDIX 3:  STUDY GOVERNANCE CONSIDERATIONS 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
• Applicable International Conference on Harmonization (ICH) Good Clinical Practice 
(GCP) Guidelines. 
• Applicable laws and regulations under the IND. 
• The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB by the Investigator and 
reviewed and approved by the IRB & Competent Authority/Regulatory Authority before the 
study is initiated.  
• Any amendments to the protocol will require IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
• The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB. 
• Notifying the IRB of SAEs or other significant safety findings as required by IRB 
procedures. 
• Overall conduct of the study at the site and adherence to requirements of 21 CFR, 
ICH guidelines, the IRB, and all other applicable local regulations. 
Financial Disclosure 
Principal Investigators and Site Investigators will provide the Sponsor with sufficient, accurate 
financial information in accordance with local regulations to allow the Sponsor to submit 
complete and accurate financial certification or disclosure statements to the appropriate 
regulatory authorities. Investigators are responsible for providing information on financial 
interests during the course of the study and for 1 year after completion of the study. 


 
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Informed Consent Process 
• The Site Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study.  
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB or study site.  
• The source documentation and CRF must include a statement that written informed consent 
was obtained before the participant was enrolled in the study and the date the written consent 
was obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the participant or his/her legally authorized 
representative.  
Data Management 
• The study will use an electronic data capture system  
• Site Investigator / Site PI will be responsible for data entry into the system.   
• Oversight for the study will be done via risk-based monitoring. 
• If adverse events require re-hospitalization, study participants will be cared for by the 
hospital staff at the local sites as per local policy. The study team will monitor the status of 
the patient while hospitalized, but will not be required to provide all aspects of care for these 
individuals. 
Data Protection 
• Participants will be assigned a unique identifier. Any participant records or datasets will 
contain the identifier only; participant names or any information that would make the 
participant identifiable will not be transferred.  
• The participant must be informed that his/her personal study-related data will be used in 
accordance with local data protection law. The level of disclosure must also be explained to 
the participant.  
• The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by UAB, Mereo 
BioPharma, by appropriate IRB members, and by inspectors from regulatory authorities. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted electronically (e.g., laboratory data). The Investigator is responsible for verifying 
that data entries are accurate and correct by physically or electronically signing the CRF.  


 
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• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
• The Investigator must permit study-related monitoring, audits, IRB review, and regulatory 
agency inspections and provide direct access to source data documents.  
• The Sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.  
• Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the Investigator for 25 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the NIH. No records may be transferred 
to another location or party without written notification to the IRB. 
Source Documents 
• Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported on the CRF or entered in the electronic CRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data can be found in the Study Manual and Monitoring 
Plan. 
Study and Site Closure 
UAB, the FDA, the IRB, or a designee may stop the study or study site participation in the study 
for medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.  


 
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APPENDIX 4:  ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING 
AE Definition 
• An AE is any untoward medical occurrence in a clinical trial subject administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of a medicinal product. 
 
Events Meeting the AE Definition  
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., EKG, radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the Investigator (i.e., not related to progression of underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study treatment administration even though it may 
have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should be 
reported regardless of sequelae. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as 
an AE/SAE. Such instances will be captured in the efficacy assessments. However, the signs, 
symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as AE/SAE if 
they fulfil the definition of an AE/SAE. 
 
Events NOT Meeting the AE Definition  
• Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the Investigator to be more 
severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected 
at the start of the study that do not worsen. 


