COVID-19 Outpatient Pragmatic Platform Study (COPPS): A Pragmatic Multi-arm, Adaptive, Phase 2, Blinded, Randomized Placebo-controlled Platform Trial to Assess the Efficacy of Different Investigational Therapeutics in Reducing Time to Disease Resolution or Viral Load Cessation, as Compared to Standard Supportive Care in Outpatients With COVID-19
Phase: PHASE2
Conditions: Covid19
Sponsor: Stanford University

 
 
 
 
COVID-19 Outpatient Pragmatic Platform Study (COPPS):  
Acebilustat Sub-Protocol   
A pragmatic multi-arm, adaptive, phase 2, blinded, randomized placebo-
controlled platform trial to assess the efficacy of different investigational 
therapeutics in reducing time to disease resolution or viral load cessation, 
as compared to standard supportive care in outpatients with COVID-19 
Study Protocol and Statistical Analysis Plan 
NCT04662060 
September 21, 2021 

Sub-protocol: Acebilustat                                                                             V7 | 20210921 
 
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COVID-19 Outpatient Pragmatic Platform Study (COPPS): 
Sub-protocol: Acebilustat 
 
 
 
Document History 
Notes 
Version 1       Date: 06 October 2020 
Initial Approval 
Version 2       Date: 17 November 2020 
PIND recommendations  
Version 3       Date: 18 January 2021 
Multisite & Endpoint changes 
Version 4.      Date: 04 May 2021 
Imaging substudy added 
Version 5.      Date: 01 June 2021 
LFT exclusion rule change 
Version 6.      Date: 07 July 2021 
LFT exclusion change 
Version 7.      Date: 21 September  
2021 
Schedule of assessments 
 
Principal Investigators: 
Angela Rogers, MD 
Assistant Professor, Division of Pulmonary, Allergy & Critical Care Medicine, 
Department of Medicine, Stanford University 
Address: 300 Pasteur Dr. 
, Stanford CA 94305 
Email: ajrogers@stanford.edu 
 
Joseph Levitt, MD 
Assistant Professor, Division of Pulmonary Medicine, Department of Medicine, Stanford 
University 
Address:  
, Stanford, CA 94305 
Email: jlevitt@stanford.edu 
 
Sub-Investigators – Imaging: 
Roham T. Zamanian, MD, FCCP 
Associate Professor of Medicine 
Director, Adult Pulmonary Hypertension Program 
Vera Moulton Wall Center for Pulmonary Vascular Disease 
Division of Pulmonary & Critical Care Medicine 
Stanford University School of Medicine 
Email: zamanian@stanford.edu 
 
 
 
 

Sub-protocol: Acebilustat                                                                             V7 | 20210921 
 
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SUMMARY OF CHANGES FROM VER 6 TO VER 7 
• Updated schedule of assessments to align with Master Protocol Ver 9 
• Changed Visit 10 from in-person to telehealth visit 
• Removed pharmacokinetic assessment 
 
 

Sub-protocol: Acebilustat                                                                             V7 | 20210921 
 
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Table of Contents 
0. Summary paragraph ...................................................................................................................3 
1. Background ................................................................................................................................3 
2. Inclusion Exclusion Criteria .........................................................................................................6 
3. Acebilustat Treatment ................................................................................................................7 
Dosing Justification .............................................................................................................................................. 7 
Dosing .................................................................................................................................................................. 7 
Management of Progression of Disease .............................................................................................................. 8 
CT Imaging Substudy ............................................................................................................................................ 8 
4. Known product related Adverse Events..................................................................................... 17 
5. Additional Endpoints (Safety, Secondary, and Exploratory) ....................................................... 17 
6. Deviations to timing of measurements ..................................................................................... 17 
7. Preparation, Handling, and Storage .......................................................................................... 17 
Formulation, Appearance, Packaging, and Labeling .......................................................................................... 18 
Product Storage and Stability ............................................................................................................................. 18 
Preparation ........................................................................................................................................................ 18 
8. References ............................................................................................................................... 18 
 
 
0. Summary paragraph 
Acebilustat (CTX-4430) is a novel, synthetic, small molecule, LTA4H inhibitor being 
developed for the treatment of inflammatory conditions and could reduce the morbidity 
and mortality associated with COVID-19. It is a potent inhibitor of leukotriene A4 
hydrolase (LTA4H), the rate-limiting enzyme in the production of LTB4. In cystic fibrosis 
(CF) patients, a 100-mg once-daily oral dose of acebilustat reduced white blood cell 
counts in the lungs (sputum) by up to 65% and reduced the occurrence of pulmonary 
exacerbations (episodes that frequently lead to hospitalization) by up to 48% in patients 
with early stage lung disease. The safety of 100mg once daily oral acebilustat has been 
profiled in 327 human adults (4 Phase 1 studies and 2 Phase 2 studies), including over 
100 CF patients receiving 50mg or 100-mg once-daily oral acebilustat for 48 weeks. 
Because of its ability to inhibit LTA4H with concomitant reduction in LTB4 production, 
and potential to reduce neutrophil swarming and macrophage-mediated immune 
activation in a number of human inflammatory lung and vascular diseases, acebilustat 
warrants entry into a controlled study of symptomatic COVID-19 in the outpatient 
setting. 
1. Background 
Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), a sarbecovirus 
subgenus of the Orthocoronavirinae subfamily, is identified as the pathogen of 

