Clinical trial NCT04662060
Conditions: Covid19
Keywords: Outpatient
Sponsor: Stanford University
Start date: 2021-04-23; Completion date: 2023-02-02
Enrollment: 120 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The overall objective of this study is to efficiently evaluate the clinical efficacy and safety of different investigational therapeutics among adults who have COVID-19 but are not yet sick enough to require hospitalization. The overall hypothesis is that through an adaptive trial design, potential effective therapies (single and combination) may be identified for this group of patients.

COVID-19 Outpatient Pragmatic Platform Study (COPPS) is a pragmatic platform protocol designed to evaluate COVID-19 treatments by assessing their ability to reduce viral shedding (Viral Domain) or improve clinical outcomes (Clinical Domain). To be included into the platform, every investigational product will collect data for both Domain primary endpoints. Individual treatments to be evaluated in the platform will be described in separate sub-protocols.

Detailed description:
The platform study allows investigational products with objectives either: evaluating viral shedding (Virology Domain); and COVID-19 related Clinical Outcomes (Clinical Domain).

The primary objective for investigational products within the Viral Domain is:

A. To evaluate the efficacy of each therapeutic intervention in addition to standard supportive care (SSC) compared with SSC in reducing viral shedding of SARS-CoV-2 virus in outpatients with COVID-19 disease.

The primary objective for investigational products within for the Clinical Domain is:

B. To evaluate the efficacy of each therapeutic intervention in addition to SSC as compared to SSC in improving sustained clinical outcomes in outpatients with COVID-19 disease.

Secondary objectives are:

1. The objective of the non-assigned domain an investigational product is under.

   1. If under Clinical Domain, reduction in viral shedding.
   2. If under Viral Domain, time to resolution of symptoms.
2. To evaluate the efficacy of each therapeutic intervention in reducing SARS-CoV-2 related hospitalizations, ED visits, or death in outpatients with COVID-19 disease.
3. To assess the development of antibodies against SARS-CoV-2
4. To evaluate the safety and tolerability of each therapeutic intervention compared with placebo (supportive care).

Arms: arm 1: Participants are randomized to receive acebilustat for 28 days. arm 2: Participants are randomized to receive placebo to match acebilustat for 28 days.
Interventions: intervention 1: Acebilustat intervention 2: Placebo
Intervention descriptions: intervention 1: 100 mg capsule administered orally once daily intervention 2: Placebo to match acebilustat administered orally once daily

Protocol documents:
Prot_SAP_001.pdf: 
 
 
 
 
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 
 
 
 
 


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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 
 
 


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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 


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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 


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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. 


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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. 


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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 


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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. 


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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 


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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.   
 


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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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Page 14 of 23 
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 
 
 
 
 
 
 


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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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Parizel PM, De Backer W. Int J Chron Obstruct Pulmon Dis. 2013 ; 8:569-79. doi: 
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2. A case series on lung deposition analysis of inhaled medication using functional imaging 
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using conventional outcome parameters and a novel computational fluid dynamics 
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4. The acute effect of budesonide/formoterol in COPD: a multi-slice computed tomography 
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Sub-protocol: Acebilustat                                                                             V7 | 20210921 
 
 
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Vinchurkar S, Ides K, De Backer J, Germonpre P, De Backer W. Int J Chron Obstruct 
Pulmon Dis 2011; 6: 615-624. 
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biomarker for predicting outcomes in COVID-19 disease. Eur Respir J 2021; in press 
(https://doi.org/10.1183/13993003.04133-2020).  
 

Prot_SAP_000.pdf: 
 
 
 
 
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 
Study Protocol and Statistical Analysis Plan 
NCT04662086 
September 21, 2021 


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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 
 
 
 
 
Document History 
Notes 
Version 1       Date: 06 October 2020 
Initial Approval 
Version 2       Date: 17 November 2020 
PIND recommendations  
Version 3       Date: 11 December 2020 
Second PIND recommendation 
Version 4       Date: 29 January 2021 
Ops language, Inclusion, & viral endpoint 
Version 5       Date: 09 March 2021 
New viral endpoint, clinical missing data 
Version 6       Date: 30 March 2021 
Ops language, alignment of visits 
Version 7       Date: 04 May 2021 
Updated blind, schedule of events, DSMB 
Version 8       Date: 07 Jul 2021 
Monoclonal antibody (MAB) EUA criteria 
Version 9       Date: 21 September  
2021 
Updated assessment schedule 
 
 
SUMMARY OF CHANGES FROM VERSION 8 TO VERSION 9 
 
• 
Updated schedule of assessments 
• 
Changed Visit 10 from in-person to telehealth visit for clinical subprotocol 
• 
Removed pharmacokinetics assessment from clinical subprotocol 
• 
Added windows for visits 
 
 


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TITLE: 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 
 
ClinicalTrials.gov registration Number: NCT04662086  
Study Document: Protocol (Version 9, 21 September, 2021)  
Study Phase: 2 
IND Number:  
 
Sponsor: Manisha Desai 
 
Version 9/ Version Date (21 September, 2021) 
 
 
 
 
 
 
 
 
 
CONTACT INFORMATION: 
 
Principal Investigator: 
Manisha Desai Ph.D. 
Professor (Research) of Medicine (Biomedical Informatics) 
Professor of Biomedical Data Science 
1701 Page Mill Rd 
 
Palo Alto,  California  94304-1210 
Email: manishad@stanford.edu 
Phone: 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL SIGNATURE PAGE 
 
 
Protocol Title: 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 
 
Protocol/IND Number: 
 
 
Protocol Version/Date:  Version 9 / 21 September  2021 
 
Sponsor Name:  
Manisha Desai Ph.D. 
Professor (Research) of Medicine (Biomedical Informatics) 
Professor of Biomedical Data Science 
1701 Page Mill Rd 
 
Palo Alto,  California  94304-1210  
Email: manishad@stanford.edu 
Phone: 
 
 
Declaration of Investigator 
I confirm that I have read the above-mentioned protocol and its attachments. I agree to conduct 
the described trial in compliance with all stipulations of the protocol, regulations and ICH E6 
Guideline for Good Clinical Practice (GCP). 
 
Principal Investigator Name:  __________________________________________ 
 
Principal Investigator Signature:  _______________________________________ 
 
Date:  ___________________ 
Date (MM/DD/YYYY) 
 
Statement of Compliance 
The signature below provides the necessary assurance that this study will be conducted 
according to all stipulations of the protocol including statements regarding confidentiality, and 
according to local legal and regulatory requirements, US federal regulations, and ICH E6(R2) 
GCP guidelines. 
 
Site Investigator Name:  __________________________________________ 
 
Site Investigator Signature:  _______________________________________ 
 
Date:  ___________________ 
Date (MM/DD/YYYY) 


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TABLE OF CONTENTS 
 
 
Protocol Team Roster ................................................................................................................................ 7 
PROTOCOL SYNOPSIS ........................................................................................................................... 8 
1. 
OBJECTIVES ................................................................................................................................ 16 
1.1. 
Primary Objective ................................................................................................................ 16 
1.2. 
Secondary Objectives ........................................................................................................ 16 
1.3 
  Exploratory Objectives ..................................................................................................... 17 
2. 
BACKGROUND ............................................................................................................................ 17 
2.1 
Study Disease...................................................................................................................... 17 
2.2 
Treatment Rationale and Investigational Agent Information ........................................ 17 
2.3 
Study Design........................................................................................................................ 18 
2.3.1 Selection of Study Sites ......................................................................................................... 18 
2.3.2 Subject Information and Consent ......................................................................................... 19 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES .................................... 20 
3.1 
Inclusion Criteria.................................................................................................................. 20 
3.2 
 Exclusion Criteria ............................................................................................................... 20 
3.3 
 Randomization Procedures .............................................................................................. 22 
3.4 
 Common Control Arm ........................................................................................................ 22 
3.4.1 Maintaining the Blind in the Presence of Drugs Administered Heterogeneously .......... 22 
3.4.2 Benefits and trade-offs to the common control group ....................................................... 22 
3.5    
Prohibited Concomitant Therapy for Viral Domain ........................................................ 23 
3.6    
Prohibited Concomitant Therapy for Clinical Domain.................................................... 23 
4.      STUDY PROCEDURES .............................................................................................................. 24 
4.1 Schedule of Assessments ............................................................................................................ 24 
4.2 Study Procedures .......................................................................................................................... 26 
4.3 
 Clinical Lab Biomarkers .................................................................................................... 27 
5. 
MEASUREMENTS ....................................................................................................................... 28 
5.1  
Primary and Secondary Outcome measures .................................................................. 28 
5.1.1 Relevant Subset 
 ............................................................................................................... 28 
5.1.2 Measurement Definition ......................................................................................................... 28 
5.1.3 Measurement Methods .......................................................................................................... 29 
5.2 
Secondary Outcomes ......................................................................................................... 31 
6. 
STATISTICAL CONSIDERATIONS ........................................................................................... 32 
6.1 
Statistical Design ................................................................................................................. 32 
6.1.1 
Randomization ................................................................................................... 32 
6.2 
Descriptive Statistics and Exploratory Data Analysis .................................................... 33 
6.3 
Primary Analysis.................................................................................................................. 33 
6.3.1 
Analysis Population........................................................................................... 33 
6.3.2 
Analysis Plan ..................................................................................................... 33 
6.4 
Secondary Analysis ............................................................................................................ 34 


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6.4.1 
Analysis Population........................................................................................... 34 
6.4.2 Analysis Plan 
 ............................................................................................................... 34 
6.5 
 Interim analyses ................................................................................................................. 34 
6.6 Missing Data Handling .................................................................................................................. 34 
6.6.1 Missing Data Methods – Viral Domain ................................................................................. 35 
6.6.2 Missing Data Methods – Clinical Domain ............................................................................ 35 
6.6.3 Missing Data Methods – Censoring ..................................................................................... 36 
6.7  
Sample Size Justification ................................................................................................... 36 
6.8 
Criteria for stopping enrollment into a treatment ............................................................ 37 
7. DATA AND BIOSPECIMEN COLLECTION, RETENTION AND MONITORING ....................... 37 
7.1 Data collection instruments .......................................................................................................... 37 
7.2 Data management procedures .................................................................................................... 38 
7.3 Data quality control and reporting ............................................................................................... 38 
7.4 Archival of data ............................................................................................................................... 38 
7.5 Availability and retention of investigational records .................................................................. 38 
7.6 Subject confidentiality .................................................................................................................... 38 
7.7 Audit  ............................................................................................................................................... 39 
8 
ADVERSE EVENT REPORTING AND DOCUMENTATION ................................................. 39 
8.1 Adverse Events .............................................................................................................................. 39 
8.2 Definition of an Adverse Event ..................................................................................................... 40 
8.2.1 Evaluating and Reporting of Adverse Events ..................................................................... 40 
8.3 Serious Adverse Events (SAEs) .................................................................................................. 42 
8.3.1 Definition of Serious Adverse Events................................................................................... 42 
8.3.2 SAE Reporting Requirements to the Sponsor .................................................................... 43 
8.4 Suspected Unexpected Serious Adverse Reactions (SUSARs) ............................................ 43 
8.4.1 Reporting SUSARs to the FDA: IND Safety Reports ........................................................ 44 
8.5 Clinical Laboratory Abnormalities and Other Abnormal Assessments .................................. 44 
8.6 Handling of Overdose .................................................................................................................... 44 
8.7 Management of Progression of Disease .................................................................................... 44 
9 WITHDRAWAL OF SUBJECTS AND MANAGEMENT OF PROTOCOL VIOLATIONS ........... 46 
9.1 Withdrawal of subjects from the study ........................................................................................ 46 
9.2 Removal of subjects from the study ............................................................................................ 46 
9.3 Protocol Violations ......................................................................................................................... 46 
10 DATA, SAFETY, & MONITORING ................................................................................................... 46 
10.1 Data and Safety Monitoring Board (DSMB) ............................................................................. 47 
11. GOVERNANCE ................................................................................................................................. 49 
12. ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS ....................................... 50 
12.1 Institutional review board ............................................................................................................ 50 
12.2 Informed consent form ................................................................................................................ 50 
12.3 Discontinuation of the Study ...................................................................................................... 50 
12.4 Use of Information and Publication ........................................................................................... 51 
APPENDIX 1: SUB-PROTOCOLS ........................................................................................................ 51 