 
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Unanticipated Problem (UP) Definition 
• In general, an AE observed during the conduct of a study should be considered an 
Unanticipated Problem (UP) involving risk to human subjects, and reported to the IRB, only if 
it were unexpected, serious, and would have implications for the conduct of the study (e.g., 
requiring a significant, and usually safety-related, change in the protocol such as revising 
inclusion/exclusion criteria or including a new monitoring requirement, informed consent, or 
investigator’s brochure).   
• An individual AE occurrence ordinarily does not meet these criteria because, as an isolated 
event, its implications for the study cannot be understood.  
• AEs listed in the Investigator’s Brochure (IB) are not by definition UPs because they have been 
previously observed with a drug and would not be considered unexpected and thus would not be 
unanticipated problems.  
• Possible exceptions would include situations in which the specificity or severity of the event is 
not consistent with the description in the investigator’s brochure, or it can be determined that the 
observed rate of occurrence for a serious, expected AE in the clinical trial represents a clinically 
important increase in the expected rate of occurrence. 
 
Events Meeting UP Definition  
• A single occurrence of a serious, unexpected event that is uncommon and strongly associated 
with drug exposure (such as angioedema, agranulocytosis, hepatic injury, or Stevens-Johnson 
syndrome).  
• A single occurrence, or more often a small number of occurrences, of a serious, unexpected 
event that is not commonly associated with drug exposure, but uncommon in the study 
population (e.g., tendon rupture, progressive multifocal leukoencephalopathy).  
• Multiple occurrences of an AE that, based on an aggregate analysis, is determined to be an 
unanticipated problem. There should be a determination that the series of AEs represents a signal 
that the AEs were not just isolated occurrences and involve risk to human subjects (e.g., a 
comparison of rates across treatment groups reveals higher rate in the drug treatment arm versus 
a control).  
• An AE that is described or addressed in the investigator’s brochure, protocol, or informed 
consent documents, but occurs at a specificity or severity that is inconsistent with prior 
observations. For example, if transaminase elevation is listed in the investigator’s brochure and 
hepatic necrosis is observed in study subjects, hepatic necrosis would be considered an 
unanticipated problem involving risk to human subjects.  
• A serious AE that is described or addressed in the investigator’s brochure, protocol, or informed 
consent documents, but for which the rate of occurrence in the study represents a clinically 
significant increase in the expected rate of occurrence (ordinarily, reporting would only be 
triggered if there were a credible baseline rate for comparison).  
• Any other AE or safety finding (e.g., based on animal or epidemiologic data) that would cause 
the sponsor to modify the investigator’s brochure, study protocol, or informed consent 
documents, or would prompt other action by the IRB to ensure the protection of human subjects. 


 
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Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death or; 
b. Is life-threatening or; 
The term “life-threatening” in the definition of “serious” refers to an event in which the participant 
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 were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization or; 
In general, hospitalization signifies that the participant has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not 
have been appropriate in the physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfils any other serious criteria, 
the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is 
not considered an AE. 
d. Results in persistent disability/incapacity or; 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle) that may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect or; 
f. 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the participant or may require 
medical or surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization, or development of drug dependency or drug abuse. 
 


 
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Recording AEs and SAEs 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation 
(e.g., hospital progress notes, laboratory, and diagnostics reports) related to the event. 
• The Investigator will then record all relevant AE/SAE information in the CRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical records 
to the Safety Reporting Group in lieu of completion of the AESI/AE/SAE CRF page. 
• There may be instances when copies of medical records for certain cases are requested by the 
Safety Reporting Group. In this case, all participant identifiers, with the exception of the 
participant number, will be blinded on the copies of the medical records before submission to the 
Safety Reporting Group 
• The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the study 
and assign it to one of the following categories:  
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not 
interfering with everyday activities. 
• Moderate: An event that causes sufficiently discomfort and interferes with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as severe 
should not be confused with an SAE. Severe is a category utilized for rating the intensity of an 
event; and both AEs and SAEs can be assessed as severe. 
• An event is defined as “serious” when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
Assessment of Causality 
• The Investigator is obligated to assess the relationship between study treatment and each 
occurrence of each AE/SAE. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study treatment administration will be 
considered and investigated. 
• The Investigator will also consult the Investigator’s Brochure and/or Product Information, for 
marketed products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 