Sub-protocol: Acebilustat                                                                             V7 | 20210921 
 
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coronavirus disease 2019 (COVID-19) pneumonia (Xu 2020), (Yin 2020). More than 
80% of patients with severe SARS-Cov-2 infection may develop dyspnea and 
hypoxemia within 1 week, which may quickly progress to acute respiratory distress 
syndrome (ARDS), fibrosis, and organ failure (Xu 2020), (Tian 2020). Emerging reports 
on the epidemiological features and clinical characteristics of COVID-19 are noted, and 
suggest that age, hypertension, diabetes, and chronic pulmonary conditions may be risk 
factors leading to poor clinical outcomes (Xu 2020), (Yin 2020), (Tian 2020), (Hussain 
2020), (Vishnevetsky 2020), (Pal 2020).  
Growing evidence has revealed that hyper-inflammatory responses (cytokine storm) 
induced by SARS-Cov-2 is a major cause of disease severity and death in COVID-19 
patients (Del Valle 2020). Specifically, high serum IL-6 and TNF-a levels and increased 
numbers of innate-immunity lineage cells (neutrophils and macrophage in particular) at 
the time of hospitalization are significant and independent predictors of worse clinical 
presentations and poor survival (Del Valle 2020), (Lucas 2020). Consistently, a “core 
COVID-19 signature”, shared by both moderate and severe groups of COVID-19 
patients, is defined by elevated inflammatory molecules released by macrophage and 
neutrophils, including IL-1, IL-6, TNF-a and IFN (Fan 2020). The macrophage and 
neutrophils immune profiles also correlate with the SARS-Cov-2 viral load (Fan 2020). 
Neutrophils and macrophages synthesize and secrete proteases, reactive oxygen 
species, eicosanoids and cytokines that perpetuate inflammatory responses. These 
cells may also coordinate to interact with epithelial cells, lymphocytes and endothelial 
cell and result in augmented proinflammatory lung microenvironment and accentuated 
tissue injury. Collectively, these data support the possible benefits of immunological 
interventions at the early stage of the disease (Hussman 2020). Circulating (blood) 
innate myeloid responses are noted in moderate and severe COVID-19 cases and 
highlights the potential usage of monocyte and neutrophil secreted-calprotectin as 
biomarker to discriminate patients with severe form of disease (Silvin 2020). 
Calprotectin presents around 45% of cytoplasmic proteins in neutrophils and are 
released under inflammatory conditions. Calprotectin promotes immune migration and 
the secretion of IL-6, TNF-a (Vogl 2018), (Freise 2019), (Evrard 2018). Patients with 
severe COVID-19 exhibit abnormal partition of circulating monocytes and neutrophils 
expressing prominent levels of calprotectin, which may then generate a pathological 
hyperinflammatory loop. 
The COVID-19 pandemic has also seen a surge of patients with ARDS globally (Fan 
2020). More than 80% of patients with severe SARS-Cov-2 infection may develop 
ARDS followed by increased risk of venous thrombosis and pulmonary embolism (Fan 
2020) (Contou 2020). Despite the phenotypic heterogeneity in patients with COVID-19-
associated ARDS, clinical conditions are generally characterized by profound infiltration 
of neutrophils and macrophages and the associated alveolar destruction with 

Sub-protocol: Acebilustat                                                                             V7 | 20210921 
 
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extravasation of protein-rich edema fluid into the airspace; all of these are common 
pathogenic features of ARDS and sepsis. Vascular derangements are another recently 
recognized feature COVID-19 with post mortem lung tissues demonstrating significant 
pulmonary endothelial alterations in intercellular junction, cell swellings, loss of contact 
with basal membrane (Ackermann 2020). ACE-2 (angiotensin-converting enzyme 2), 
the established key receptor for SARS-CoV entry, is widely expressed on endothelial 
cells and facilitate viral infection of the endothelium (Varga 2020). Endothelial 
dysfunction may further promote perivascular inflammation and intravascular 
coagulopathy.  
Leukotriene B4 (LTB4) is a pro-inflammatory lipid mediator initiating inflammation and 
mounting adaptive immune response for host defense (Peters-Golden 2007), 
(Haeggstrom 2011). Activated LTB4 signaling is implicated in inflammatory 
manifestations of a variety of pathologies, including ARDS, hypertension, diabetes, 
obesity, chronic obstructive pulmonary disease (COPD) and cancer (Peters-Golden 
2007), (Wang 2010), (Eun 2012), (Marvar 2016), (Seggev 1991), (Li 2015), (Horrillo 
2010). Canonical function of LTB4 includes chemotaxis, endothelial adherence, 
leukocytes activation, and regulation of smooth muscle contractility, with LTB4 being 
one of the most powerful chemotactic molecules for neutrophils, macrophages, mast 
cells, dendritic cells NK cells and T cells to the site of infection (Peters-Golden 2007), 
(Goodarzi 2003), (Monteiro 2011), (Ford-Hutchinson 1980). Elevated LTB4 
concentrations in plasma and bronchoalveolar fluid of ARDS patients correlate with the 
acute phase of disease and are used as clinical marker in predicting pulmonary 
complications (Auner 2012), (Stephenson 1988). LTB4 plays an important role in the 
evolution of polymorphonuclear-neutrophils in ARDS (Partrick 1996); this priming effect 
of sequestered neutrophils may result in an exaggerated immunological response to the 
infected organs, e.g. cytokine storm (Kuppalli 2020). Chemical intervention or genetic 
ablation of LTB4 signaling pathway prevents the development of ARDS in multiple 
animal models (Eun 2012). Aside from its modulatory function in the innate immunity, 
LTB4 may directly influence the pulmonary blood and lymphatic vasculature: LTB4 
causes the early death of pulmonary endothelium and transforms the surviving 
endothelial cells into an apoptosis-insensitive, hyperproliferative and cancer stem cell-
like phenotype expressing endogenous inflammatory molecules in the IL-6, TNF-a and 
IFN signaling; LTB4 also promotes the growth, hypertrophy and migration of lung 
vascular smooth muscle cells and adventitial fibroblasts, which then lead to an 
angioocclusive vasculopathy; and finally, LTB4 may damage the lymphatic vessels by 
blocking the lymphangiogenic pathways. Collectively, given the pathogenic roles of 
LTB4 in inducing hyper-inflammatory responses and vascular alterations, LTB4 
blockade may limit pulmonary inflammation, reduce endothelial dysfunction and viral 
manifestations.  