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Protocol Team Roster 
Investigators for COPPS                                        
  
Manisha Desai, PhD, Professor of Medicine and of Biomedical Data Science, 
Quantitative Sciences Unit, Stanford University 
Address: 1701 Page Mill Road, Palo Alto, CA 94304 
Email: manishad@stanford.edu 
 
Upinder Singh, MD, Professor, Division of Infectious Diseases and Geographic 
Medicine, Department of Medicine, Stanford University 
Address: Lane Building, 
, 300 Pasteur Dr, Stanford, CA 94305 
Email: usingh@stanford.edu 
 
Yvonne Maldonado, MD, Professor, Division of Infectious Diseases, Department of 
Pediatrics, Stanford University 
 
Address: 730 Welch Road, 
, Palo Alto, CA 94304 
 
Email: bonnim@stanford.edu 
 
Chaitan Khosla, PhD, Professor, Department of Chemical Engineering, Stanford 
University 
 
Address: 290 Jane Stanford Way, 
, Stanford, CA, 94305 
 
Email: khosla@stanford.edu 
 
Haley Hedlin, PhD, Associate Director of Clinical Trials, Quantitative Sciences Unit, 
Stanford University 
Address: 1701 Page Mill Road, Palo Alto, CA 94304 
Email: hedlin@stanford.edu 
 
Investigators for COPPS Sub-Protocols 
Investigators for COPPS Sub-Protocol for Acebilustat 
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 
 
Investigator for COPPS Sub-Protocol for Camostat Mesilate 
Julie Parsonnet, MD, Professor, Stanford University, Division of Infectious Diseases and 
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Address: Lane Building Room 
, Stanford, CA 94305-5107 
Email: parsonnt@stanford.edu 
 
 
Multi-Site Coordinator: 
, MPH, MSED, Study Startup Operations Associate, Stanford 
University 
Email: 
@stanford.edu 
 
PROTOCOL SYNOPSIS 
TITLE 
COVID-19 Outpatient Pragmatic Platform Study 
(COPPS):  
A 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 PHASE 
2 
DESIGN 
The platform trial allows arms to have one of two primary 
objectives: one evaluating viral shedding (A. Viral Domain); 
and another evaluating clinical outcomes (B. Clinical 
Domain).  The investigational product of interest and its 
mechanism of action and scientific rationale will dictate 
which objective is primary under its sub-protocol (i.e., either 
A. Viral Domain or B. Clinical Domain). The other Domain 
objective will be a secondary measure for the 
investigational product of interest. The platform trial will 
also include a common control arm that will be used as a 
comparator for all arms in both Domains. Investigational 
products will not be compared to each other. 
 
The primary purpose of the Viral Domain endpoint is to 
examine the basic mechanisms of action on the viral 
shedding and viral load for the investigational therapies in 
this Domain.  The primary purpose of the Clinical Domain is 
to evaluate if one or more of the investigational therapies in 
this Domain is effective in treating the symptoms and 
clinical manifestation of COVID-19.   
 
This is an adaptive study, wherein investigational therapies 
can be dropped or added during the trial.  Patients will be 
randomized to one of the investigational therapies in either 
the Viral or Clinical Domain, or to the control group.  
Currently, there is one interventional product in the Viral 
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Domain. All sub-protocols will be double-blinded at the drug 
level. Investigators and participants will know to which sub-
protocol the participants are assigned; they will not know if 
they are receiving drug or placebo. The study is a 
multicenter trial that will be conducted in up to 5 sites 
nationwide. 
INDICATION 
Outpatients with confirmed positive symptomatic mild-to-
moderate COVID-19 
INVESTIGATIONAL 
PRODUCT(S) OR 
PROCEDURE(S) 
A. Viral Domain 
1. Camostat, administered as 200 mg, four times a day for 
ten days 
B. Clinical Domain 
1.  Acebilustat administered as a 100-mg capsule once 
daily for 28 days 
Common Control 
Placebo tablets; the appearance (and dosing scheme) will 
be randomized out of available therapies.  
PRIMARY 
OBJECTIVE(S) 
The platform study has two key domains evaluating either 
(A) viral shedding or (B) clinical events. Each 
investigational product will belong in only one domain. 
The primary objective for each respective domain is as 
follows, tailored to the mechanism of action and scientific 
rationale of the drugs being considered in each domain.  
A. (Viral Domain) To evaluate the efficacy of each 
therapeutic intervention in addition to standard 
supportive care compared with standard supportive 
care in reducing viral shedding of SARS-CoV-2 virus in 
outpatients with COVID-19 disease. 
B. (Clinical Domain) To evaluate the efficacy of each 
therapeutic intervention in addition to standard 
supportive care as compared to standard supportive 
care in improving sustained clinical outcomes in 
outpatients with COVID-19 disease. 
SECONDARY 
OBJECTIVES 
Secondary objectives are:  
1. To address the primary objective for the non-
membership domain of the investigational product (see 
above).  
a. For example, if Drug X falls under the Viral 
Domain, a secondary objective will be the 
primary objective listed under the Clinical 
Domain. 
2. To evaluate the efficacy of each therapeutic intervention 
in reducing SARS-CoV-2 related hospitalizations, ED 


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visits, or death in outpatients with COVID-19 disease. 
3. To assess the development of antibodies against SARS-
CoV-2  
4. To evaluate the safety and tolerability of each 
therapeutic intervention compared with placebo 
(supportive care). 
INCLUSION 
CRITERIA 
Inclusion Criteria can be tailored to each investigational 
product. However, some inclusion criteria are shared 
among all arms in the platform in both domains 
1. Adults (18-80 years inclusive) 
2. Outpatient 
3. Symptomatic 
4. FDA-cleared molecular diagnostic assay positive for 
SARS-CoV-2 within 72 hours from initial swab to the 
time of commencing informed consent 
5. Subject’s COVID-19 related symptom onset occurred 
within 7 days prior to time of randomization. 
6. Willing and able to comply with responsibilities 
necessary for trial integrity. 
7. Other inclusion criteria specific to the investigational 
product that may, in the eyes of the investigator, be 
deemed necessary.  
EXCLUSION 
CRITERIA 
Exclusion Criteria is tailored to each investigational 
product. However, some exclusion criteria are shared 
among all arms in the platform in both domains 
1. At screening, the subject needs to be admitted to the 
hospital or is being evaluated for potential admission 
2. Previous use of experimental drugs that may be 
active against COVID-19 in the eyes of the 
investigators. 
3. At screening, subject tests positive by a urine 
pregnancy test. 
4. Subject is using adrenocorticosteroids (except topical 
or inhaled preparations or oral preparations 
equivalent to or less than 10 mg of oral prednisone) 
or immunosuppressive or immunomodulatory drugs 
(e.g., immunosuppressants, anticancer drugs, 
interleukins, interleukin antagonists or interleukin 
receptor blockers). 
NOTE: Treatment of study participants 
following institutional COVID-19 treatment 
policies or guidelines, including the use of 


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immunomodulatory medications, is permitted. 
This excludes treatment with agents that have 
the potential for direct antiviral activity, 
including convalescent plasma and NO, and 
co-enrollment into other clinical studies that 
evaluate investigational agents for COVID-19.  
5. Subject has a serious chronic disease (e.g., 
uncontrolled human immunodeficiency virus [HIV], 
cancer requiring chemotherapy within the preceding 
6 months, and/or moderate or severe hepatic 
insufficiency). 
6. Has renal insufficiency including severe renal 
impairment and ESRD and/or requiring hemodialysis 
or continuous ambulatory peritoneal dialysis (CAPD). 
7. Has liver impairment greater than Child Pugh A. 
8. Has a history of alcohol or drug abuse in the previous 
6 months. 
9. Has a psychiatric disease that is not well controlled 
where controlled is defined as: stable on a regimen 
for more than one year. 
10. Has taken another investigational drug within the 
past 30 days. 
11. Is deemed by the Investigator to be ineligible for any 
reason. 
OUTCOME 
MEASURES 
The primary outcome is determined by its Domain. 
The primary outcome in the non-assigned Domain is a 
required secondary outcome. 
Viral Domain Primary Outcome (Clinical Domain Secondary 
Outcome): 
● Change in viral shedding of SARS-CoV-2 virus 
through day 10 from self-collected nasal swabs. 
Clinical Domain Primary Outcome (Viral Domain 
Secondary Outcome): 
● Time from randomization to sustained symptom 
resolution. Resolution is defined as the first day 
where no symptoms are self-reported on all 
succeeding days through and including day 28, not 
including sense of taste or smell, and defining 
recovery for fatigue and cough as mild or none. 
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new investigational products may choose a different 
primary endpoint given the available data collected 
under the platform (see below). 
Study 
Measurements: 
Efficacy, Safety 
  
  
 
Study measurements are largely shared between both 
domains with a pragmatic, shared infrastructure  
While the infrastructure is shared, each investigational 
product may have necessary details tailored to the product 
of study to meet the needs for research and participant 
safety. 
Shared in both Domains: 
● Daily self-assessed symptomology surveys (days 1-
28) 
● In-person clinic assessments on days 1, 5, and 28 
● Laboratory panels at screening and at each in 
person visit to ensure safety (Liver & Renal function, 
urinalysis) 
● Self-administered nasal swabs on days 1-
10,14,21,28 for SARS-COV-2 viral quantification 
● Telehealth call on days 120, 210, 300 
Viral Domain Specific: 
● In-person clinic assessments on day 10  
Clinical Domain Specific: 
● Day 10 and 35 telehealth visits 
SAMPLE SIZE  
60 participants for each arm including the shared control 
arm. Total participants will change dynamically based on 
the number of investigational products in the platform. 
STATISTICAL 
CONSIDERATIONS 
We will evaluate the intention-to-treat (ITT) population, 
defined according to the assigned randomization arms, for 
the primary efficacy analysis. We will analyze the as-
treated population as supportive evidence for the primary 
efficacy analysis. We conservatively assume that 90% of 
participants will complete follow-up. The primary endpoint 
will be assessed in all patients within their respective 
domain.  
 
With 60 patients randomized per arm, we will have 80% 
power to detect an effect size of 0.5 in virologic shedding in 
participants receiving one of the investigational therapies 
from the Viral Domain. 
 
With 60 patients randomized per arm, we will have 80% 
power to detect a hazard ratio of 1.91  (assuming a median 
time to event of 10 days in the control arm) in time to 
symptom resolution, assuming a 5% loss to follow up in 
each arm and 5% significance level (two-sided).   


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Figure 1. Schema for study inclusion; A1, A2, B1 represent different theoretical 
investigational products  
 
   
Figure 2. Enrollment timeline; A1, A2, A3, B1 represent different theoretical 
investigational products.  


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
AE 
Adverse event 
BID 
Twice daily 
CBC 
Complete blood count 
CI 
Confidence interval 
CRF 
Case report/Record form 
DAIDS 
Division of AIDS 
DSMB 
Data Safety Monitoring Board 
EUA 
Emergency Use Authorization 
GI 
Gastrointestinal 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
IRB 
Institutional Review Board 
MAb 
Monoclonal antibody 
Platform Trial 
A clinical trial to evaluate several interventions simultaneously 
PLT 
Platelet 
QD 
Once daily 
SAE 
Serious adverse event 
Sub-Protocol 
Aspects of the protocol that are specific to an intervention 
Domain 
A study of interventions evaluated by a shared primary 
endpoint 
WBC 
White blood cell 
WHO 
World Health Organization 
 
 
 


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1. OBJECTIVES 
While global efforts to identify effective therapeutics to treat COVID-19 are intensifying 
and limited anecdotal data suggests that some drugs may be effective, particularly in 
the inpatient setting, we currently lack robust data that demonstrate the efficacy of 
widely available therapeutic agents for outpatients with COVID-19. There remains an 
urgent public health need to develop novel interventions. The overall objective of this 
study is to efficiently evaluate the clinical efficacy and safety of different investigational 
therapeutics among adults who have COVID-19 but are not yet sick enough to require 
hospitalization. Our overall hypothesis is that through an adaptive trial design, we will be 
able to identify potential effective therapies (single and combination) for this group of 
patients. 
 