 
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• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to. However, it is very important that the 
Investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to the Safety Reporting Group. 
• The Investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AE and SAE 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Safety Reporting 
Group to elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up period, the 
Investigator will provide the Safety Reporting Group with a copy of any postmortem findings 
including histopathology. 
• New or updated information will be recorded in the originally completed CRF. 
• The Investigator will submit any updated SAE data to the Safety Reporting Group within 24 
hours of receipt of the information. 
SAE Reporting  
• SAEs will be reported to the safety reporting group using a paper based system 
• Contacts for safety reporting can be found in the COSTA Site File 
• Initial reporting can be updated when additional information is obtained but this should not delay 
submission. 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
• An adverse reaction (AR) is any untoward or unfavorable medical occurrence in a clinical 
research study participant, including any abnormal sign (e.g. abnormal physical exam or 
laboratory finding), symptom, or disease, temporally associated with the participants’ 
involvement in the research, whether or not considered related to participation in the research. 
• An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed. 
• SUSAR events are AR events that fulfil criteria for seriousness (outlined in SAE above).  
SUSARs should be reported to the safety reporting group, Mereo BioPharma, and the FDA using 
the instructions listed for SAE reporting. 
 


 
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APPENDIX 5:  CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION 
Alvelestat has a low genotoxic potential and reproductive toxicology studies have not 
demonstrated any effects in either the reproductive function or in embryo-fetal development. 
Therefore, the following precautions are required to protect women of childbearing potential and 
female partners of males in the study.  
It is expected that participants with COVID-19 will avoid becoming pregnant or fathering a child 
during the acute infection and that abstinence will be the expected form of contraception. 
However, full guidance is given below. 
Definitions 
Woman of Childbearing Potential  
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
Women in the following categories are not considered women of childbearing potential 
 
1) Premenopausal female with one of the following: 
a) Documented hysterectomy 
b) Documented bilateral salpingectomy 
c) Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s: review of participant’s medical 
records, medical examination, or medical history interview. 
2) Premenarchal  
3) Postmenopausal female 
a) A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single follicle stimulating hormone measurement is 
insufficient.  
b) Females on HRT and whose menopausal status is in doubt will be required to use 1 of the 
non-hormonal highly effective contraception methods if they wish to continue their HRT 
during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrolment. 


 
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Contraception Guidance 
Male participants 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following:  
1) Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent 
on a long-term and persistent basis) and agree to remain abstinent for duration of study and 
for 4 days from last dose  
2) Female partner is using a highly effective contraceptive method  
3) Agree to use a male condom plus an additional method with a failure rate of <1% per year as 
described in the table below when having penile-vaginal intercourse with a woman of 
childbearing potential.   
4) Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-
vaginal intercourse or use a male condom during each episode of penile penetration and for 4 
days from last dose. 
Highly Effective Contraceptive Methods That Are User Dependent  
Failure rate of <1% per year when used consistently and correctlya.  
Combined (estrogen and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationb  
• 
Oral  
• 
Intravaginal  
• 
Transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulationb  
• 
Oral  
• 
Injectable  
Highly Effective Methods That Are User Independent  
• 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
Vasectomized partner  
(A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, 
an additional highly effective method of contraception should be used.)  
Sexual abstinence  
(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 treatment. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.)  


 
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NOTES:  
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants participating in clinical studies.  
b) Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy of 
the contraceptive method. In this case, 2 highly effective methods of contraception should be utilized during the 
treatment period and for at least 4 days from last dose.  
 