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Acebilustat (CTX-4430) is a potent inhibitor of leukotriene A4 hydrolase (LTA4H), the 
rate limiting enzyme in the production of LTB4. The nonclinical testing of acebilustat 
included a comprehensive program of pharmacology, pharmacokinetic (PK), 
metabolism, and toxicology studies conducted to support chronic treatment in human 
clinical studies. Acebilustat is rapidly absorbed and broadly distributed to tissues and 
then eliminated primarily via liver-bile-feces. Nonclinical toxicology studies support 
chronic administration of acebilustat in doses up to 200 mg/day to humans aged 2 years 
and older. 
In cystic fibrosis (CF) patients, a 100-mg once-daily oral dose of acebilustat reduced 
white blood cell counts in the lungs (sputum) by up to 65% and reduced the occurrence 
of pulmonary exacerbations (episodes that frequently lead to hospitalization) by up to 
48% in patients with early stage lung disease. The safety of 100mg once-daily oral 
acebilustat has been profiled in 327 human adults1 (4 Phase 1 studies and 2 Phase 2 
studies), including over 100 CF patients receiving 50 mg or 100 mg once-daily oral 
acebilustat for 48 weeks. 
Thus, emerging science and clinical experience support study of once-daily oral 
acebilustat in patients with COVID-19 and suggest the potential for improved clinical 
outcomes based on reduced lung and vascular inflammatory effects of SARS-CoV2 
infection. 
 
2. Inclusion Exclusion Criteria 
Inclusion criteria clarification: 
1. This subprotocol will accept patients with up to 7 days of symptoms (10 days if 
worsening within past 7 days) and up to 5 days since their positive swab. 
2. This subprotocol will accept patients who are considered high-risk based on 
criteria for receiving monoclonal antibody therapy under EUA by FDA, following 
offer of referral to receive MAb as background standard supportive care (see 
“NOTE” under Master Protocol section 3.2 for further details). 
Additional exclusion criteria are warranted for Acebilustat beyond those already 
mentioned in the platform: 
1. Patient is pregnant or breastfeeding. 
2. Patients with a baseline AST or ALT ≥ 5.00 x ULN (Severity grade 2 or moderate 
per DAIDS Table) will be excluded.   
                                                 
1 Includes 6 subjects who received a single dose of 100-mg [14C]-acebilustat. 

Sub-protocol: Acebilustat                                                                             V7 | 20210921 
 
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Note: Clinical screening laboratory evaluations will be performed locally by the site or site-
designated laboratory. 
3. Acebilustat Treatment 
Dosing Justification 
Nonclinical studies in animals considered to be equivalent to humans aged 2 years and 
older support chronic administration of once-daily oral doses of up to 200 mg in 
humans. Safety pharmacology studies in nonclinical animal species support acute 
human doses up to 649 mg per day.  Clinical studies to date provide safety and 
tolerability data for two weeks administration of up to 200 mg once daily and 48 weeks 
administration of up to 100 mg once daily acebilustat.  
In Phase 1 studies, acebilustat showed dose-dependent inhibition of LTB4 production 
(the mechanistic target) which largely reached its plateau at or above 100 mg dose. 
This is confirmed by PK/PD analysis showing near-maximal target engagement at 
plasma concentrations produced by the 100 mg dose. Furthermore, evidence of a dose-
dependent reduction in neutrophils in the lungs of adult CF patients suggest that the 
100 mg dose level is superior to the 50 mg dose level and that there is close correlation 
between inhibition of LTB4 production (65-80%) and reduction of neutrophils in the 
lungs (65%).  
In the Phase 2 CF study, the 100 mg daily dose of acebilustat exhibited a numerical, 
though not statistically significant, advantage over the 50 mg daily dose in the study 
endpoints of rate of pulmonary exacerbations (PEx), time to first PEx and change from 
baseline ppFEV1 for the target population of CF patients having mild lung disease. 
Considering that the 100 mg dose has shown near-maximal target engagement and 
evidence of pharmacologic effect on the pathway and disease processes while at the 
same time exhibiting a favorable safety profile in chronically infected CF patients. 
Therefore, in the context of the current initial study of COVID-19 patients, the 100 mg 
once daily dose is believed to be the most suitable dose level for study. 
A treatment duration of 28 days is based on the WHO interim guidance, which reports 
“a median duration of viral RNA detection of 20.0 days (interquartile range of 17.0-24.0) 
in survivors, but COVID-19 virus was detectable until death in nonsurvivors.”23 
Dosing  
Enrolled patients randomized to active acebilustat or its blinding regimen will receive, in 
addition to current standard of care, acebilustat 100-mg capsule or matching placebo 
capsule administered orally once daily for 28 days. 

Sub-protocol: Acebilustat                                                                             V7 | 20210921 
 
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Management of Progression of Disease 
 
Should the patient be admitted to the hospital, they may continue study drug while 
following protocol for inpatient procedure, however the ultimate decision to continue 
study drug will be left to the admitting team in consultation with study investigators. 
 
CT Imaging Substudy 
 
Objectives:  
The primary objective of the computed tomography (CT) sub-protocol to the COPPS 
Acebilustat sub-study is to evaluate the therapeutic effect of Acebilustat on lung and 
distal pulmonary vascular structure.  Specifically, we will evaluate the effect of treatment 
on airway and lobular volumes (siVaw and iVLobe, respectively) as well as distal 
pulmonary vascular blood volumes [blood vessel cross sectional areas <5 mm, 5-10 
mm and >10 mm (BV5, BV5-10, and BV10, respectively)].  Previous observations have 
demonstrated reduced blood volumes in BV5 vessels in patients with moderate to 
severe COVID-19 pneumonia. We hypothesize that participants treated with Acebilustat 
will show greater improvement in BV5 blood volume at day 28 and day 90 as compared 
to the placebo controls. We further hypothesize that changes in BV5 will correlate with 
other markers of pulmonary and general health measured in the study. 
 
Rationale for using FRI: 
Functional Respiratory Imaging (FRI) is a novel, quantifiable method to measure 
biological responses to therapeutic interventions using high-resolution CT and 
computational fluid dynamics. FRI also provides detailed visualization and evaluation of 
the lungs and airway structures, allowing for an in-depth description of baseline lung 
health and level of deterioration and a better understanding of post-treatment effects. By 
assessing changes close to the site of action of the intervention, the method is more 
sensitive (higher effect size) compared with standard lung function tests. Several clinical 
trials in asthmatic and COPD patients showed significant correlations between the 
change in FEV1 and the change in both image-based volume and airway resistance 
following acute bronchodilation. The background variance of well controlled imaging 
such as FRI is lower relative to pulmonary function testing due to the exclusion of 
confounding factors such as upper airway properties, patient effort, and coaching. This 
means that FRI has enhanced sensitivity (better signal to noise ratio) compared with 
conventional spirometry1-3. 
 
In a double-blind study in COPD patients, image-based parameters more reliably 
distinguished between patients receiving placebo and active treatment. The FEV1/FVC 

Sub-protocol: Acebilustat                                                                             V7 | 20210921 
 
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ratio performed the worst, followed by the FEV14.  However, the minimal clinically 
relevant difference in image-based parameters remains unclear. 
In a study aiming to assess long-term effects of extra fine beclomethasone/formoterol 
on small airways of asthmatic patients, Vos et al reported that FRI provided more detail 
and clinical relevance compared to lung function tests and that changes in imaging 
parameters correlated significantly with clinically relevant improvements (asthma 
symptom scores). In asthmatic patients who were well controlled with non-extra fine 
combinations, the switch to extra fine beclomethasone/formoterol led to a significant 
improvement in pre-bronchodilator imaged airway volume, which occurred 
predominantly at the level of the small airways and was more sensitive than changes in 
FEV15. 
 
In a study investigating the mode of action of Roflumilast in COPD patients on top of 
triple therapy (LABA/LAMA/ICS), the FRI outcome parameters were able to provide a 
hypothesis for the mode of action of roflumilast leading to observed improvements in the 
lung function6. The study showed a significant reduction of the lobar hyperinflation 
(iLobes_FRC) at the FRC level in the patients with >120 mL improvement in FEV1, the 
so-called responder group7. The study supports the hypothesis that orally administered 
roflumilast reaches, via the vasculature, areas that were previously undertreated by the 
inhaled medication. Opening smaller airways or preventing airway collapse, presumably 
by reducing inflammation and edema, results in a reduction of regional hyperinflation, 
eventually cascading into enhanced efficacy of the concomitant ICS/LAMA/LABA 
treatment. The study suggested that patients who are prone to dynamic hyperinflation 
are the responder phenotype, suggesting that Roflumilast reduces inflammation and, 
hence, hyperinflation in smaller airways. This shows that FRI appears to be a sensitive 
tool to describe the mode of action of novel compounds in COPD8.  
 
FRI was used to assess the bronchodilator effects of salbutamol and ipratropium 
bromide in five patients with severe but stable COPD in an open randomized two-way 
crossover study9. The patients were given a single dose of salbutamol or ipratropium 
bromide with a 1-week interval between treatments. Patients underwent PFT (FEV1 and 
FVC) and a multi-slice computed tomography scan of the thorax that was used for 
functional respiratory imaging. PFT and FRI were performed before and two hours after 
dosing. All measured parameters (PFT and FRI) changed significantly after 
administration of each product. However, FRI revealed that the bronchodilator effect 
was greater in the distal airways with a corresponding drop in airway resistance 
compared with the central airways. Even more intriguing, was that although PFT 
revealed that salbutamol and ipratropium bromide were equally effective, FRI showed 
that hypo-responsiveness was found for salbutamol in one patient and that salbutamol 
was more effective in the other patients. 

Sub-protocol: Acebilustat                                                                             V7 | 20210921 
 
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In a study to understand the effects of a long-term noninvasive ventilation (NIV) 
treatment and which factors may predict a response in terms of improved oxygenation 
and lowered CO2 retention, 15 hypercapnic COPD patients were randomized to a 
routine pharmacological treatment or to a routine treatment and NIV10. FRI showed that 
patients actively treated with NIV developed a more inhomogeneous redistribution of 
mass flow. Subsequent analysis indicated that in NIV-treated patients who improved 
their blood gases, mass flow was also redistributed towards areas with higher vessel 
density and less emphysema, indicating that flow was redistributed towards areas with 
better perfusion. The improved ventilation–perfusion match and recruitment of 
previously occluded small airways can explain the improvement in blood gases. Control 
patients improved homogeneously in airway volumes and local airway resistance, 
without improvement in gas exchange, because there was no improved 
ventilation/perfusion ratio or increased alveolar ventilation. These differences in 
response could be detected through FRI, which gives a more detailed report on regional 
lung volumes and airway resistance than classical lung function tests do. It is possible 
that only patients with localized small airway disease are good candidates for long-term 
NIV treatment. This study generated the hypothesis that COPD patients benefit from 
NIV treatment (i.e., are responders) if the treatment redirects incoming air to better-
perfused areas. If the NIV treatment does not change the internal airflow distribution or 
more air is going to areas with less perfusion, then the patient tends to be a non-
responder.  
 
An IPF-cohort (treated with pamrevlumab for 48 weeks) was retrospectively studied 
using FRI by Clukers et al. in 2018. Serial CT’s were compared from 66 subjects and 
post-hoc analysis was performed using FRI, FVC and mixed effects models. Clukers et 
al. showed that in patients with IPF, FRI parameters (siRADaw, percentage of fibrotic 
tissue at TLC and predicted lobe volume at TLC) allow monitoring of regional changes 
in disease and may capture disease progression in patients with preserved FVC11. They 
concluded that in IPF, FRI is a superior tool than FVC in capturing of early and clinically 
relevant, disease progression in a regional manner. 
 
Functional Respiratory Imaging aims to provide additional information by measuring 
lung health rather than just lung function. Conventional pulmonary function test results 
(FVC, FEV1, etc.) are derived from forceful inhalation and exhalation maneuvers, 
thereby measuring all lung regions at once, each having an internal variability on its 
own. As a result, a diagnosis is often based on highly derivative parameters with little 
understanding of the regional manifestation of the disease. FRI not only provides an 
accurate measure of various lung parameters (i.e., lobe volume, airway volume, airway 
radii, blood vessel density, emphysema, fibrosis), but it also carries less variability than 

Sub-protocol: Acebilustat                                                                             V7 | 20210921 
 
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current pulmonary function tests. As a result, FRI is a technology that overcomes 
various issues in current pulmonary assessments and is an applicable measure of 
treatment efficacy in clinical trials as well as pulmonary health status in general practice. 
FRI has proven to be able to distinguish between responders and non-responders to 
different therapies in several respiratory diseases. Using the same approach, i.e., by 
looking regionally at all lung structural and functional parameters, FRI aims to provide 
additional and novel information showing the effects of Acebilustat in symptomatic 
COVID-19 patients. 
 
In a retrospective analysis of 103 COVID-19 patients hospitalized in China, Lins et al 
compared FRI imaging to normal controls.  COVID-19 patients had a markedly 
decreased percent total of pulmonary vascular blood distribution to BV5 vessels (BV5% 
41% vs. 56%, p < 0.001)13. In a separate retrospective analysis, Morris et al compared 
chest CT scans from 10 hospitals across two state in 313 COVID-19 positive and 195 
COVID-19 negative patients seeking acute medical care14. BV5% was predictive of 
outcomes in COVID-19 patients in a multivariate model, with a BV5% threshold below 
25% associated with an odds ratio (OR) 5.58 for death, OR 3.20 for intubation, and OR 
2.54 for the composite of death or intubation. A model using age and BV5% had an 
area under the receiver operating characteristic curve 0.85 to predict the composite of 
intubation or death in COVID-19 patients. BV5% was not predictive of clinical outcomes 
in patients without COVID-19. 
 
 
Criteria for Evaluation: 
All patients enrolled into the parent COVID-19 COPPS Acebilustat protocol will be 
eligible to participate on a voluntary basis under a separate Informed Consent Form.  
Airway, Lobular and Pulmonary Blood Vascular volumes (BVx), and proportional blood 
volume distribution (percent total for each BVx) will be assessed at baseline (Day 0-3) 
and at the end of treatment (Day 28), and during long-term follow up (Day 90) using a 
standardized chest computed tomography protocol.  Changes in BVx across 3 
compartments [<5 mm cross sectional area (BV5), 5-10 mm cross sectional area (BV5-
10), and >10 mm cross sectional area (BV10)] will be assessed over the total duration 
of the study compared across intervention vs placebo arms.   
 
Sub Study Design: 
Enrollment for this CT imaging sub-study will parallel that of the parent Acebilustat 
subprotocol of the COPPS master protocol.  The sub-study will enroll symptomatic 
patients who have consented for the primary clinical study and who additionally 
volunteer and consent to participate in the CT imaging sub-study.  The CT imaging sub-
study is designed to compare up to 60 total patients including both Acebilustat and 

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placebo treated patients, according to level of voluntary participation and the outcome of 
randomization to the Acebilustat subprotocol within the COPPS master.  Imaging will be 
performed at baseline (within 72 hours from enrollment), at day 28 (end of treatment), 
and day 90 (long-term follow-up). All parent study inclusion and exclusion criteria apply. 
The only additional inclusion criterion is voluntary consent to participate in this CT 
imaging sub-study. There are no further additional exclusion criteria that pertain to this 
sub-study.  
 
When a subject consents to participate in the study with CT imaging, the following 
actions will be performed during relevant study visit:  
• Schedule appropriate CT times with radiology for baseline, day 28, day 90 
scans. 
• Explain the study procedure and practice the breathing patterns with the 
subject.  
• Conduct the HRCT scans at end-inspiratory breath hold.   
 
Actions to be performed after the study visit:  
• Send the CT images and relevant reports to Fluidda for FRI analysis. 
 
Exploratory Efficacy Endpoints: 
The primary efficacy endpoint will be change in percent BV5 measured by computed 
tomography from baseline to day 28 after treatment initiation. 
 
The secondary efficacy endpoints will be as follows: 
1. Change in percent BV5-10 measured by computed tomography from baseline to 
day 28 after treatment initiation. 
2. Change in percent BV10 measured by computed tomography from baseline to 
day 28 after treatment initiation. 
3. Change in percent BV5 measured by computed tomography from baseline to day 
90 after treatment initiation. 
4. Change in percent BV5-10 measured by computed tomography from baseline to 
day 90 after treatment initiation. 
5. Change in percent BV10 measured by computed tomography from baseline to 
day 90 after treatment initiation. 
6. Airway (siVaw) and lobar (iVLobe) Volumes at end-inspiration (TLC). 
 
Images and Analyses:  
Functional Respiratory Imaging (FRI) analysis for pulmonary vascular segmentation and 
lobar volumes will be carried out by Fluidda.   
 

Sub-protocol: Acebilustat                                                                             V7 | 20210921 
 
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Sample Size and Power:   
This sub-study will include up to 60 subjects randomized to either Acebilustat or 
matched placebo.  Given the sub-study nature of this protocol, enrollment and ratio of 
active treatment to placebo will be determined by 1) randomization at the level of 
primary protocol (COVID-19 COPPS), 2) COPPS Acebilustat sub-study enrollment, and 
3) success of CT-sub-study recruitment itself.   
 
Power calculations were performed to evaluate the power of the sub-study under a 
range of assumptions. These calculations are based on a two-sided t-test comparing 
the change from baseline between the acebilustat and placebo arms. In all calculations, 
a total sample size of 60 and a Type I error of 0.05 were assumed. 
 
Power 
N - ace 
N - placebo 
δ 
0.76 
30 
30 
0.7 
0.86 
30 
30 
0.8 
0.93 
30 
30 
0.9 
0.97 
30 
30 
1 
0.75 
35 
25 
0.7 
0.85 
35 
25 
0.8 
0.92 
35 
25 
0.9 
0.96 
35 
25 
1 
0.71 
40 
20 
0.7 
0.82 
40 
20 
0.8 
0.90 
40 
20 
0.9 
0.95 
40 
20 
1 
 
The assumptions varied were 1) the randomization ratio (1:1, 1.4:1, and 2:1) and 2) the 
effect size (δ = 0.7, 0.8, 0.9, 1). The effect size is defined as the difference between the 
two arms divided by the standard deviation. δ = 1 corresponds to a difference between 
the two arms that is equal to 1 standard deviation.  δ = 0.7 corresponds to a difference 
of 0.7 standard deviations between the two arms. The table above shows the power 
under the various settings. We are well-powered to observe differences of δ = 0.8 or 
larger under any of the randomization ratios.  
 
Statistical Analyses: 
The primary efficacy analysis of change in percent BV5 from baseline to day 28 and 90 
will be performed on the intention-to-treat (ITT) population.  We will fit a linear mixed 
effects model regressing the day 28 and 90 changes in percent BV5 from baseline on 

Sub-protocol: Acebilustat                                                                             V7 | 20210921 
 
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treatment arm. The model will additionally include fixed effects for visit, a visit by 
treatment interaction, and lobe. To address our primary hypothesis, we will test whether 
the coefficient corresponding to a treatment effect at day 28 is non-zero. A random 
intercept for lobe and participant will be included to account for the correlation induced 
by repeated measures within a participant. An unstructured variance-covariance matrix 
will be assumed. If this model fit fails to converge, a compound symmetry covariance 
structure will be considered to model correlation. If necessary, a per-scan composite 
from across all lobes may be formed in order to conduct analyses at the participant 
rather than the lobe level. For clinical outcomes, a similar approach will be taken, 
excluding the lobar component. Secondary analyses will repeat the primary analysis for 
the following outcomes: change in percent BV5, percent BV5-10, percent B10 from 
baseline to days 28 and 90.   Additional secondary analyses will consider the change 
observed in each lobe and the maximum observed change in any lobe. 
 
Safety Considerations: 
HRCT (High Resolution Computed Tomography) scans will be performed with a low 
radiation protocol. The average exposure per scan is 1.806 mSv. The low dose CT 
examinations in this trial have an effective dose less than yearly background radiation 
exposure.   
 
In this study patients will receive 3 scans with an average total exposure of 5.4 mSv. 
The natural background radiation exposure from natural sources in the US equals 3.1 
mSv12. Patients completing the study will receive the same radiation exposure they 
would naturally receive from slightly less than 2 years background radiation. In clinical 
practice, patients with COVID-19 lung disease are not subjected to many HRCT scans, 
so extra attention will be paid to reduce the radiation even more in this clinical trial by 
providing tailored scan protocols during an on-site FRI site training. 
 
Protocol of HRCT scan and FRI method  
 
1. Protocol of CT scan 
 
For small vessel and airways scanning, one thorax HRCT scan without contrast will be 
taken during an end inspiratory breath hold coached by the clinical coordinator using a 
GE VCT LightSpeed 64-slice scanner or a scanner yielding equivalent results. 
 
Monitoring the breathing signal: 
For end-inspiratory (TLC) scan, the patient is asked to breathe in fully and to hold 
her/his breath for the duration of the scan. When we see the patient is correctly holding 
her/his breath, a CT scan is taken. 

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Page 15 of 23 
 
Due to concerns for infection risks during baseline CT imaging, inspiratory and 
expiratory (requiring specialized spirometer to monitor respiratory cycle) imaging will not 
be performed in lieu of acquisition of a single image during a breath hold at total lung 
capacity which should provide adequate data acquisition for the parameters being 
assessed. 
 
Scanning protocols: 
A full helical scan is taken with a 
• rotation time of 0.6 s 
• detector coverage of 40 mm 
• helical thickness of 0.625 mm 
• pitch and speed of 1.375:1 and 55 mm/s. 
• Tube voltage: 100 kV 
• Tube current: variable between 10 and 200 mAs 
• Noise index: 45 
Tube current is determined by a smart algorithm using a noise factor of 45 in the interval 
of [10 mAs, 200 mAs]. The field of view is set as small as possible, but the lung should 
be seen completely in all axial slices. Scan time lies around 5 seconds. Images are 
reconstructed at 0.3mm interval using a lung filter. The resulting data set has about 700-
1200 images with a pixel size of about 0.4-0.65mm2. The scans taken during all visits 
will be obtained with the same radiologic technical conditions. 
 
If the scanning equipment can not comply with the above-mentioned requirements, 
settings yielding equivalent results can be applied. 
 
2. Detailed description of the FRI method 
HRCT images are imported into Mimics, a commercial, Food and Drug Administration 
approved, medical image processing software package. (Materialise, Leuven, Belgium, 
Food and Drug Administration, K073468; CE certificate, BE 05/1191 CE01). This 
software package converts the HRCT images into patient specific, three-dimensional 
computer models of the lung lobes, the airway lumen and wall, and the vascular tree. 
These models can be used for (regional) volume calculations and further evaluations of 
(regional) resistance. The airway and vascular tree are evaluated at TLC level and can 
be segmented down to bronchi/vessels with a diameter of around 1-2 mm. Beyond this 
point the HRCT resolution is insufficient to distinguish alveolar and intraluminal air, or 
blood vessel tissue and surrounding lung tissues. A typical airway model includes 5-10 
generations, depending mainly on the disease state of the individual patient. Airway 
lumen (iVaw), airway wall (iVaww) and blood vessel volume (Vbv) can be assessed at 
individual airways/vessels or in different regions.  

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Page 16 of 23 
2-Denotes additional telehealth visit if needed for following any ongoing AEs. 
3-Imaging visit window: the baseline scan should occur up to and including Day 3 while on trial. D28 and D90 have a window of ±3 Days. Women 
of childbearing potential are required to complete a pregnancy test prior to their Baseline, Day 28, and Day 90 scans.
Table 1. Acebilustat Sub-protocol Assessments (I indicates imaging sub-study specific assessment) 
 
 
 
 
Day of study 
1 
2 3 
4 
5 
±1 
6 
7 
8 
9 
10
±1 
14 
21 
28
+7 
35
+7 
90
±7 
120
±7 
210 
±7 
300 
±7 
Assessments in the clinic 
X 
  
  
  
X 
  
  
  
  
 
  
  
X 
 
 
 
 
 
Physical exam 
X 
  
  
  
X 
  
  
  
  
 
 
 
X 
 
 
 
 
 
Vitals 
X 
  
  
  
X 
  
  
  
  
 
 
 
X 
 
 
 
 
 
Clinical status 
X 
  
  
  
X 
  
  
  
  
 
 
 
X 
 
 
 
 
 
SpO2 
X 
  
  
  
X 
  
  
  
  
 
 
 
X 
 
 
 
 
 
Urine Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
 
I3 
 
I3 
 
 
 
Self-collected nasal swab 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
COSS self-assessment 
Every day from days 1-28 inclusive 
X 
 
X 
X 
X 
Oropharyngeal swab 
X 
  
  
  
X 
  
  
  
  
 
 
 
X 
 
 
 
 
 
Blood collected by phlebotomy for clinical labs 
X 
  
  
  
X 
  
  
  
  
 
 
 
X 
 
 
 
 
 
Blood collected by phlebotomy for biobanking 
X1 
  
  
  
  
  
  
  
  
  
 
 
X1 
 
 
 
 
 
Telehealth visit 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
X2 
CT Imaging 
I3 
 
 
 
 
 
 
 
 
 
 
 
I3 
 
I3 
 
 
 
Administration of drug - Acebilustat sub-protocol 
Every day from days 1-28 inclusive 
 
 
 
 
 
 

Sub-protocol: Acebilustat                                                                             V7 | 20210921 
 
 
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4. Known product related Adverse Events 
 
Sporadic liver enzyme elevations, primarily AST and ALT, assessed as related to 
acebilustat treatment were observed in a 12-week clinical study of patients with acne 
vulgaris. 
 
In a 48-week study of patients with Cystic Fibrosis, the most frequent Adverse Event 
assessed as related to acebilustat was headache (8%). 
 
5. Additional Endpoints (Safety, Secondary, and Exploratory) 
 
Exploratory Endpoints: 
Quantitative changes in blood-borne biomarkers, including LTB4. 
 
 
6. Deviations to timing of measurements 
 
Not applicable for acebilustat unless otherwise noted. 
 
 
7. Preparation, Handling, and Storage 
Acebilustat, also known by the code name CTX-4430, is a novel, synthetic, small 
molecule, LTA4H inhibitor being developed for the treatment of inflammatory conditions. 
The chemical name of CTX-4430 is 4-[[(1S,4S)-5-[[4-[4-(2-
oxazolyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]-benzoic acid. 
It is a chiral molecule that is manufactured as a single, stable isomer. 
Each unit of acebilustat or matching placebo is supplied by the sponsor as a quantity of 
36 capsules packaged in round, white high-density polyethylene (HDPE) bottles topped 
with polyester coil and fitted with a white, screw-top HDPE closure. 
The site investigator is responsible for study drug distribution and disposition and has 
ultimate responsibility for study product accountability. The site investigator may 
delegate responsibility for study drug accountability to the participating site’s research 
pharmacist. Complete records and documentation will be maintained for study drug 
receipt, accountability, dispensation, storage conditions, and final disposition of the 
study drug. Time of study drug administration to the patient will be recorded on the 
appropriate electronic case report form (eCRF). 
After the study treatment period has ended, or as appropriate over the course of the 
study after study drug accountability has been performed, unused and used active and 
placebo drug product should be saved until instructed by the sponsor, at which point 

Sub-protocol: Acebilustat                                                                             V7 | 20210921 
 
 
18
they can be returned to the sponsor or destroyed on-site following applicable site 
procedures. 
Formulation, Appearance, Packaging, and Labeling 
Acebilustat is manufactured as an immediate-release powder blend in size 0, white, 
opaque, hard gelatin capsules in 100-mg strength. The contents of the investigational 
product capsules include acebilustat (active ingredient) and the following commonly-
used pharmaceutical excipients: mannitol, microcrystalline cellulose, crospovidone, 
magnesium stearate, and silicon dioxide. 
The placebo control capsules contain matching excipients with no acebilustat. 
Product Storage and Stability 
Acebilustat and matching placebo capsules are stable at controlled room temperature 
(15°C to 25°C/59°F to 77°F) for at least 4 years when protected from exposure to 
ultraviolet light. 
Preparation 
Detailed information on the preparation, labeling, storage, and administration of 
acebilustat and matching placebo will be provided in a protocol-specific Pharmacy 
Manual. 
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Sub-protocol: Acebilustat                                                                             V7 | 20210921 
 
 
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2. A case series on lung deposition analysis of inhaled medication using functional imaging 
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Sub-protocol: Acebilustat                                                                             V7 | 20210921 
 
 
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