COVID-19 Outpatient Pragmatic Platform Study (COPPS) is a pragmatic platform 
protocol designed to evaluate COVID-19 treatments by assessing their ability to reduce 
viral shedding (Viral Domain) or improve clinical outcomes (Clinical Domain). To be 
included into the platform, every investigational product will collect data for both Domain 
primary endpoints. Individual treatments to be evaluated in the platform will be 
described in separate sub-protocols. 
 
1.1. 
Primary Objective  
The platform study allows investigational products with objectives either: evaluating viral 
shedding (Virology Domain); and COVID-19 related Clinical Outcomes (Clinical 
Domain).  
The primary objective for investigational products within the Viral Domain is:  
A. To evaluate the efficacy of each therapeutic intervention in addition to standard 
supportive care (SSC) compared with SSC in reducing viral shedding of SARS-
CoV-2 virus in outpatients with COVID-19 disease. 
The primary objective for investigational products within for the Clinical Domain is: 
B. To evaluate the efficacy of each therapeutic intervention in addition to SSC as 
compared to SSC in improving sustained clinical outcomes in outpatients with 
COVID-19 disease. 
 
1.2. 
Secondary Objectives 
Secondary objectives are:  
1) The objective of the non-assigned domain an investigational product is under.  
a. If under Clinical Domain, reduction in viral shedding. 
b. If under Viral Domain, time to sustained resolution of symptoms. 
2) To evaluate the efficacy of each therapeutic intervention in reducing SARS-CoV-
2 related hospitalizations, ED visits, or death in outpatients with COVID-19 
disease. 
3) To assess the development of antibodies against SARS-CoV-2  


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4) To evaluate the safety and tolerability of each therapeutic intervention compared 
with placebo (supportive care). 
1.3  
 Exploratory Objectives 
Exploratory objectives are specific to each sub-protocol and will be specified in their 
respective appendices. 
 
2. BACKGROUND 
 
2.1 Study Disease 
The COVID-19 pandemic is an unprecedented global health crisis. COVID-19 is a 
respiratory disease caused by a novel coronavirus (SARS-CoV-2). The virus is highly 
transmissible and causes life-threatening acute respiratory symptoms in a high 
percentage of cases, especially amongst the elderly and in patients with underlying 
conditions. Globally, there are currently over 120 million cases of COVID-19 and more 
than 2.79 million fatalities. In the United States alone, there have been over 500,000 
deaths. These numbers continue to grow each day, with projections of hundreds of 
thousands of deaths in the United States alone before the pandemic is fully controlled.  
 
Given the enormous and rapidly escalating scale of the pandemic, there is an urgent 
public health need to identify effective therapeutics for treating COVID-19. We propose 
to conduct a clinical trial to evaluate several investigational therapeutics for the 
treatment of adults with COVID-19. The multi-site trial (anticipating up to 5 additional 
sites) is based at Stanford University. We will evaluate a suite of potential therapeutics 
including antivirals and immunomodulatory agents. Together, we are situated to conduct 
this trial, with world renowned experts in immunology, infectious diseases, biostatistics 
and a sophisticated infrastructure for efficiently conducting clinical trials. The 
unprecedented nature of the COVID-19 pandemic requires a collaborative approach to 
address this public health crisis. In addition, collecting clinical and virologic data on 
enrolled subjects should provide valuable information about the clinical course of and 
morbidities associated with COVID-19 in a diverse group of patients. At the conclusion 
of this clinical trial we expect to have identified potentially effective therapeutic 
strategy/ies for treating COVID-19, which will have a transformative impact on precision 
medicine and public health.  
 
2.2 Treatment Rationale and Investigational Agent Information 
For drugs considered under the Viral Domain, we look for candidates with potential 
activity to influence viral mechanism of activity, including those that block viral entry in 
vitro, viral replication and/or viral trafficking. 
 
For drugs considered for the Clinical Domain, we look for candidates with potential 
ability to improve clinical outcomes. 
 
See individual treatment sub-protocols in Appendix 1 for robust rationale. 
 


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2.3 Study Design 
This platform study is designed to primarily evaluate efficacy compared to standard of 
care (SOC) in addition to placebo. The platform trial allows arms to have one of two 
primary objectives: one evaluating viral shedding (A. Viral Domain); and another 
evaluating clinical outcomes (B. Clinical Domain).  The investigational product of 
interest, likely anti-viral or anti-inflammatory in nature, and its mechanism of action and 
scientific rationale will dictate which objective is primary under its sub-protocol (i.e., 
either A. Viral Domain or B. Clinical Domain). The other Domain objective will be a 
secondary measure for the investigational drug of interest. The platform trial will also 
include a common control arm that will be used as a comparator for all arms in both 
Domains. Investigational products will not be compared to each other. 
 
The primary purpose of the Viral Domain endpoint is to examine the basic mechanisms 
of action on the viral shedding and viral load for the investigational therapies in this 
Domain.  The primary purpose of the Clinical Domain is to evaluate if one or more of the 
investigational therapies in this Domain is effective in treating the symptoms and clinical 
manifestation of COVID-19.   
 
This is an adaptive study, wherein investigational therapies can be dropped or added 
during the trial.  Patients will be randomized to one of the investigational therapies in 
either the Viral or Clinical Domain, or to the control group.  Currently, there is one 
interventional product in the Viral Domain and one interventional product in the Clinical 
Domain. All sub-protocols will be double-blinded at the drug level. Investigators and 
participants will know to which sub-protocol a participant is assigned; they will not know 
if they are receiving drug or placebo. 
 
SOC at Stanford is defined as methods Stanford University Healthcare is using for 
COVID-19 patients at the time of study initiation. Each site’s local SOC to be defined 
and shared with Sponsor prior to study initiation. 
 
2.3.1 Selection of Study Sites 
 
This study is being supported by the Stanford Innovative Medicines Accelerator (IMA), 
Clinical Trials Research Unit (CTRU), and the Stanford Center for Clinical Research. 
The study will be performed at up to 5 sites nationally, to be determined by the Clinical 
Coordinating Center at Stanford. 
 
The local sites will be responsible for screening patients and evaluating the 
appropriateness of therapy administration for each participant at study enrollment in 
addition to the conduct of the trial protocol. The local site investigators will also be fully 
responsible for ensuring timely data collection, adverse event monitoring, maintenance of 
regulatory compliance. Compensation, if any, may be determined locally and in 
accordance with local IRB requirements and approval.  
 


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Each investigator or group of investigators at a clinical site must obtain Institutional Review 
Board (IRB) approval for this protocol and submit all required regulatory documents 
(including any protocol specific documents) to their respective IRB as required per 
institution. Sites can submit through a Stanford-designated central IRB for this trial. All 
subsequent mentions of IRB related activity in this document will reflect whichever choice 
they decide, be it local or central IRB. 
Requirements for site selection and site registration: Sites will be evaluated by 
Stanford team and the main PI prior to selection or activation. 
Stanford requires documentation that verifies IRB-approval for this protocol, informed 
consent documents, and associated documents prior to recruitment, screening, and 
enrollment 
of subjects, and any IRB-approvals for continuing review or amendments. 
 
Please refer to the MOP for information on:  
• 
Requesting and submitting regulatory documents 
• 
Patient enrollment & randomization 
• 
Randomization notification 
• 
Requesting study drug 
• 
Withdrawals 
• 
Lost to follow-up 
• 
Protocol deviations 
• 
Data submissions 
 
2.3.2 Subject Information and Consent 
It is the responsibility of the Site Investigator to ensure that written informed consent is 
obtained from the subject or legal representative before any activity or procedure is 
undertaken that is not part of routine care. The informed consent must comply with local 
regulations. 
The background of the study, the procedures, the potential benefits and risks of the 
treatment, and the fact that treatment is voluntary for the subject must be explained to the 
subject or legal representative. The subject or representative must be given sufficient time 
to consider whether to receive other treatment options. A copy of the ICF, signed and 
dated by the subject/representative and the Site Investigator (or designee), must be given 
to the subject/representative. Confirmation of a subject’s informed consent must also be 
documented in the subject’s medical record prior to any treatment. 
Each consent form should contain an authorization allowing the Investigator and the 
Sponsor (or designee) to use and disclose protected health information (PHI) (i.e., subject-
identifiable health information) in compliance with local law. The signed consent form will 
be retained with the treatment records. 
 


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3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
Participants of this trial are meant to be those with diagnosed COVID-19 with severity 
ranging from mild through moderate disease without contraindications for a given 
investigational product. 
3.1 Inclusion Criteria 
 
1. Outpatient setting 
2. Age ≥ 18 years and ≤ 80 years at the time of the assessment 
3. Able and willing to understand the study, adhere to all study procedures, and provide 
written informed consent  
4. Initial diagnosis of COVID-19 disease as defined by an FDA-cleared molecular 
diagnostic assay positive for SARS-CoV-2 with no more than 72 hours from the 
initial swab used in the diagnosis to the time of commencing informed consent.  
5. At baseline, at least two symptoms should have mild or higher severity score, where 
at least one of the mild symptoms is not cough, fatigue, or loss of smell/taste OR at 
least one symptom has a moderate or higher severity score on the COVID 
Outpatient Symptom Scale (COSS). 
6. Subject’s COVID-19 related symptom onset occurred within 7 days prior to time of 
randomization. 
7. Additional inclusion criteria may pertain to specific drugs and will be described in 
Appendix 1 
 
3.2  Exclusion Criteria 
 
1. At screening, the subject needs to be admitted to the hospital or is being evaluated 
for potential admission. 
2. Previous use of experimental drugs that may be active against COVID-19 in the 
eyes of the investigators  
3. Participant yields a positive urine pregnancy test at screening. 
4. Subject is using adrenocorticosteroids (except topical or inhaled preparations or oral 
preparations equivalent to or less than 10 mg of oral prednisone) or 
immunosuppressive or immunomodulatory drugs (e.g., immunosuppressants, 
anticancer drugs, interleukins, interleukin antagonists or interleukin receptor 
blockers). 
NOTE: Treatment of study participants following institutional COVID-19 treatment 
policies or guidelines, including the use of immunomodulatory medications, is 
permitted. This excludes treatment with agents that have the potential for direct 
antiviral activity, including convalescent plasma and NO, and co-enrollment into 
other clinical studies that evaluate investigational agents for COVID-19.  


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5. Subject has a serious chronic disease (e.g., uncontrolled human immunodeficiency 
virus [HIV], cancer requiring chemotherapy within the preceding 6 months, and/or 
moderate or severe hepatic insufficiency). 
6. Has renal insufficiency including severe renal impairment and ESRD and/or requiring 
hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). 
7. Has liver impairment greater than Child Pugh A. 
8. Has a history of alcohol or drug abuse in the previous 6 months. 
9. Has a psychiatric disease that is not well controlled where controlled is defined as: 
stable on a regimen for more than one year. 
10. Has taken another investigational drug within the past 30 days. 
11. Is deemed by the Investigator to be ineligible for any reason. 
12. Additional exclusions may pertain to specific drugs’ sub protocol listed under 
Appendix 1 
 
NOTE: 
Additional Criteria for Monoclonal Antibody (MAb) Therapy Under Emergency Use 
Authorization (EUA): 
 
Patients who are considered high-risk based on criteria for receiving monoclonal 
antibody therapy under EUA by FDA must be informed of its availability and offered 
referral to receive MAb as background standard supportive care. These high-risk 
patients are identified as those with the following conditions:  
• 
Older age (aged ≥65 years) 
• 
Obesity (BMI >30) 
• 
Diabetes  
• 
Cardiovascular disease (including congenital heart disease) or hypertension 
• 
Chronic lung diseases (e.g., chronic obstructive pulmonary disease, moderate-to-
severe asthma, interstitial lung disease, cystic fibrosis, pulmonary hypertension)  
• 
An immunocompromising condition or immunosuppressive treatment 
Note: These criteria may be revised based on any future updates to the “FDA panel 
recommendations Food and Drug Administration Emergency Use Authorization Criteria 
for Use of Anti-SARS-CoV-2 Monoclonal Antibodies”. 
Patients will be referred to receive MAb therapy based on the study site/institution’s 
referral process. The site will document whether referral for MAb therapy was offered 
and whether the patient accepted or refused such therapy. This information will be 
entered in RedCapCloud Electronic Data Capture system as part of the case report 
form. 
 


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3.3  Randomization Procedures 
Patients will be randomized to one of the investigational therapies or the common 
control arm (See Figure 1).  A biased coin randomization using age (>=50 years of 
age), sex, receipt of baseline monoclonal antibodies, and site as inputs will be used to 
balance each arm. Patients randomized to the placebo arm will be further randomized 
to a sub-protocol that will determine the type of placebo treatment the patient receives 
and study procedures for any minor processes that may differ across sub-protocols to 
maintain blinding. Randomization will be performed from a centralized web-based 
system that all sites will have access to. 
 
3.4  Common Control Arm 
A subset of the common control arm will be used as the comparison for each individual 
treatment. The subset will be determined by participant eligibility and time of enrollment. 
Patients in the common control arm will be included in the comparison group for any 
treatment that the patient could have been randomized to, regardless of which sub-
protocol they were randomized to, similar to implementation of other Master Trials 
including the U.K.-based RECOVERY trial. At the time of randomization, we will record 
the treatments the patient could have been randomized to (based on eligibility criteria 
and the treatments available under the pragmatic platform protocol at the time of 
randomization). This maintains comparability between the study arm of interest and the 
controls used as comparators with respect to secular time and eligibility criteria.  
 
Treatment arm randomization odds can and will change under COPPS as drugs are 
introduced and graduated over time. Controls can only be shared for the purpose of 
answering a particular question about an investigational product if the participant could 
have been randomized to that particular investigational product and they were eligible 
for that particular investigational product at time of participant enrollment. In a special 
case where an ongoing trial is incorporated into COPPS, only newly randomized eligible 
controls may be shared. 
 
3.4.1 Maintaining the Blind in the Presence of Drugs Administered Heterogeneously 
Patients in the common control arm will be randomized to receive a placebo treatment 
corresponding to one of the treatments currently available under the pragmatic platform 
protocol (selected at random). Each treatment will have matching placebo tablets to be 
taken on the same schedule as the active tablets. If a treatment is added to the 
pragmatic platform protocol that are not tablets (e.g. an injection), a placebo for that 
treatment will be available for all patients. Thus, as study arms are added, placebos that 
look like that study arm will also be added. The chosen placebo type will be randomly 
selected. Study investigators and patients will know to which sub-protocol a patient is 
assigned to. Patients and investigators will be blinded to whether a patient receives an 
active or placebo version of the treatment.  
 
3.4.2 Benefits and trade-offs to the common control group 
The benefits of the common control group involve improvements from both the 
perspective of the participant and investigator. From the participant point of view, the 


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pragmatic platform trial reduces the number of participants needed to complete the trial, 
thus it puts fewer patients at risk. From an investigator’s point of view, there is efficiency 
gained from sharing controls and coordinating recruitment and screening rather than 
competing for participants. 
 
However, the common control group has tradeoffs in logistics for sharing control 
participants. Since a control participant may be utilized in the analyses for more than 
one sub-protocol, data used for a key endpoint from any arm must be collected for all 
individuals in the platform. While each investigational arm may have nuances tailored to 
the specific drug, the data collected must remain consistent across all arms, or the 
shared controls will have missing data when included in the analysis of a sub-protocol 
other than the one they were randomized to. 
 
Another logistical consideration is the slight differences in inclusion criteria resulting 
from clinical considerations of each investigational product under consideration. An 
individual randomized to the common control group may be eligible for a single sub-
protocol or sub-protocols for every investigational product currently available. 
3.5    Prohibited Concomitant Therapy for Viral Domain 
Any other antiviral medication whether investigational or approved. 
3.6    Prohibited Concomitant Therapy for Clinical Domain 
Any other immunomodulatory treatment whether investigational or approved 
 
 
 


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4.      STUDY PROCEDURES 
4.1 Schedule of Assessments 
 
 
Table 1. Domain Assessments (X is all domains, A is Acebilustat sub-protocol only, C is Camostat sub-protocol only, I is 
Acebilustat imaging sub-study only) 
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 
  
  
  
  
C 
  
  
X 
 
 
 
 
 
Physical exam 
X 
  
  
  
X 
  
  
  
  
C 
 
 
X 
 
 
 
 
 
Vitals 
X 
  
  
  
X 
  
  
  
  
C 
 
 
X 
 
 
 
 
 
Clinical status 
X 
  
  
  
X 
  
  
  
  
C 
 
 
X 
 
 
 
 
 
SpO2 
X 
  
  
  
X 
  
  
  
  
C 
 
 
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 
A 
 
X 
X 
X 
Oropharyngeal swab 
X 
  
  
  
X 
  
  
  
  
C 
 
 
X 
 
 
 
 
 
Blood collected by phlebotomy for 
clinical labs 
X 
  
  
  
X 
  
  
  
  
C 
 
 
X 
 
 
 
 
 
 
 


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Table 1. Domain Assessments (X is all domains, A is Acebilustat sub-protocol only, C is Camostat sub-protocol only, I is Acebilustat 
imaging sub-study only) 
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 
Blood collected by phlebotomy for 
biobanking 
X1 
  
  
  
  
  
  
  
  
  
 
 
X1 
 
 
 
 
 
Blood collected by phlebotomy for PK  
 
  
  
  
C1 
  
  
  
  
 
  
  
  
 
 
 
 
 
Telehealth visit 
 
 
 
 
 
 
 
 
 
A 
 
 
 
A 
 
X 
X 
X2 
CT Imaging  
I3 
 
 
 
 
 
 
 
 
 
 
 
I3 
 
I3 
 
 
 
Administration of drug - Camostat sub-
protocol 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
 
 
 
 
 
 
 
 
Administration of drug - Acebilustat sub-
protocol 
Every day from days 1-28 inclusive 
 
 
 
 
 
1-Denotes optional assessment. 
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. 


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4.2 Study Procedures  
Day 1 (PRE-DOSE)  
• Obtain informed consent. 
• Verify eligibility per the inclusion and exclusion criteria.  
o Review and record medical history to ensure there are no exclusionary illnesses. 
o Review and record concomitant medications for possible prohibited medications.  
o Record date of onset of symptoms  
• If subject is female of child-bearing potential and meets inclusion criteria obtain urine 
pregnancy test and proceed if result is negative. 
• Measure and record vital signs (BP, HR, Temp, Resp, SPO2).  
• Perform Physical exam (may be done by the Principal Investigator or their designee)  
• Collect oropharyngeal swab for virologic testing.  
• Collect blood samples for: 
o Antibodies to SARS-CoV-2. 
o Hematology and clinical chemistry laboratory analyses 
o Biobanking, if applicable 
• Randomize to available treatments. 
• Explain in home procedures for the study (self-sampling of nasal swabs, temperature, 
SPO2, completing the daily questionnaire). 
• Provide supplies to research subject and review the calendar of return visits 
 
Day 1 (FIRST DOSE AND POST-DOSE) 
NOTE: Day 1 is deemed to be the first 24 hours after enrollment into the study, with time 
0 (time of first dose) occurring as quickly as possible after the subject’s eligibility has been 
confirmed.  
• Administer first dose at time 0. 
o Subjects randomized to the camostat mesilate arm will receive 200mg of active 
camostat mesylate or matching placebo one hour before meals (breakfast, lunch, 
and dinner) and before bedtime, for 800mg total in a day over 4 dosing periods. 
Camostat mesilate is provided as 100 mg tablets and dosed orally. Subjects will be 
instructed to take their doses at least two hours after a meal and one hour before 
the next meal, and at bedtime  
o Subjects randomized to the acebilustat arm will receive a 100-mg capsule of 
active acebilustat or matching placebo capsule administered orally once daily for 
28 days. 
• Monitor participant for at least 15 minutes after their first dose. 


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• Educate participant on the dosing schedule for the arm to which they are assigned. 
 
In Person Follow-Up Visit or Early Termination Visit 
Days 5 (± 1 day), 10 (± 1 day) if applicable, 28 (+ 7 days) 
• Conduct and record the results of a Physical Exam. 
• Review and record concomitant medications (Note: if there have been changes in 
concomitant medications during the study, determine whether the change is due to an 
AE). 
• Measure and record vital signs (BP, HR, Temp, Resp, SPO2). 
• Collect blood samples for: 
o Antibodies to SARS-CoV-2. (Day 28) 
o Biobanking (Day 1 and Day 28) 
o Hematology and clinical chemistry laboratory analyses (Day 5, 10 if applicable, 28) 
o Drug PK level one hour after dosing (Day 5, if applicable) 
 
• Assess and record clinical status according to the following study-specific 7-point 
scale: 
1. Not hospitalized 
2. Hospitalized, not requiring hospital care due to lack of housing 
3. Hospitalized, not requiring supplemental oxygen 
4. Hospitalized, requiring supplemental oxygen 
5. Hospitalized, on non-invasive ventilation or high flow oxygen devices 
6. Hospitalized, on invasive mechanical ventilation or ECMO 
7. Death 
• Collect oropharyngeal swab for virologic testing (RT-PCR) and resistance analysis.  
• Collect and record adverse events (see Section 8.1.3 for detailed instructions).  
Telehealth Follow-up Visit  
 
 
 
Days 120 (±7), 210 (±7), 300 (±7) under Camostat sub-protocol 
 
Days 10 (±1), 35 (+7), 120 (±7), 210 (±7), 300 (±7) under Acebilustat sub- 
protocol 
• Contact participant via phone for telehealth visit 
 
4.3  Clinical Lab Biomarkers 
• Hematology 
Hemoglobin (Hgb)  
Hematocrit (Hct) 
Platelet count 
Red blood cell count 
White blood cell count with differential 


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• Chemistry 
Blood Urea Nitrogen (BUN) 
Creatinine 
Total bilirubin 
Alkaline Phosphatase 
Aspartate transaminase (AST) 
Alanine transaminase (ALT) 
Glucose 
Lactic dehydrogenase (LDH) 
Total protein 
Albumin 
Potassium 
Bicarbonate 
Calcium 
Sodium 
Urate 
Chloride 
 
C-reactive protein 
 
 
5. MEASUREMENTS 
For Viral Domain: 
● Primary Outcome Measure Change in shedding of SARS-CoV-2 virus through 
day 10 attained from self-collected nasal swab RT-PCR data after transformation 
using a referenced standard curve. 
● Title: Change in Viral Shedding 
● Time Frame: 10 days  
● Safety Issue: No 
 
For Clinical Domain: 
Primary Outcome Measure Time from randomization to sustained symptom 
resolution assessed over a 28-day period. Resolution is defined as the first day 
where no symptoms are self-reported on all succeeding days through and 
including day 28, not including sense of taste or smell, and defining recovery for 
fatigue and cough as mild or none.  
● Title: Time-to-sustained-resolution 
● Time Frame: 28 days 
● Safety Issue: No 
 
5.1  
Primary and Secondary Outcome measures 
5.1.1 Relevant Subset 
 
For each interventional therapy comparison, the common control arm will be truncated 
to include only those who were eligible for the corresponding interventional therapy. 
  
5.1.2 Measurement Definition 
 
For Viral Domain: SARS-CoV2 viral RNA levels, through day 10 using self-collected 
nasal swabs, will be estimated by transforming CT values with a standard Reference 


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curve. We will utilize a generalized linear mixed effects model with parameterization to 
capture the difference in change in viral shedding at day 10 between treatment arms. To 
generate data from the nasal swabs, we rely on Stanford’s assay, which was issued an 
Emergency Use Authorization (EUA number is EUA200036). 
 
For Clinical Domain: Time from randomization to sustained symptom resolution 
assessed over a 28-day period. Resolution is defined as the first day where no 
symptoms are self-reported on all succeeding days through and including day 28, not 
including sense of taste or smell, and defining recovery for fatigue and cough as mild or 
none. Participants who never experienced resolution will be censored at their last 
survey completion day. 
 
5.1.3 Measurement Methods 
 
 
 
COVID-19 Outcome Symptom Scale (COSS) Daily Questionnaire 
The following questions are about how you feel and how things have been during the past 24 hours compared to 
your typical health. Give the one answer that comes closest to the way you have been feeling. Select "None" if you 
have not had this symptom. 
How do you feel compared to yesterday? 
 
I feel better than yesterday 
 
I feel the same as yesterday 
 
I feel worse than yesterday 
How do you feel compared to last week? 
 
I feel better than last week 
 
I feel the same as last week 
 
I feel worse than last week 
Cough? 
 
None 
 
Mild; just a 
few coughs 
per day 
 
Mild/ 
Moderate 
 
Moderate; frequent but 
I can tolerate it 
 
Moderate
/ Severe 
 
Severe; I am very 
uncomfortable 
Shortness of breath (difficulty breathing)? 
 
None 
 
Mild; just 
short of 
breath with 
exercise 
 
Mild/ 
Moderate 
 
Moderate; I get short 
of breath doing daily 
activities 
 
Moderate
/ Severe 
 
Severe; I feel I can't 
get enough air even 
at rest 
Fatigue (low energy)? 
Please take your oral temperature and 
assess your oxygen saturation with your 
pulse oximeter. 
Oral temperature. ________ F 
Time temperature was obtained. ________ AM/PM 
Blood oxygen saturation. ________ % 
Did you take a nasal swab today (study day 1-10,14,21,28)? Yes       /       No 
Have you taken your study drug as prescribed in the last 24 
hours?  Yes       /       No 


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None 
 
Mild; I go 
about my day 
normally 
 
Mild/ 
Moderate 
 
Moderate; I rest more 
and restrict activity 
 
Moderate
/ Severe 
 
Severe; I am staying 
in bed I'm so tired 
Headache? 
 
 
None 
 
Mild; I can 
ignore it 
 
Mild/ 
Moderate 
 
Moderate; I need to 
take medication  
 
Moderate
/ Severe 
 
Severe; it is markedly 
limiting my life 
Body Ache? 
 
 
None 
 
Mild; I can 
ignore them 
 
Mild/ 
Moderate 
 
Moderate; I need to 
restrict some activities 
 
Moderate
/ Severe 
 
Severe; they are 
markedly limiting my 
life 
Joint pain? 
 
 
None 
 
Mild; I can 
ignore them 
 
Mild/ 
Moderate 
 
Moderate; I need to 
restrict some activities 
 
Moderate
/ Severe 
 
Severe; they are 
markedly limiting my 
life 
Chest pressure? 
 
 
None 
 
Mild; I feel it 
occasionally 
but can ignore 
it most of the 
time 
 
Mild/ 
Moderate 
 
Moderate; I notice it a 
lot and it limits my 
activity 
 
Moderate
/ Severe 
 
Severe; I have bad 
pain and pressure 
that bothers me most 
of the time 
Abdominal pain? 
 
 
None 
 
Mild; I can 
ignore it 
 
Mild/ 
Moderate 
 
Moderate; it is limiting 
my activities 
 
Moderate
/ Severe 
 
Severe; it hurts a lot. 
I may need to see a 
doctor 
Sore Throat? 
 
 
None 
 
Mild; I can 
ignore it 
 
Mild/ 
Moderate 
 
Moderate; it is painful 
to swallow and speak 
 
Moderate
/ Severe 
 
Severe; it is limiting 
my ability to swallow 
or speak 
Nasal Congestion? 
 
 
None 
 
Mild; I can 
ignore it 
 
Mild/ 
Moderate 
 
Moderate; I notice it a 
lot 
 
Moderate
/ Severe 
 
Severe; it is markedly 
limiting my life 
Chills? 
 
 
None 
 
Mild; I can 
ignore it 
 
Mild/ 
Moderate 
 
Moderate; I notice it a 
lot 
 
Moderate
/ Severe 
 
Severe; I am very 
uncomfortable 
Feeling hot or feverish? 
 
 
None 
 
Mild; I can 
ignore it 
 
Mild/ 
Moderate 
 
Moderate; I notice it a 
lot 
 
Moderate
/ Severe 
 
Severe; I am very 
uncomfortable 
Runny Nose? 
 
 
None 
 
Mild; I can 
ignore it 
 
Mild/ 
Moderate 
 
Moderate; frequent 
but I can tolerate it 
 
Moderate
/ Severe 
 
Severe; I am very 
uncomfortable 
Taste? 
 
 
None 
 
Mild; tastes 
aren’t as 
strong as 
usual 
 
Mild/ 
Moderate 
 
Moderate; I’ve noticed 
I can’t taste certain 
foods 
 
Moderate
/ Severe 
 
Severe; I cannot taste 
my food at all 
Smell? 


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None 
 
Mild; smells 
aren’t as 
strong as 
usual 
 
Mild/ 
Moderate 
 Moderate; I’ve noticed 
I can’t smell certain 
odors  
 
Moderate
/ Severe 
 
Severe; I cannot 
smell anything at all 
Diarrhea? (loose or watery stools in 24 hours) 
 
 
None 
 
Mild; less 
than 3 times 
 
Mild/ 
Moderate 
 
Moderate; 3-6 times 
 
Moderate
/ Severe 
 
Severe; more than 6 
times 
Nausea (feeling like you want to throw up)? 
 
 
None 
 
Mild; I'm 
eating and 
ignoring it 
 
Mild/ 
Moderate 
 
Moderate; I don't want 
to eat and can't ignore 
it 
 
Moderate
/ Severe 
 
Severe; I am feeling 
quite uncomfortable 
Vomiting? 
 
 
None 
 
Mild; only 
once or 
occasionally 
 
Mild/ 
Moderate 
 
Moderate; 3-4 times 
per day 
 
Moderate
/ Severe 
 
Severe; I am having 
trouble keeping food 
down 
How many times have you vomited today? 
 
______ 
Do you have a rash? 
Yes               /              No 
The rash is (check all that apply): 
 
No rash 
 
Covering a small amount of my body 
 
Extensive covering of my body 
 
Involving the inside of my mouth or lips 
 
Itchy 
 
Itchy with hives 
In the past 24 hours, have you returned to your usual health (before your 
COVID-19 illness)? 
Yes             /                     No 
 
 
5.2 Secondary Outcomes 
1) The primary outcome of the non-assigned domain for an investigational 
therapy (see section 5.1.2 above). 
2) Time to viral cessation, defined as the time in days from randomization to the 
first of two consecutive negative RT-PCR results of self-collected nasal 
swabs. 
3) Time to first resolution, defined as the first study day where no symptoms are 
self-reported, not including sense of taste or smell, and defining recovery for 
fatigue and cough as mild or none. 
4) Time to full resolution, defined as the study day where no symptoms are first 
self-reported. 
5) To evaluate the efficacy of each therapeutic intervention in reducing SARS-
CoV-2 related hospitalizations, ED visits, or death in outpatients with COVID-
19 disease. 
6) To assess development of antibodies to SARS-CoV-2  


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7) To evaluate the safety and tolerability of each therapeutic intervention 
compared with placebo (supportive care). 
a. Adverse events AEs and clinical laboratory tests for systemic safety 
including hematology and clinical chemistry 
 
 
6. STATISTICAL CONSIDERATIONS 
 
6.1 Statistical Design 
This is an adaptive platform trial with two separate domains and a common control arm.  
Under the Viral Domain we will examine the viral load of a set of investigational therapies; 
under the Clinical Domain we will examine clinical efficacy of a set of investigational 
therapies.  The common control arm, only including participants eligible for each 
treatment, will be used as a comparator for each investigational therapy (from either 
Domain). Due to logistics of arms beginning and ending and differing eligibility criteria, 
the overall size of the COPPS common control arm will be larger than the subset of the 
common control arm used to make a comparison for a given investigational therapy. Each 
Domain is adaptive, such that therapies in the Viral Domain can be dropped for early 
superior efficacy or therapies can be added based on emerging pre-clinical data; and 
therapies in the Clinical Domain can be dropped for futility or therapies can be added 
based on emerging pre-clinical data. 
 
 
6.1.1 Randomization 
Participants will be randomized to one of the investigational therapies or the common 
control group.  A biased coin randomization using age, sex, receipt of baseline 
monoclonal antibodies, and site as inputs will be used to balance the mix of old/young 
and female/male randomized to each arm. Participants will be randomized with equal 
probabilities to control and each of the interventions that they are eligible to receive. 
That is, participants eligible for the two treatments currently under consideration be 
randomized in a 1:1:1 (2:1 active treatment:placebo) ratio while participants eligible for 
only one treatment will be randomized in a 1:1 ratio to the treatment and control. If a 
participant is randomized to placebo, it will be specifically noted what investigational 
therapies he is eligible to be used as a common control.  
 
Treatment arm randomization odds can and will change under COPPS as drugs are 
introduced and graduated over time. Controls can only be shared for the purpose of 
answering a particular question about an investigational product if the participant could 
have been randomized to that particular investigational product and they were eligible for 
that particular investigational product at time of participant enrollment. 
  


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6.2 Descriptive Statistics and Exploratory Data Analysis 
For all arms, descriptive statistics (proportions for categorical variables, means, 
medians, standard deviations and interquartile ranges for continuous variables) will be 
reported for all key patient variables, including baseline and demographic 
characteristics, use of medications, compliance, and study completion status. Data that 
are missing on key patient characteristics and the outcome will be fully described, 
including any patterns of missingness (i.e., any relationships between missingness of a 
variable and patient characteristics). A CONSORT diagram displaying the number of 
patients screened, eligible, and consented along with reasons for ineligibility will be 
provided. Graphical tools such as histograms, boxplots, and scatterplots will be created 
to assess quality of data and to display patterns over time. 
 
6.3 Primary Analysis  
 
6.3.1 Analysis Population 
We rely on intention-to-treat principles when addressing the primary objective. 
Specifically, we will evaluate the primary outcome using the intention-to-treat (ITT) 
population. The intent-to-treat (ITT) population includes all patients randomized to that 
treatment. Patients will be analyzed according to their assigned treatment arm. All 
efficacy analyses will be completed in the ITT population. The as-treated population will 
include all randomized patients who received study treatment according to the treatment 
received. All efficacy analyses will be also be completed in the as-treated population as 
supportive evidence for the primary efficacy analysis.  
 
Control participants will be shared across the treatment arms. Those randomized to 
control will be used as controls in the analyses for the treatments for which they were 
eligible. Eligibility includes both inclusion/exclusion criteria and if at time of participant 
enrollment, the treatment was available in the randomization. 
 
6.3.2 Analysis Plan 
For the proposed Viral Domain endpoint, we will utilize a generalized linear mixed 
effects model with parameterization to capture the difference in change in viral shedding 
at day 10 between treatment arms. SARS-CoV2 viral RNA CT values will be 
transformed using a standard Reference curve. The test will be performed at the two-
sided alpha = 0.04999 level of significance. 
 
The hazard ratio for reduction in viral shedding will be estimated, along with its 95% 
confidence interval, from a Cox proportional hazards model. If the proportional hazards 
assumption is not met, we will consider an extended Cox model that relaxes the 
proportional hazards assumption..  
 
For the proposed Clinical Domain endpoint, time to symptom resolution will be 
compared between the treatment and control arms using a two-sided Cox proportional 
hazards model adjusted for age, sex, receipt of baseline receipt of monoclonal 
antibodies, and site. The test will be performed at the alpha = 0.04999 level of 


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significance. The hazard ratio for disease progression will be estimated, along with its 
95% confidence interval, from a Cox proportional hazards model. If the proportional 
hazards assumption is not met, we will consider an extended Cox model that relaxes 
the proportional hazards assumption. The distribution of disease progression will be 
estimated using the Kaplan-Meier method, and Kaplan-Meier curves will be presented 
for each treatment arm. Median time to sustained symptom resolution at the end of the 
study period along with 95% confidence intervals will be presented for each treatment 
arm.  
 
6.4 Secondary Analysis 
 
6.4.1 Analysis Population 
The safety analyses will be performed using the as-treated population and will include 
all patients who receive study treatment. Patients will be analyzed according to actual 
treatment received. All safety analyses will be completed in the as-treated population. 
 
6.4.2 Analysis Plan 
There will be no formal adjustment for multiple testing, since this study is a phase 2 trial 
aimed at efficacy signals detection. Results from all aforementioned analyses will be 
reported regardless of their significance level and effect size to avoid cherry picking and 
allow post-hoc adjustment of multiple testing.  
 
The frequency of adverse events (AEs) and serious adverse events will be tabulated by 
type and by treatment arm. AEs will be compared by arm using the Chi-squared test or 
Fisher’s exact test, as appropriate, in the safety analysis set. 
 
Clinical laboratory and biomarker results at each time point and change from Baseline 
will be displayed using summary statistics (n, mean, standard deviation [SD], median, 
minimum and maximum values) by treatment group. For certain measures, logarithmic 
normalization or geometric statistics may be evaluated. Values at each time point and 
change from Baseline for weight, and vital sign measurements will be summarized with 
descriptive statistics (n, mean, SD, median, minimum, and maximum) at each time point 
by treatment group. 
 
6.5  Interim analyses 
There will be one interim analysis in each experimental arm after 50% of the patients 
have been treated.  Using a Wald test based on the Cox proportional hazards model 
detailed above, an arm will stop early if the corresponding p-value is less than 
alpha=0.00001. 
 
6.6 Missing Data Handling 
All efforts will be made to minimize instances of missing data. However, we expect 
some missing data will occur.  


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6.6.1 Missing Data Methods – Viral Domain 
Our analyses will assume data are missing at random. Change in viral shedding will be 
defined by a single participant’s logarithmic base 10 viral load from self-collected nasal 
swab tests collected on days 1 through 10. We will utilize the exact times of collection of 
each nasal swab. Multiple imputation using chained equations will be used to impute 
missing viral load data prior to modeling. Five data sets will be imputed, and imputed 
values will be calculated using non-missing viral load on each of the 13 sample 
collection days (days 1:10,14,21,28), treatment arm, age, sex, receipt of baseline 
receipt of monoclonal antibodies, site, and whether or not a participant was hospitalized. 
A pooled linear mixed effects model will be fit to log-transformed viral shedding as a 
function of treatment, age, sex, receipt of baseline receipt of monoclonal antibodies, and 
site using the 5 imputed data sets. Difference in viral shedding by treatment arm and 
corresponding 95% confidence intervals will be reported using Rubin’s Rules. The 
difference in change in viral shedding by treatment arm will also be done after refitting 
the model without participants who were hospitalized to assess sensitivity of results. 
 
6.6.2 Missing Data Methods – Clinical Domain 
Analyses will assume data are missing at random. Specifically, if a COSS is only 
partially completed, resolution is undetermined and considered censored. Note, 
however, that in a previous clinical trial where the COSS was used, we did observe 
some timepoints where participants did not fill out a COSS, however, we found no 
cases where COSS was only partially scored.  
For the primary endpoint of time to sustained symptom resolution, any participant who 
dies or drops out prior to having one survey indicating mild to no symptoms will be 
censored at day 28.  
Sensitivity to assumptions regarding missingness will be addressed through sensitivity 
analyses. 
 
Missing data will be adjusted as follows: 
• Let m be the last day with reported data for patients where m <=28 
• If no symptoms are reported at day m, m-1, and m-2 (total of 48 hours), 
we would classify the patient as having resolved symptoms at day m even 
if m<28. 
• On the other hand, if symptoms are not reported at day m, but symptoms 
are reported at day m-1 or m-2, we would classify the patient as not 
having resolved symptoms at day 28 (censored). 
• If symptoms are reported at day m, we would classify the patient as not 
having resolved symptoms at day 28 (censored), even if m<28. 
 


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If more than 5% of participants do not have the symptomology data observed (i.e. they 
are right-censored), we will perform a sensitivity analysis to evaluate the robustness of 
our findings to missing data assumptions. In the sensitivity analysis, among those 
missing timing of resolution, we will assume varying proportions (e.g. 25%, 50%) of 
participants in each arm who would have resolved symptoms by Day 28. The 
proportions will differ by arm so we can evaluate whether our findings stand if it were 
true that people who dropped out had symptom resolution earlier in the placebo arm vs 
the active arm.  
 
 
6.6.3 Missing Data Methods – Censoring 
 
Death: Participants who die while in COPPS should be censored at day 28 for the 
clinical domain primary endpoint and any other time-to-event secondary endpoint. 
 
Withdrawal: Individuals who withdraw from the study will be censored at last day of 
observation. Additionally, we will provide a sensitivity analysis in the case where 
discontinuation from study (not study drug) is differential by treatment arm where 
participants are censored at Day 28. Importantly, if participants discontinue from the 
study, we will make every attempt to capture the reason why. Note that ‘withdrawal of 
consent’ or ‘loss to follow up’ are  the only acceptable reasons for withdrawal from the 
study. 
 
Hospitalization: Hospital admission will be censored at day 28 in the case where a 
patient is hospitalized and discontinues hospital drug, we will still consider them in the 
study unless they explicitly withdraw from the study, in which case we will record the 
clinical event and attempt to capture their reason for withdrawal. 
 
6.7  
Sample Size Justification 
For the Viral Domain, the use of a two-sided log rank test at the alpha=0.04999 level of 
significance for the final analysis, 120 patients (60 per arm) will provide 80% power to 
detect an effect size of 0.5 using a two-sample t-test. This leaves alpha=0.00001 to 
check for overwhelming efficacy after 50% of participants have completed 24 hours of 
follow-up. 
 
For the Clinical Domain, assuming the use of a two-sided log rank test at the 
alpha=0.04999 level of significance for the final analysis, 78 events will provide 80% 
power to detect a hazard ratio of 1.91. This leaves alpha=0.00001 to assess 
overwhelming efficacy after 50% of participants have completed 24 hours of follow-up. 
Assuming the control and treatment arm median time to resolution is 10 and 5 days, 
respectively, a three-month accrual period, a 28 day follow-up period after 
randomization of the last patient, and a drop out of 5% in both the control and treatment 
arms, it is estimated that the total sample size required to achieve 78 events is 120 (60 
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6.8 Criteria for stopping enrollment into a treatment  
Participants will be enrolled and randomized to a treatment arm until that treatment is 
stopped due to efficacy as determined by stopping rules pre-specified in that treatment’s 
protocol or if the DSMB recommends that enrollment into the treatment arm be stopped. 
7. DATA AND BIOSPECIMEN COLLECTION, RETENTION AND MONITORING  
The Data Coordinating Center (DCC) housed within Stanford’s Quantitative Sciences 
Unit (QSU), led by PI Manisha Desai PhD, will oversee data-related activities including 
data management, monitoring, and analysis. Stanford will serve at the central laboratory 
and storage facility, responsible for the processing of all assessments of SARS-COV-2 
RNA, such as nasal swabs. Other samples will be collected and stored for concurrent or 
retrospective virologic assessments (e.g., viral RNA in blood, saliva, stool/rectal swabs, 
and lower respiratory tract samples in subjects who become hospitalized; resistance 
analyses), as feasible. Criteria for resistance monitoring include those who receive an 
antiviral but do not respond. 
 
 
7.1 Data collection instruments 
 
Any paper data (e.g. informed consent documents, screening, and contact information) 
will be maintained in a research chart. The remaining clinical data-- daily 
questionnaires, case record forms (CRFs), and laboratory results--will be entered and 
maintained in Stanford's REDCap database using the minimum number of personal 
identifiers (DOB, dates of visit). Physical copies of laboratory data from point of care 
devices will be stored in a file. Specimen containers and blood tubes will be labeled by 
the clinical research coordinator only with study ID and date.  Virologic measurements 
will be entered into a database stored on secured servers and provided from the clinical 
laboratory to the study team. Biobanked specimens (e.g. PaxGene, plasma, PBMC) will 
be entered into the Stanford Biobank database stored on secure servers. Stanford will 
serve as the centralized biobank and lab for processing biospecimens collected across 
all sites. 
The site will be suitably trained on the use of the eCRF and appropriate site personnel 
will be provided electronic signatures. All site entries will be made in a secured web site 
and the Site Investigator will review the record for completeness.  Upon completion of 
the review, they will sign electronically in the signature page of the eCRF. The Site 
Investigator or designee will make necessary eCRF corrections.  The investigator must 
authorize the corrections to the entered data on eCRF. Specific instructions on use of 
the EDC system and guidelines for data entry and correction will be provided to the 
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7.2 Data management procedures 
  
All subjects will be given a study ID.  Symptom questionnaires and CRFs used at clinic 
visits will be completed by subjects and or study personnel using only study ID.   
Specimen containers will be labeled by the CRC only with study ID and date, time of 
collection.   Virologic measurements and other biomarkers will be provided back to the 
study team electronically once available and entered into the database. 
  
7.3 Data quality control and reporting 
In order to ensure data quality, the study CRC will perform a regular data quality 
assessments.  All study forms entered into the data management system will be 
assessed for accuracy with source documents.  In addition, the Data Coordinating 
Center will perform weekly reviews of the checks described in the data management 
plan to identify potential data quality issues. The data will be owned by Stanford 
University. 
 
Erroneous data will be communicated to the trial management team and site staff for 
clarification from the source. Data management staff will work with site staff to address 
queries. 
  
7.4 Archival of data 
Electronic data including all study databases and supporting electronic documentation 
will be archived to cloud-based servers on a daily basis.  
  
7.5 Availability and retention of investigational records 
All data will be kept in secured RedCap and Box servers.  Only the research team will 
have access to the data.    
All records connected with this clinical study will be retained for at least two years 
following the date of an approved marketing application [21 CFR 312.62(c)]; or at least 
three years from the formal discontinuation the applicable sub protocol study drug, or 
seven years from the end of the study, whichever is longer.  All local laws regarding 
retention of records must also be followed.  Study sites are required to retain all records 
until written notification allowing destruction is received from the Sponsor. 
 
7.6 Subject confidentiality 
Participants will be asked at screening (after the consent is signed) if it is permissible for 
the study staff to contact them via telephone. If so, the participant's preferred telephone 
number will be documented in the research record. Computerized questionnaires via 
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The following health information related to this study may be used or disclosed in 
connection with this research study, including, but not limited to, name and initials, 
address, email, phone number(s), date of birth, age, sex, race, ethnicity, medical record 
number, information related to COVID-19 disease, symptoms, physical exams, symptoms 
that might relate to medication side effects, vital signs including temperature and oxygen 
saturation levels laboratory tests, radioimaging results, pregnancy test and tests of viral 
shedding of Covid-19 and other viruses, medications received including study drug, and 
phone call records. 
  
All subjects will be given a sequential study ID. The code for this ID with personal 
identifiers will be maintained in a locked research file accessible only to study personnel.  
Only research personnel will have access to the research records. The data will be keyed 
into a secure study website in a coded fashion by the study coordinator.   Any paper 
research documents will be kept in a locked file cabinet with limited access. The study 
coordinator is the only one that has the key to the locked cabinet where the research 
charts are stored. Laboratory personnel will have access to study specimens. The data 
is transferred by computer via password protected electronic network. When transferring 
via electronic networks a password protected encrypted computer will be used. 
 
7.7 Audit 
ICH guidelines for GCP require independent inspection of clinical program activities.  Such 
inspections may be performed at any time - before, during and/or after the study.  The site 
Investigator and site study staff are responsible for maintaining the site master file 
containing all study-related regulatory documentation as outlined by the Sponsor that will 
be suitable for inspection at any time by the Sponsor, its designees, and/or regulatory 
agencies.  The Investigator understands and agrees to give access to the necessary 
documentation and files. 
8 ADVERSE EVENT REPORTING AND DOCUMENTATION 
  
8.1 Adverse Events 
Treatment-emergent AEs will be defined as those occurring coincident with start of 
treatment through 28 days post-enrollment. 
Subjects will be instructed to report AEs during the study and staff will query subjects 
regarding AEs throughout the study. The Site Investigator (and/or designee) must 
document all AEs reported through completion of the Day 28 visit. Any subject who is 
withdrawn from the study due to an AE shall be followed until the event has resolved or 
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available follow-up information on the subject’s source documentation and CRF. Serious 
adverse events (SAEs) potentially related to the study and those possibly unexpected will 
be reported to the local site principal investigator and the Clinical Coordinating Center 
(CCC) for review.   
 
8.2 Definition of an Adverse Event 
The FDA Safety Guidance, referencing 21CFR312.32(a), defines an Adverse Event as 
follows: 
Adverse event means any untoward medical occurrence associated with the use of a drug 
in humans, whether or not considered drug related.   
An adverse event (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a drug and does not imply any judgment about causality.  An 
adverse event can arise with any use of the drug (e.g., off-label use, use in combination 
with another drug) and with any route of administration, formulation, or dose, including an 
overdose.  
Adverse Events are NOT: 
·  
Clinical events related to the progression of COVID-19. 
·  
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion).  The condition that leads to the procedure is the AE. 
·  
Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for elective surgery, social and/or convenience admissions). 
8.2.1 Evaluating and Reporting of Adverse Events 
For each adverse event identified and graded as severe or life threatening and felt to be 
possibly, probably or definitely related to study drugs, an adverse event report form will be 
completed.  In addition, an adverse event form will be completed for all serious adverse 
events and unexpected events, regardless of severity. An adverse event report form will 
not be completed for events classified as mild or moderate (unless they are serious or 
unexpected), as mild and moderate symptoms are common and difficult to distinguish from 
signs and symptoms due to COVID-19 and other common illnesses.  The Site Investigator 
must follow all AEs until the AE resolves, or until the Investigator and/or the Medical 
Monitor determine the event is chronic or clinically stable.  If an AE remains unresolved at 
the conclusion of the study, the Site Investigator and Medical Monitor will make a clinical 
assessment to determine whether continued follow-up of the AE is warranted.  All subjects 
who have received at least one exposure to study therapy will be evaluated for safety of 
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The Site Investigator should attempt to establish a diagnosis of the event based on signs, 
symptoms and/or other clinical information.  In such cases, the diagnosis should be 
documented as the AE and not the individual signs/symptoms. 
All AEs must be promptly documented on the Adverse Event eCRF and assessed by the 
Investigator.  Details of the event must include the dates of onset and resolution, severity, 
relationship to study drug, seriousness, and whether the event caused the subject to 
withdraw from the study, outcome and timing with regard to administration of the study 
drug. 
AEs will be categorized using the Division of AIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events.  
Severity: Severity should be graded and recorded as follows: 
1. Grade 1 Mild: No or minimal interference with usual activities; intervention not 
indicated 
2. Grade 2 Moderate: Greater than minimal interference with usual activity; intervention 
indicated 
3. Grade 3 Severe: Inability to carry out usual activity, incapacitating; requires 
intervention or hospitalization 
4. Grade 4 Potentially life-threatening: Inability to perform self-care; intervention 
indicated to prevent permanent impairment, disability or death 
5. Grade 5 Death 
Relationship: The relationship of the Adverse Event to the study drug will be determined 
initially by the Site Investigator, and assessed using the following definitions: 
• Definite: the AE is clearly related to the research procedures 
• Probably: the AE is likely related to the research procedures 
• Possible: the AE may be related to the research procedures 
• Unlikely: the AE is doubtfully related to the research procedures 
• Unrelated: the AE is clearly not related to the research procedures 
• 
Possibly related to participation in the research: There is a reasonable possibility that 
the adverse event, experience, or outcome may have been caused by the procedures 
involved in the research. 
Final determination of relatedness will be made by the Sponsor. 
Expectedness:  
OHRP defines an unexpected AE as any AE occurring in one or more participants 
participating in a research protocol, the nature, severity, or frequency of which is not 
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1) 
the known or foreseeable risk of AEs associated with the procedures involved in 
the research that are described in a) the protocol-related documents, such as the IRB-
approved research protocol, any applicable investigator brochure, and the current IRB-
approved informed consent document, and b) other relevant sources of information, such 
as product labeling and package inserts; or 
2) 
the expected natural progression of any underlying disease, disorder, or condition   
of the participant(s) experiencing the AE and the participant’s predisposing risk factor 
profile for the AE. 
These criteria, in addition to good clinical judgment, should be used as a guide for 
determining the causal assessment.  If it is felt that the event is not related to study drug 
therapy, then an alternative explanation should be provided. 
8.3 Serious Adverse Events (SAEs) 
All SAEs as defined below and that occur after the first treatment and up to 28 days post-
enrollment must be reported to the Sponsor as soon as the Site Investigator becomes 
aware of them.  Any SAEs occurring more than 28 days after last study drug administration 
and considered at least possibly drug-related must also be reported. 
8.3.1 Definition of Serious Adverse Events 
An SAE is an AE from this study that results in any of the following outcomes: 
·  
Death (even if caused by COVID-19 all deaths are recorded as SAEs) 
·  
Life-threatening situation (subject is at immediate risk of death) 
·  
Inpatient hospitalization or prolongation of existing hospitalization 
·  
Persistent or significant disability/incapacity 
·  
Congenital anomaly/birth defect in the offspring of a subject who received study 
drug 
NOTE: Important medical events that may not result in death, be immediately life-
threatening, or require hospitalization, may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. 
A life-threatening AE is defined as any adverse experience that places the subject in the 
view of the Site Investigator, at immediate risk of death from the event as it occurred.  This 
does not include an event that might have led to death, if it had occurred with greater 
severity. 
 “Inpatient hospitalization” means the subject has been formally admitted to a hospital for 
medical reasons, for any length of time with a minimum one overnight stay.  Presentation 
and care within an emergency department does not necessarily constitute an SAE.  


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Complications that occur during hospitalization are AEs.  If a complication prolongs 
hospitalization, it is an SAE. 
8.3.2 SAE Reporting Requirements to the Sponsor 
The procedure for reporting SAEs, regardless of causal relationship, is as follows: 
·  
Within 24 hours of the Site Investigator’s knowledge of an SAE, the site must notify 
the Sponsor by phone call to their site monitor, medical monitor or other Sponsor 
representative. They should also immediately complete the AE eCRF and select “Serious”. 
·  
This initial reporting of an SAE should contain as much information as is available 
to the Site Investigator.  Submission of the SAE via the Electronic Data Capture (EDC) 
should not be delayed in order to collect additional information to complete the form. 
·      Follow-up SAE reports may be generated in cases in which additional information 
becomes available.  Hospital records, autopsy reports, and other documents may become 
available and scanned copies can be provided to the Sponsor when applicable.  The 
follow-up SAE report should describe whether the event has resolved or continues, if and 
how it was treated, whether the blind was broken or not, and whether the subject continued 
or withdrew from study participation. 
·  
The Sponsor (or designee) will distribute completed SAE forms, which may be used 
to notify the IRB when applicable, via a secure internet-based document depository. 
·  
The Site Investigator should notify the IRB of Serious Adverse Events occurring 
and other adverse reports received from the Sponsor in accordance with local procedures. 
The Site Investigator must take all therapeutic measures necessary for resolution of the 
SAE.  Any medications necessary for treatment of the SAE must be recorded onto the 
concomitant medication section of the subject’s eCRF.  However, treatment medication 
should only be recorded in the narrative description section of the SAE form. 
8.4 Suspected Unexpected Serious Adverse Reactions (SUSARs) 
A SUSAR carries specific and time-based reporting requirements for the Sponsor of a 
clinical trial. Thus, after a Site Investigator reports an SAE, the FDA expects the Sponsor 
will determine whether it meets the definition of a SUSAR. 
A SUSAR is defined according to 3 criteria: 
1.     The AE is deemed a “suspected adverse reaction” if there is a reasonable possibility 
that the study drug caused the AE.  A “reasonable possibility” means there is evidence to 
suggest a causal relationship between the drug and adverse event. 
2.     The AE is “Serious” if it meets the definition of an SAE provided in section 8.4.5 
3.     The AE is deemed “unexpected” if it is not listed in the Investigator’s Brochure (IB) or 
if in the IB, has not been reported at the severity observed. 


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In cases where the Sponsor deems a SUSAR has occurred, it must file an IND Safety 
Report with the FDA.  PI will require the assistance and cooperation of the Site Investigator 
and staff to provide accurate and complete information on the subject and observed SAE 
so that reporting requirements to the FDA can be met. All SUSAR’s will be additionally 
reported to the DSMB and the IRB. 
8.4.1 Reporting SUSARs to the FDA: IND Safety Reports 
IND safety reports are used to submit reports of SUSARs to the FDA.  There are 2 types 
of reports: 
· A “15-day report” is used when the reported SAE is a SUSAR and requires that as much 
information as is available to the investigator and the sponsor, be submitted to the FDA in 
on the appropriate form. For US trials, the appropriate form is the FDA Form 3500A also 
commonly known as a “MedWatch” form. 
· A “7-day report” is used when the SUSAR is considered to be fatal or life-threatening. 
The 7-day and 15-day reports will be submitted by the Sponsor to the FDA as per the 
regulatory requirements.   
8.5 Clinical Laboratory Abnormalities and Other Abnormal Assessments 
Laboratory abnormalities are usually not recorded as AEs unless considered to be 
clinically significant by the clinician.  An abnormal laboratory result will be considered an 
AE if it induces clinical signs or symptoms, if the abnormality is of a degree that requires 
active management (e.g. discontinuation of the study drug, dose modification) or when 
the event is requiring treatment or other therapeutic intervention (e.g. iron supplements, 
blood transfusion, etc.). 
The Investigator will evaluate the relationship of any significantly abnormal result to 
protocol treatment and clinical condition, if possible.  All clinically significant abnormal 
laboratory results will be followed until they return to normal or become stabilized. 
8.6 Handling of Overdose 
An overdose is defined as any dose greater than the highest daily dose included in this 
document. Any overdose must be recorded. If the overdose is associated with an AE, 
that AE must be recorded, assessed for seriousness, and reported as an SAE. 
8.7 Management of Progression of Disease 
Research coordinators will be advised to contact study PI’s with any concerns of 
worsening clinical status.  Specifically, if a patient reports worrisome worsening of 
symptoms (e.g. light-headedness or worsening shortness of breath or new hypoxemia), 
they will be advised to be seen in the Emergency Department. Note that such an 
incident is considered an important clinical event that will be recorded and captured in 
our electronic data capture system.  
 


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Each sub-protocol may specify continuation of study drug in these cases (see sub-
protocol appendices). However, the ultimate decision to continue study drug will be left 
to the admitting team in consultation with study investigators. In all cases, we will 
continue to monitor the patient and encourage retention in the COPPS trial. Importantly, 
it will be the charge of the DSMB to evaluate such clinical and adverse events so that 
the study may be halted in event of an excess of such events. We will not unblind study 
patients requiring hospitalization unless necessitated by specific circumstances. 
 
8.7.1 Liver Function Test Monitoring 
 
Liver function tests (ALT, AST, GGT, alkaline phosphatase [ALP], and total bilirubin) 
will be monitored at all in person visits. These tests will be monitored for the remainder 
of the study per the Schedule of Events. 
 
Subjects with new treatment-emergent ALT, AST or GGT elevations of ≥3 × ULN 
should be followed closely, including repeat confirmatory testing within 48 to 72 hours of 
the initial finding and subsequent close monitoring of these liver enzyme levels, as 
clinically indicated. In subjects in whom confirmatory testing within 48-72 hours 
confirms elevated ALT, AST or GGT ≥3 × ULN, prothrombin time (PT) including 
international normalized ratio (INR) and partial thromboplastin time (PTT) should be 
tested. 
 
Study drug administration must be permanently discontinued immediately, and the 
medical monitor must be notified if any of the following criteria is met: 
• ALT or AST ≥8 × ULN 
• ALT, AST or GGT ≥5 × ULN for more than 2 weeks 
• ALT or AST ≥3 × ULN, in association with total bilirubin ≥2 × ULN and/or clinical 
jaundice 
• ALT or AST ≥3 × ULN, in association with symptoms (e.g. nausea, vomiting, 
fatigue, right upper quadrant abdominal pain) 
 
In subjects in whom study drug administration is permanently discontinued, a thorough 
investigation of potential causes for these abnormalities, including alternative etiologies 
(e.g.,acetaminophen use, other concomitant medications [including those for CF], viral 
hepatitis, or alcohol ingestion), should be conducted, and the subject should be followed 
closely for clinical progression/improvement, including close monitoring of the liver 
function tests until levels normalize or return to baseline. Any subject who discontinues 
from study treatment for alterations in liver function tests as described above should not 
be withdrawn/discontinued from the study and should complete the remaining study 
visits. 
 
 


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9 WITHDRAWAL OF SUBJECTS AND MANAGEMENT OF PROTOCOL 
VIOLATIONS 
  
9.1 Withdrawal of subjects from the study 
  
Participants will be followed until they reach 28 days post-randomization.  Study 
participants will be prematurely withdrawn from the study for: 1) loss to follow up, 
defined as the inability to be located for >7 consecutive days, or 2) withdrawal of 
informed consent. 
 
9.2 Removal of subjects from the study 
The participation of a subject in the study or the administration of treatment may be 
terminated at any time for one of the following reasons: 
• The subject desires to discontinue study treatment. 
• The subject withdraws consent to participate in the study. 
• The subject is unwilling or unable to comply with the safety procedures. 
• The subject is discovered to be pregnant.  
• The subject experiences a medical emergency that necessitates withdrawal. 
• The subject is withdrawn at the discretion of the Investigator for medical reasons or 
non- compliance. 
 
 
9.3 Protocol Violations 
  
All protocol violations will be noted and reported to the site’s Institutional Review Board 
within 5 days of the protocol violation report.  The PI will develop a corrective action 
plan to present to the IRB for review and approval. For more information please 
reference the manual of operations for this study. 
10 DATA, SAFETY, & MONITORING 
  
The proposed study will conform to rigorous standard monitoring procedures, 
standardized reporting of adverse events (Adverse Event Report Forms are completed 
by study coordinators and sent immediately to the investigators), and review of the 
study by Data and Safety Monitoring Boards (DSMB). The sub-protocol PI has primary 
responsibility for the overall conduct of the sub-protocol, including the safety of human 
subjects enrolled in the sub-protocol. The PI will ensure appropriate (1) conduct of the 
informed consent process (e.g. that informed consent is obtained before proceeding 
with study procedures); (2) enrollment of study subjects; (3) collection and analysis of 


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data; (4) implementation of study procedures to ensure consistent monitoring of 
subjects for possible adverse events; (5) review of adverse events and reporting to the 
DSMB and the IRBs; and (6) maintenance of the privacy and confidentiality of study 
subjects. The PI maintains ultimate responsibility for the project and for the safety of 
study participants.  The PI will be in contact with the research team on a regular basis to 
review the progress of the study and address any human subject issues that occur. 
These discussions may involve adverse event prevention measures, recruiting of 
appropriate study subjects, research staff training on protection of human subjects, as 
well as occurrence of adverse events, unexpected incidents, or protocol problems. 
 
Due to the restrictions imposed on clinical and hospital visits by the COVID-19 
pandemic, most monitoring activities of this study will be conducted remotely. Monitors 
will work with the study staff at each site to determine times for “joint” remote or in-
person monitoring – meaning that the monitor and the site study staff will review data 
together over the telephone. 
 
Monitoring will be conducted according to the applicable ICH and GCP guidelines to 
ensure protocol adherence, quality of data, drug accountability, compliance with 
regulatory requirements and continued adequacy of the investigational site and its 
facilities.  The site study staff will cooperate in the monitoring process by ensuring the 
availability of the eCRFs, source documents and other necessary documents at the time 
of remote monitoring and by prompt attention to any matters brought to their attention 
by the monitor. 
  
10.1 Data and Safety Monitoring Board (DSMB) 
 
We have employed a unique structure for our DSMB. The COPPS trial will have two co-
chairs serving the overarching DSMB, while each sub-protocol will have its own mini-
DSMB (at least three members plus a chair).  
 
The two COPPS DSMB co-chairs are charged with understanding safety and monitoring 
across the sub-protocols so that issues that occur within any given sub-protocol are 
shared and can inform other sub-protocols. The mini-DSMBs are charged with focused 
safety and monitoring of a given sub-protocol. The COPPS DSMB kick-off meeting will 
include the two COPPS DSMB co-chairs.  
 
A mini-DSMB will be established for each sub-protocol by the study team in cooperation 
with the sponsor to assess at intervals the progress of a clinical trial, safety data, and 
critical efficacy variables and recommend to the sponsor whether to continue, modify or 
terminate the trial. While each sub-protocol mini-DSMB will have a chair assigned to 
oversee that sub-protocol, there will be two over-arching DSMB chairs for COPPS. 
Each mini-DSMB will operate according to guidelines documented in their respective 


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mini-DSMB charters. Minutes will be taken to provide a written record of the mini-DSMB 
meetings, including interim results; these will be available for review when the trial is 
complete. The COPPS DSMB, composed of mini-DSMBs, will be a separate entity from 
the Institutional Review Board (IRB). The independence of the DSMBs is intended to 
control the sharing of important comparative information and to protect the integrity of 
the clinical trial from adverse impact resulting from access to trial information. DSMB 
members will not participate in the study as investigators and will not have conflicts of 
interest regarding the study or the investigational product. The composition of the mini-
DSMBs will include at minimum: 
  
● DSMB Chair, having experience and expertise in clinical trials 
● Scientist with expertise in viral infectious diseases 
● Biostatistician with expertise in clinical trials 
● Additional members may be required with scientific knowledge or clinical 
expertise specific to a sub-protocol. 
  
At a minimum, the mini-DSMBs will meet before randomization begins on the sub-
protocol and to review any interim analysis performed and the clinical trial and safety 
data. Additionally, there will be at least one interim analysis for each sub-protocol. The 
mini-DSMBs will review the study for progress and safety. The PI will provide 
information that will allow the mini-DSMB to review and assess the following: 
● The research protocol, informed consent documents and plans for data safety 
and monitoring; 
● Periodic assessments of data quality and timeliness, participant recruitment, 
accrual and retention, participant risk versus benefit, and other factors that can 
affect study outcome; 
● Factors external to the study when relevant information, such as scientific or 
therapeutic developments, may have an impact on the safety of the participants 
or the ethics of the trial; 
● Study performance to make recommendations and assist in the resolution of 
problems;  
● The safety of the study participants; 
● The safety and scientific progress of the trial; 
● The continuation, termination or other modifications of the trial based on the 
observed beneficial or adverse effects of the treatment under study; 
● The confidentiality of the data and the results of monitoring; and 
● Any problems with study conduct, enrollment, sample size and/or data collection. 
  
Meetings shall be closed to the public because discussions may address confidential 
patient data. An emergency meeting of the Board may be called at any time should 


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questions of patient safety arise. The DSMB may request the presence of study 
investigators at such meetings. 
  
The sub-protocol PI will distribute study information to the mini-DSMB prior to a 
scheduled meeting. The mini-DSMB may request additions and other modifications to 
this information on a one‑time or continuing basis. This information will consist of two 
parts: (1) information on study progress such as accrual, baseline characteristics, and 
other general information on study status and (2) any confidential data on study 
outcomes, including safety data. A formal report from the mini-DSMB should be 
supplied to the sub-protocol PI and the pragmatic protocol PI within 3 days of each 
meeting. Each report should conclude with a recommendation to continue, to modify, or 
to terminate the study. This recommendation should be made by consensus or, when 
consensus is not achieved, a formal majority vote. A recommendation to terminate the 
study should be transmitted to the PIs and IRBs as rapidly as possible, by immediate 
telephone and email if sufficiently urgent. In the event of a split vote in favor of 
continuation, a minority report should be contained within the regular DSMB report.   
11. GOVERNANCE  
The trial will be governed by an Executive Committee (EC) that will drive operational 
decisions and a larger Steering Committee (SC) -- comprised of the EC and other 
members including the sub-protocol principal investigators – who will meet on a 
quarterly basis and drive key scientific decisions (Figure 2).  A subset of the SC will form 
the Drug Working Group that will advise the SC on drugs for consideration. An 
independent data and safety monitoring board (DSMB) will serve as advisory to the SC 
on issues regarding safety, ethical issues, and prompt dissemination of information 
important to the public. A Statistical Analysis Committee (SAC) of key unblinded 
members from the study team will support and inform the DSMB. More specifically, we 
will have an unblinded team and a blinded team within our Data Coordinating Center 
(DCC). We rely on standard operating procedures for upholding a firewall throughout 
database lock to avoid unblinding of results. Both blinded and unblinded teams are 
involved in research and operational meetings through launch of the study. Upon 
launch, the blinded and unblinded teams no longer meet and the unblinded team is no 
longer included in the larger research meetings. Upon launch, only the blinded team is 
involved in operational decisions and any design changes throughout the study period. 
The unblinded team that makes up the SAC works closely with the DSMB to provide 
relevant reports. 
The EC will be the primary decision-making body for day-to-day operations of COPPS. 
The Steering Committee (SC) will drive key scientific decisions and will address high-
level trial policy, protocol and operational issues, and dissemination of findings. In 
particular, the SC will be responsible for introducing additional treatment arms for 
inclusion in the protocol and successful study completion. The EC will be chaired by Dr. 


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Desai and will meet weekly by teleconference. The SC will meet quarterly and more 
frequently as needed in order to review and have final sign-off on the trial protocol, 
manual of operations, risk-based monitoring plan, data management plan, and 
statistical analysis plan.   
 
 
Figure 2. Governance for COPPS 
 
 
12. ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
  
12.1 Institutional review board 
This study protocol, all procedures and consent forms, and any subsequent protocol 
amendments must be reviewed and approved by the site Institutional Review Boards. 
  
12.2 Informed consent form 
All study participants will provide written informed consent for participation in the study 
and future use of biologic specimens. (Attachment 4) 
  
12.3 Discontinuation of the Study 
The Sponsor reserves the right to discontinue the study at any time for any reason. 


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12.4 Use of Information and Publication 
All information concerning any investigational agent, Sponsor operations, patent 
applications, formulas, manufacturing processes, basic scientific data, formulation, and 
other information supplied by the Sponsor to the Investigator and not previously published 
is considered confidential and remains the sole property of the Sponsor. The Investigator 
agrees to use this information only to treat this patient and will not use it for other purposes 
without written consent of the Sponsor. 
The information obtained in this study will be used by the Sponsor in connection with the 
continued development and, if approved, commercialization of any investigational agent. 
Thus, Sponsor may disclose such information as required to other clinical Investigators, 
contractors, and government regulatory agencies. 
Publication or other public presentation of results from this study and related information 
is subject to the provisions of the Clinical Trial Agreement between Sponsor and the Study 
Site. 
 
APPENDIX 1: SUB-PROTOCOLS 
Please see sub-protocols included as attachments; 
• Attachment 3.2 contains sub-protocol (camostat mesilate), version 5  
• Attachment 3.3 contains sub-protocol (acebilustat), version 6