Female participants 
Female participants of reproductive potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in the table 
above.  
Pregnancy Testing  
Women of childbearing potential should only be included after a negative highly sensitive serum 
pregnancy test. 
Additional pregnancy testing should be performed at regular intervals as per the SoA 
Pregnancy testing, with a sensitivity of 5 mIU/mL will be performed and assayed at the study 
site.  
Collection of Pregnancy Information  
Male participants with partners of reproductive potential who become pregnant  
Investigator will attempt to collect pregnancy information on any female partner of a male study 
participant who becomes pregnant while participating in this study. This applies only to 
participants who receive study treatment. 
If a pregnancy is reported for a subject’s partner, study treatment will be immediately 
discontinued.  
After obtaining the necessary signed ICF from the pregnant female partner directly, the 
Investigator will record pregnancy information on the appropriate form within 24 hours of 
learning of the partner’s pregnancy. 
Partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the Safety Reporting Group. 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. 
Any termination of the pregnancy will be reported regardless of fetal status (presence or absence 
of anomalies) or indication for procedure. 


 
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Female participants who become pregnant  
Investigator will collect pregnancy information on any female participant who becomes pregnant 
while participating in this study. 
Information will be recorded on the appropriate form and submitted to the Safety Reporting 
Group within 24 hours of learning of a participant's pregnancy. 
Participant will be followed to determine the outcome of the pregnancy. The Investigator will 
collect follow-up information on participant and neonate, which will be forwarded to the Safety 
Reporting Group. Generally, follow-up will not be required for longer than 6 to 8 weeks beyond 
the estimated delivery date. 
Any termination of pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for procedure. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. 
A spontaneous abortion is always considered to be an SAE and will be reported as such. 
Any SAE occurring as a result of a post-study pregnancy that is considered reasonably related to 
the study treatment by the Investigator will be reported to the Safety Reporting Group as 
described in Appendix 4. While the Investigator is not obligated to actively seek this information 
in former study participants, he/she may learn of an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating will be withdrawn from the 
study.


 
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APPENDIX 6:  WORLD HEALTH ORGANISATION 9-POINT ORDINAL SCALE 
WHO 9-point ordinal scale: 
0. Uninfected, no clinical or virological evidence of infection 
1. Ambulatory, no limitation of activities 
2. Ambulatory, limitation of activities 
3. Hospitalized – mild disease, no oxygen therapy 
4. Hospitalized – mild disease, oxygen by mask or nasal prongs 
5. Hospitalized – severe disease, noninvasive ventilation or high flow oxygen 
6. Hospitalized – severe disease, intubation and mechanical ventilation 
7. Hospitalized – severe disease, ventilation and additional organ support – vasopressors, 
renal replacement therapy (RRT), extracorporeal membrane oxygenation (ECMO) 
8. Death 
 


 
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APPENDIX 7:  COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS  
 
(CTCAE) v5.0 Publish Date: November 27, 2017 
 
1 CTCAE v5.0 incorporates certain elements of the MedDRA terminology. For further details on MedDRA refer to the MedDRA MSSO Web site (https://www.meddra.org/).


 
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APPENDIX 8:  STUDY ORGANIZATION 
UAB 
Name 
Title 
Contact  
Study PI, Medical 
Oversight 
Mike Wells, MD 
Associate Professor 
+1 205 996 0101 
jmwells@uabmc.edu 
Sub-Investigator 
Mark Dransfield, MD Professor 
+1 205 996 0101 
mdransfield@uabmc.edu 
Mereo BioPharma  
Mereo BioPharma 
Medical Expert 
Jackie Parkin 
Therapeutic Area 
Head 
jp@mereobiopharma.com 
Mereo BioPharma 4 Ltd. 
1 Cavendish Place 
London, W1G 0QF 
United Kingdom 
Clinical Operations 
William Moore 
Director, Clinical 
Operations 
wm@mereobiopharma.com 
Mereo BioPharma 4 Ltd. 
1 Cavendish Place 
London, W1G 0QF 
United Kingdom 
Safety Scientist 
Adzoa Ekue 
Safety Scientist 
adzoa.ekue@mereobiopharma.com 
Mereo BioPharma 4 Ltd. 
1 Cavendish Place 
London, W1G 0QF 
United Kingdom 
Syneos Health 
Safety Reporting 
Group 
Jelena Jevtović 
Safety Specialist, 
Safety and 
Pharmacovigilance 
jelena.jevtovic@syneoshealth.com 
OR 
safetyreporting@syneoshealth.com 


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APPENDIX 9:  SUMMARY OF VERSIONS AND CHANGES 
Summary of Versions: 
Protocol 
Version 
Date 
Summary of Change 
Original 
1.0 
August 12, 2020 
Not Applicable 
Amendment 1.0 
2.0 
April 20, 2021 
• CPK testing has been added to Appendix 2
(Safety and Efficacy Parameters) in the
protocol as requested by FDA
• Dosing to Day 5 with optional extension to
Day 10
• Removal of study drug dose escalation
• Administrative corrections and formatting
changes
Protocol Amendment 1 Summary of Changes: 
Protocol Amendment 1 Changes 
Sections Applied 
Rationale 
Primary endpoint mortality rate to 
day 90 moved as secondary endpoint 
and clarified as a safety endpoint 
Objectives and 
Endpoints 
To enable unblinding at Day 60 for 
development decision, Mortality hard 
endpoint not expected to be impacted by 
unblinding 
Study design change from a 10 day 
dosing regime to a 5 day dosing 
regime with extension to 10 days for 
those still hospitalized at Day 5  
Overall Purpose 
and Design: 
Objectives and 
Endpoints: and 
throughout 
To account for changes in outcomes for 
patients with COVID where the mean 
hospital stay is now 5 days, whilst 
allowing for extension to 10 days for 
those whose disease has not resolved 
Safety endpoints moved from Day 10 
and Day 14 to Day 5 and Day 10 
throughout 
Overall Purpose 
and Design: 
Objectives and 
Endpoints: and 
throughout 
To reflect the inclusion of a 5 day dosing 
regime with optional extension to 10 
days 
Early efficacy endpoints changed 
from Days 7, 10, 14 to Days 5 and 10 
throughout 
Overall Purpose 
and Design: 
Objectives and 
Endpoints: 
To reflect the inclusion of a 5 day dosing 
regime with optional extension to 10 
days 
Table amended to reflect changes in 
study safety and efficacy assessments 
Schedule of 
Assessments 
Due to reduction in study drug dosing 
period from 10 to 5 days 
End of treatment safety follow-up 
visit window increased from +/-1 day 
to +/-2 days 
Schedule of 
Assessments 
Increased flexibility for discharged 
patients to attend hospital  


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Protocol Amendment 1 Changes 
Sections Applied 
Rationale 
Removal of study drug dose 
escalation steps to initiate alvelestat 
at dose of 240 mg bid or placebo 
from Day 1 
Schedule of 
Assessments; 
Study Design; 
Treatments 
Administered 
For faster time to required alvelestat 
levels for rapid maximal anti-
inflammatory effect and in light of 
absence of safety/toleration issues and 
protocolized dose de-escalation if 
needed 
Reduction of EKG and PK 
assessments 
Schedule of 
Assessments 
Removal of EKG and PK at dose 
escalation steps in line with removal of 
dose escalation 
Multiple changes 
Schedule of 
Assessments 
Multiple updates for clarification of 
activities to align with other changes 
outlined in this table 
Changes to Study Schematics 
Study Schematic 
To reflect changes in study design to a 
5 day dosing regime with extension to 
10 days 
Addition of use of antigen testing for 
SARS-CoV-2 for diagnosis 
Inclusion Criteria; 
Key Screening 
Assessments 
To reflect current medical practice 
Addition of other COVID-19 
therapies, including antibody 
treatment 
Exclusion Criteria To reflect current medical practice 
Addition of CPK testing 
Appendix 2: 
Clinical 
Laboratory Tests 
As requested by the FDA 
Various updates to study organization Appendix 8: Study 
Organization 
Updates and corrections to study 
organization 
Formatting changes 
Throughout 
To improve readability 

SAP_001.pdf: