Clinical trial NCT04478071
Conditions: Acute Respiratory Distress Syndrome Coronavirus Infection
Keywords: COVID-19 ARDS
Sponsor: The University of Texas Health Science Center, Houston
Start date: 2020-08-22; Completion date: 2022-03-25
Enrollment: 448 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy of vadadustat for the prevention and treatment of acute respiratory distress syndrome (ARDS) in hospitalized patients with Coronavirus Disease 2019 (COVID-19).

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: vadadustat intervention 2: placebo
Intervention descriptions: intervention 1: Participants will receive vadadustat once daily for 14 days. intervention 2: Participants will receive matching placebo once daily for 14 days.

Protocol documents:
Prot_SAP_000.pdf: 
IRB NUMBER: HSC-MS-20-0395 
IRB APPROVAL DATE: 01/20/2022 
1 – VSTAT | Revised December 23, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VSTAT COVID: Vadadustat Study Targeting ARDS Therapy in COVID and VSTAT-LoTuS: A 
Long-Term Follow-Up Study of COVID-19 patients treated with either vadadustat or placebo. 
 
NCT04478071 
 
Version Date: 1/20/2022 


IRB NUMBER: HSC-MS-20-0395 
IRB APPROVAL DATE: 01/20/2022 
2 – VSTAT | Revised December 23, 2021 
 
/ 
Protocol Title: 
VSTAT COVID: Vadadustat Study Targeting ARDS Therapy in COVID 
and VSTAT-LoTuS: A Long-Term Follow-Up Study of COVID-19 
patients treated with either vadadustat or placebo. 
Principal Investigator: 
Bentley Bobrow, MD (Akebia), Holger Eltzschig, MD, PhD (DoD) 
Co-Investigators: 
Elizabeth Jones, MD, Samuel Luber, MD, Paulina Sergot, MD, George 
Williams, MD, David Robinson, MD, Richard Gordon, MD, Benjamin 
Karfunkle, MD, Katheryn Larimore, MD, Rachel Bower, MD, Emily 
Ayub, MD 
Study Coordinators: 
Misty Ottman, BSN, RN, Misha Granado, MPH, MS, Christian Noval, 
MCR, BSN, RN, Katelyn Stout, BSN, RN, Neomi Sepulveda, BS, Talha 
Mubashir, BSc, MD, Marium Kaukab, MBBS, MD, Ashley Holt, RN, 
Alfredo Castellano, MBBS 
Sponsor: 
The University of Texas Health Science Center, ||||||||||||||||||||||||||||||||||||||||, 
Houston, Texas 77030 
Study Type: 
Randomized, double-blind, placebo-controlled clinical trial 
Study Number: 
HSC-MS-20-0395 
ClinicalTrials.gov Identifier: 
NCT04478071 
Investigational Drug: 
Vadadustat 
Investigational New Drug (IND): 
150183 
Phase of Development: 
Phase 2 
Population: 
Up to 650 adult patients with COVID-19 hospitalized for hypoxemia 
Number of Sites: 
Multicenter 
Study Duration: 
18 months concluding December 31, 2023 
Patient Duration: 
28 days (24 months for the long-term follow-up) 
Protocol Version: 
Original Protocol Version 2.0 (17th June 2020) Revised Dec 23, 2021 
 
 
 
Signature Page Protocol Approval 
 
 
 
 
Signature 
Date 
 
Bentley Bobrow, MD 
Professor and Chair, Department of Emergency Medicine 
McGovern Medical School 
The University of Texas Health Science Center at Houston 


IRB NUMBER: HSC-MS-20-0395 
IRB APPROVAL DATE: 01/20/2022 
3 – VSTAT | Revised December 23, 2021 
 
1. General Information 
Vadadustat is a synthetic, orally bioavailable, small molecule which acts as an inhibitor of hypoxia- 
inducible factor prolyl-hydroxylases (HIF-PHs) and is currently being developed as a potential therapy 
for anemia of chronic kidney disease. This clinical trial aims at evaluating the efficacy of vadadustat 
on the prevention and treatment of ARDS in hospitalized patients with COVID-19 
 
2. Background Information 
2.1. Oxygen Homeostasis and Hypoxia-Inducible Factor 
Erythropoiesis is closely regulated in response to changes in tissue oxygenation levels. It is controlled 
in a large part by changing levels or the oxygen-sensitive transcription factor known as Hypoxia 
Inducible Factor, or HIF. HIF largely exists as two related but distinct isoforms: HIF-1 and 
HIF-2. HIF controls pathways that facilitate oxygen delivery to cells and allow adaptation to 
hypoxia (Siddiq et al., 2007), including the expression of EPO (Peyssonnaux et al., 2007; Semenza, 
1999). 
 
The transcriptionally active form of HIF is a heterodimeric protein consisting of an oxygensensitive 
HIF-α subunit and a constitutively expressed HIF-β subunit. Under normoxic conditions, the HIF-α 
subunit is produced and continuously degraded with a t½ of approximately 5 minutes (Berra et al., 
2001). This degradation is initiated by a family of enzymes known as the HIF-prolyl hydroxylase 
domain, (or HIF-PHD or HIF-PH) enzymes (Bishop and Ratcliffe, 2014; Ke and Costa, 2006). The 
HIF-PHs function as critical sensors of cellular oxygen levels, and regulate oxygen homeostasis in 
response to hypoxia through inhibition of hydroxylation thus leading to stabilization of HIF-α, which 
in turn signals gene transcription and translation of proteins necessary for the cellular and organ 
responses to poor oxygenation (Myllyharju, 2013; Siddiq et al., 2007). 
 
2.2. Inhibition of HIF PHD enzymes 
The general, molecular mechanism of action proposed for small molecule HIF-PHD inhibitors such as 
vadadustat has been described extensively (Joharapurkar et al., 2018; Rabinowitz, 2013) and is 
illustrated in the Figure 1. Under conditions of tissue oxygen repletion (normal O2, top Figure 1), the 
HIF-PHD enzymes rapidly hydroxylate HIF signaling its degradation in the proteasome. However, 
under low oxygen conditions (bottom, Figure 1), the HIF-PHD enzymes are substrate (O2) deficient 
and inhibited leading to the accumulation of the HIF- subunit, translocation to the nucleus and 
activation of transcriptional protocols that signal hypoxia-protective pathways. Vadadustat acts in a 
manner similar to physiological hypoxia, by inhibiting PHD enzymes in the active site, leading to 
stabilization and increased levels of HIF-α, and upregulation of hundreds of genes involved in cellular 
protection from and adaptation to pathologically low oxygen levels (Haase, 2017; Rabinowitz, 2013). 


IRB NUMBER: HSC-MS-20-0395 
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4 – VSTAT | Revised December 23, 2021 
 
Figure 1 Mechanism of Action of Vadadustat 
 
2.3. Vadadustat 
Vadadustat is a small molecule active-site inhibitor of the HIF-PHD enzymes, the inhibition of which 
leads to increases in cellular HIF—the “hypoxic response” (see Figure 1). HIF-PHD enzymes are 2- 
oxoglutarate-dependent dioxygenases that require molecular oxygen in order to affect hydroxylation 
of proline residues in the oxygen-dependent degradation domain of HIF-α, and require Fe2+ and 
ascorbate as essential cofactors (Appelhoff et al., 2004; Masson and Ratcliffe, 2003). Each of the 3 
known human HIF-PH isoenzymes regulate HIF-1α and HIF-2α in a nonredundant manner that is 
dependent upon the degree of hypoxia and the relative abundance of the specific HIF-PH isozyme in 
different tissues (Appelhoff et al., 2004; Fong and Takeda, 2008; Kant et al., 2013). Thus, 
pharmacologic inhibition of HIF-PHs represents a novel therapeutic approach to the treatment of 
anemia and also cellular and organ protection against ischemic insult (Lee et al., 2019; Schodel and 
Ratcliffe, 2019). 
 
2.4. The Role of HIF in Acute Lung Inflammatory Diseases such as COVID-19 and Associated 
Organ Failure 
Coronavirus disease 2019 (COVID-19) is a recently emerged respiratory disease caused by severe acute 
respiratory distress syndrome coronavirus 2 (SARS-CoV-2). During the past months, COVID- 19 has 
become a pandemic with currently over 2 million patients affected worldwide and over 600,000 
documented infected patients only in the US (https://coronavirus.jhu.edu/map.html). While most 
patients with COVID-19 only experience mild to moderate symptoms, approximately 15% will proceed 
to severe pneumonia and about 5% among those patients will go on to experience life- threatening 
acute respiratory distress syndrome (ARDS) (Cao, 2020; Huang et al., 2020; Wu et al., 2020; Xu et al., 
2020; Zhou et al., 2020). 


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ARDS is an acute form of lung disease characterized by acute bilateral pulmonary edema, severe 
hypoxia – usually requiring intubation and mechanical ventilation (Ranieri et al., 2012; Thompson et 
al., 2017). Using the 2012 Berlin Definition (Table 2), stages of mild, moderate, and severe ARDS 
are associated with increased mortality (27%; 95% CI, 24%-30%; 32%; 95% CI, 29%34%; and 45%; 
95% CI, 42%-48%) and increased median duration of mechanical ventilation in survivors (5 days; 
interquartile [IQR], 2-11; 7 days; IQR, 4-14; and 9 days; IQR, 5-17, respectively). 
 
Table 1: 2012 Berlin Criteria for ARDS 
Lung injury of acute onset, within 1 week of an apparent clinical insult and with progression of 
respiratory symptom 
Bilateral opacities on chest imaging (chest radiograph or CT) not explained by other lung 
pathology (e.g., effusion, lobar/lung collapse, or nodules) 
Respiratory failure not explained by heart failure or volume overload 
Decreased PaO2/FiO2 ration measured with a minimum of 5 mmHg of positive end expiratory 
Severity: 
 
Mild ARDS: 201 – 300 mmHg 
 
Moderate ARDS: 101 – 200 mmHg 
 
Severe ARDS: < 100 mmHg 
 
Therapeutic approaches for ARDS are very limited and currently focus on vigilant supportive care, 
prevention of nosocomial infections, and protective mechanical ventilation (Eltzschig et al., 2014; 
Thompson et al., 2017; Vohwinkel et al., 2015; Ware and Matthay, 2000). Similarly, treatment options 
for COVID-19 or COVID-19 associated ARDS are extremely limited. During COVID associated 
ARDS, an uncontrolled immune response with excessive infiltration of myeloid inflammatory cells 
and uncontrolled lung inflammation are characteristic features (Cao, 2020). The search for anti- 
inflammatory treatment approaches that could dampen excessive immune activation as a therapeutic 
strategy to decrease COVID-associated ARDS mortality is an area of intense investigation (Wu et al., 
2020). Based on an extensive literature documenting effects as well as organ-protective effects of HIF 
stabilization in the area of acute injury, we propose vadadustat may offer benefit to patients suffering 
from COVID-19 and related acute respiratory syndromes. 
 
2.4.1. Lung Protection 
During conditions of hypoxia and ischemia, HIF is stabilized and triggers a wide-ranging of adaptive 
responses through activation of hypoxia-responsive gene products, such as erythropoietin (Eltzschig 
and Carmeliet, 2011; Semenza, 2011; Semenza, 2012). Several HIF target-genes have been implicated 
in improving ARDS outcomes: HIF-dependent increases in extracellular adenosine signaling 
(Eltzschig et al., 2012; Idzko et al., 2014a; Idzko et al., 2014b), increases in the glycolytic capacity of 
alveolar epithelia (Eckle et al., 2013a), or other anti-inflammatory signaling pathways that promote the 
resolution of mucosal inflammation (Clambey et al., 2012; Eckle et al., 2013a; Eckle et al., 2008a; 
Eckle et al., 2007; Eckle et al., 2014; Hoegl et al., 2015; Kiers et al., 2018; McClendon et al., 2017; 
Mirakaj et al., 2010; Morote-Garcia et al., 2009; Mutz et al., 2010; Reutershan et al., 2009; Rosenberger 
et al., 2009). For example, experimental studies indicate that during ARDS, HIF is stabilized and 


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provides protection from ARDS, as part of an endogenous protective pathway that could be targeted 
therapeutically (Eckle et al., 2013a; McClendon et al., 2017). Studies in mice with targeted deletion of 
HIF in alveolar epithelia revealed a more severe degree of ARDS, including increased pulmonary 
edema, increased lung inflammation and attenuated survival time. Similarly, studies utilizing 
pharmacologic inhibitors of the HIF-pathway demonstrated increased lung injury and attenuated ARDS 
survival time. In contrast, pretreatment with pharmacologic HIF-activators is associated with protection 
from ARDS induced by mechanical ventilation including attenuated pulmonary edema, improved gas 
exchange and improved survival (Eckle et al., 2013a). Taken together, these studies provide strong 
experimental evidence showing that HIF activators can be used therapeutically to prevent or treat lung 
inflammation during ARDS. 
 
Acute lung injury (ALI) leads to pulmonary edema and hypoxia. Increase permeability of endothelial 
cells leads to protein rich fluid accumulation in alveoli (smallest airspaces in the lung) and thereby 
impairing gas (oxygen or O2 and carbon dioxide or CO2) exchange (Shimoda and Semenza, 2011; 
Urrutia and Aragones, 2018; Vohwinkel et al., 2015). Hypoxia itself may contribute to lung injury 
and thereby perpetuate the injury by impairing endothelial cells, attracting white blood cells, and 
promoting inflammation. Stabilizing HIF has been shown to be protective during ALI (Huang et al., 
2019; Li et al., 2020a; Nagamine et al., 2016). HIF-1 stabilization has been shown to reduce I 
preclinically through both optimizing carbohydrate metabolism (shift to glycolysis) (Eckle et al., 
2013a) and through upregulation of anti- inflammatory adenosine signaling (Bowser et al., 2017; 
Eckle et al., 2008a; Eckle et al., 2008b; Eckle et al., 2013b; Eckle et al., 2014; Hoegl et al., 2015) as 
well as improvements in general somatic epithelial and endothelial barrier integrity (Clerici and 
Planes, 2009; Gong et al., 2015; Huang et al., 2019; Kapitsinou et al., 2014; Rajendran et al., 2020). 
 
Long-term upregulation of HIF may have deleterious effects on chronic organ inflammatory conditions 
such as pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease, CKD, 
etc. although this seems less relevant to the acute application envisioned here (Fu and Zhang, 2018; Li 
et al., 2020b; Luo et al., 2015). 
 
2.4.2. Protection of Other Organs Against Failure During Ischemia 
In addition to its potential beneficial effects with respect to the treatment of anemia, and acute lung 
inflammation, HIF may have protective effects during ischemia, reperfusion, hypoxia, and 
inflammatory conditions (Heyman et al., 2016). Pharmacologic inhibition of PHDs is associated with 
increased HIF stabilization – even under normoxic conditions – and concomitant organ protection, 
including the heart, intestine, kidneys, liver as well as the lungs (Bowser et al., 2017; Eckle et al., 
2013a; Eckle et al., 2012; Eckle et al., 2008d; Hill et al., 2008; Kapitsinou et al., 2014; Robinson et al., 
2008). 
 
The myriad potential benefits if HIF stabilization related to hypoxia have been extensively reviewed 
(Colgan et al., 2020; Fraisl et al., 2009; Lee et al., 2019; Prabhakar and Semenza, 2015; Zhu et al., 
2019). In general: 
• 
Hypoxia results in inflammation and stabilization of HIF can dampen tissue inflammation and 
promote repair (Colgan et al., 2020; Cummins and Taylor, 2017). 


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• 
HIF stabilization upregulates glycolytic enzymes that adapt tissue to oxygen deprivation and 
anaerobic energy production (Koivunen and Kietzmann, 2018). 
• 
HIF promotes EPO and VEGF production. EPO increases red blood cell production and 
hemoglobin that carry oxygen to tissues. VEGF increases blood vessel growth to hypoxic tissue. 
The combination leads to increased oxygen delivery to hypoxic tissues (Pugh and Ratcliffe, 
2003; Tanaka et al., 2015). 
• 
HIF increases extracellular adenosine by stimulating genes that convert extracellular ATP to 
ADP, AMP, and eventually adenosine. HIF also upregulates adenosine receptors leading to cell 
signaling that decreases cellular inflammation (Eckle et al., 2014; Hart et al., 2011). 
• 
Stabilizing HIF either pharmacologically or genetically, has been shown to afford protection 
against ischemic and other damage in multiple organs apart from lung: 
o Heart (Eckle et al., 2008c; Natarajan et al., 2006; Sridharan et al., 2007) 
o Kidney (Eckardt et al., 2007; Ito et al., 2020; Yang et al., 2018) 
o Liver (Guo et al., 2015; Ju et al., 2016; Schneider et al., 2010) 
• 
HIF is a potent stimulator of EPO production, and EPO has been shown to have significant 
protective effects in the lung after ALI through a number of different protective mechanisms 
(Heitrich et al., 2016; Rocha et al., 2015; Zhu et al., 2019). 
 
2.5. Vadadustat in Clinical Trials 
A total of 34 Akebia studies spanning Phase 1 through 3 have been completed or are ongoing. In the 
studies completed to date (Phase 1 and 2 studies), a total of 1011 subjects have received vadadustat, 
including 553 healthy volunteers, 450 subjects with CKD, and 8 subjects with hepatic impairment. In 
4 ongoing Phase 3 studies, 7237 subjects have received study medication (vadadustat or darbepoetin 
alfa). 
 
Generally, in completed vadadustat studies with healthy volunteers, there were a low number of adverse 
events (AEs). The most frequently reported AEs in healthy volunteers were in gastrointestinal system 
disorders (nausea, diarrhea, abdominal pain, flatulence, dyspepsia) and nervous system disorders 
(headache, dizziness). The majority of the events were mild to moderate in severity. There were no 
serious adverse events (SAEs), deaths, or withdrawals due to AEs. There were no clinically relevant 
changes in mean laboratory values (including vascular endothelial growth factor or adrenal-related 
biomarkers), vital signs, or electrocardiograms (ECGs). 
 
In completed Phase 2 studies, the most frequently reported AEs in subjects with CKD were in 
gastrointestinal disorders (nausea, diarrhea, vomiting), cardiovascular disorders (hypertension, 
hypotension, coronary artery disease), renal disorders (renal failure chronic, renal failure acute), 
infections and infestations (gastroenteritis, urinary tract infection, pneumonia), and metabolism and 
nutrition disorders (hyperkalemia, fluid overload). 
 
The safety profile to date supports the ongoing clinical development of vadadustat as an orally 
bioavailable agent for the treatment of anemia associated with CKD. 
 
2.6. COVID-19 and ARDS 


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Patients with COVID-19 present primarily with fever, myalgia/fatigue, or dry cough. In most cases, 
COVID-19 results in mild symptoms and patients can recover in 1 to 2 weeks. Most patients have a 
favorable prognosis; however, older patients and those with chronic underlying conditions may have 
worse outcomes. Patients with severe illness may develop dyspnea and hypoxemia within 1 week of 
onset, with the potential to progress to ARDS or end-organ failure (Wu et al, 2020). Typical findings 
of chest CT images of COVID-19 positive patients who are in the ICU include bilateral multiple lobular 
and subsegmental areas of consolidation. Analysis of 1324 laboratory-confirmed cases in Wuhan China 
showed that fever (87.9%) and cough (67.7%) were among the most common symptoms. Lymphopenia 
was observed in 82.1% of patients admitted to the ICU (Jin et al, 2020). 
 
In a study of 5700 patients hospitalized with COVID-19 in New York City, the median age of patients 
affected was 63, with 39.7% female patients and 60.3% male patients. Common comorbidities included 
cancer (6%); cardiovascular disease, including hypertension (56.6%), coronary artery disease (11.1%), 
and congestive heart failure (6.9%); chronic respiratory disease, including asthma (9%), chronic 
obstructive pulmonary disease (5.4%), and obstructive sleep apnea (2.9%); immunosuppression, 
including HIV (0.8%) and history of solid organ transplant (1%); kidney disease, including chronic 
(5%) and end-stage disease (3.5%), and metabolic disease, including obesity (41.7%), morbid obesity 
(19%), and diabetes (33.8%). Among the 2634 patients who were discharged or died at the study 
endpoint, 373 (14.2%) patients were treated in the ICU, and 12.2% received invasive mechanical 
ventilation (Richardson et al, 2020). As of April 4, 2020, out of the patients requiring mechanical 
ventilation, 38 (3.3%) were discharged alive, 282 (24.5%) died, and 831 (2.2%) remained hospitalized. 
A total of 45 patients (2.2%) were readmitted during the study period. 
 
In a study of 41 patients hospitalized with COVID-19 in Wuhan China, patients with severe illness 
developed ARDS and required ICU submission and oxygen therapy. The median time from onset of 
symptoms to first hospital admission was 7 days, to shortness of breath was 8 days, to mechanical 
ventilation was 10.5 days, and to ICU admission was 10.5 days. The median time to ARDS from onset 
of symptoms was 9 days, the time between hospital admission and ARDS being as short as 2 days 
(Huang et al, 2020). 
 
2.6.1. COVID-19 and Hemoglobin 
The mean hemoglobin levels for patients infected with COVID-19 across five studies is shown in Table 
2. 


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Table 2: Mean Hemoglobin Levels in COVID-19 Positive Patients 
Study 
Country 
Sample 
Size 
(n) 
Mean 
Hb g/dL 
Clinical Characteristics of Coronavirus Disease 
2019 
China 
1099 
13.4 
Epidemiologic Features and Clinical Course of 
Patients Infected with SARS-CoV-2 in Singapore 
Singapore 
18 
13.5 
Clinical course and outcomes of critically ill 
patients with SARS-CoV-2 pneumonia in Wuhan, 
China: 
A single-centered, retrospective, 
observational study 
China 
34 
12.8 
Clinical Features of patients infected with 2019 
novel coronavirus in Wuhan, China 
China 
41 
12.6 
Epidemiological and clinical characteristics of 99 
cases of 2019 novel coronavirus pneumonia in 
Wuhan, China: a descriptive study 
China 
99 
13.0 
Source: Chen et al, 2020; Guan et al, 2020; Huang et al, 2020; Young et al, 2020; Yang et al, 2020 
In 122 COVID-19 patients admitted to UT Health, the mean Hb on admission was 11.8, 
S.D. = 2.36. During the course of their hospitalization the mean low Hb for these patients was 
10.53, S.D. = 2.45, with 12/3% (n = 15) receiving transfusions. 
2.7. Bayesian Statistical Methods 
Developing effective interventions for acute respiratory distress syndrome (ARDS) requires 
incremental improvement of theoretically sound treatments based on systematically accruing data. 
Often this incremental development is hampered by statistical tools not appropriate to the task. 
Classical, Frequentist statistics have advanced the field, but are less informative for the initial test of a 
new treatment. The reliance of the Frequentist framework on dichotomous, null hypothesis testing 
provides some control of the error rate in the context of multiple repeated trials; however, this is not 
what early-phase treatment testing requires. Developing nascent treatments requires investigators to 
bet on an alternative hypothesis. Investigators evaluating a theoretically sound intervention want to 
know the probability that the approach confers some level of benefit given the observed data: that is, 
they want to know the probability that the alternative hypothesis is true. While Frequentist inference 
does not directly address this issue, Bayesian statistical inference provides a principled approach to 
answer this question. Indeed, addressing the so-called “Pipeline Problem” in developing clinical 
applications, the FDA has indicated that Bayesian statistics offers one avenue for improved 
methodological efficiency (FDA. Innovation/Stagnation 2004, FDA. Innovation/Stagnation 2006, 
Irony 2008, O’Neill RT 2006, Woodcock 2005, Fitzmaurice & Laird 2000). 
 
Decision-making based on an initial treatment trial is assisted by estimates of the probability of an 
effect of some specified magnitude. These statements, not part of the conventional, Frequentist 
statistical lexicon, are accessible via Bayesian approaches, particularly with small sample sizes (Lilford 
et al 1995, Spiegelhalter et al 1999). Detailed descriptions of Bayesian statistical reasoning exist 
elsewhere (Berry 2006, Goodman 2005, Wijeysundera et al 2009). Succinctly, Frequentist models 


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estimate the probability of observing the data (or data more extreme) given that the null hypothesis is 
true; Bayesian analyses estimate the probability of the alternative hypothesis given the observed data 
(Wijeysundera et al 2009). Bayesian probability estimates incorporate prior information about 
plausible parameter values (i.e., the prior distribution) and the observed data (i.e., the likelihood). 
Combining these two distributions forms the posterior distribution which permits evaluation of the 
probability that the true value of the parameter falls in some range. 
 
3. Primary Objectives 
To assess the efficacy and safety of vadadustat for the prevention and treatment of ARDS in 
hospitalized patients with COVID-19 
 
4. Study Design 
This is a phase 2 multicenter, randomized, double-blind, placebo-controlled Bayesian clinical trial of 
vadadustat for the prevention and treatment of ARDS in hospitalized patients with COVID-19. 
Extended follow-up of participants will occur at 6, 12, and 24 months (see section 8.4.1). 
 
Following screening, patients will be randomized in a 1:1 ratio to either vadadustat 900 mg or placebo. 
Randomization will be stratified by site, and MSOFA score at baseline ( <4 and ≥4) 
 
Figure 1: Study Schematic 
 
 
5. Study Outcomes: 
5.1. Assessment of Efficacy 
 
5.1.1. Primary Outcome 
The proportion of patients at day 14 who are dead (8) or hospitalized, on invasive mechanical 
ventilation or ECMO (7) or hospitalized, on non-invasive ventilation or high flow oxygen devices 
(6) on the NIAID-OS. 
< 36 hours from hospitalization 
Hospitalized patients receive study drug from Randomization until D14 or 
discharge whichever comes first; unless patient meets any of the stopping criteria. 
Randomization 
D1 
Placebo 
Assess primary endpoint at 
D14 
Consent 
Screening 
Telephone 
Follow Up 
D28 
Vadadustat 


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Table 4: National Institute of Allergy and Infectious Disease Ordinal Scale (NIAID-OS) 
Death 
8 
Hospitalized, on invasive mechanical ventilation or extracorporeal membrane 
oxygenation (ECMO) 
7 
Hospitalized, on non-invasive ventilation or high flow oxygen devices 
6 
Hospitalized, requiring supplemental oxygen 
5 
Hospitalized, not requiring supplemental oxygen – requiring ongoing care 
(COVID19 related or otherwise) 
4 
Hospitalized, not requiring supplemental oxygen – no longer requires ongoing 
medical care 
3 
Not hospitalized, limitation on activities and/or requiring home oxygen 
2 
Not hospitalized, no limitations on activities 
1 
Source: https://clinicaltrials.gov/ct2/show/NCT04421027?cond=COVID19&lead=Lilly&draw=2&rank=1 
 
 
5.1.2. Secondary Outcomes: 
Proportion of patients with a score of 0 at 14 days on the MSOFA scale. 
Table 3: Modified Sequential Organ Failure Assessment (MSOFA) Score 
Organ System 
0 
1 
2 
3 
4 
Respiratory 
SpO2/FiO2 
> 400 
≤ 400 
≤ 315 
≤ 235 
≤ 150 
Liver 
No scleral 
icterus or 
jaundice 
Scleral icterus or 
jaundice 
Cardiovascular, 
hypotension 
No 
hypotension 
MAP 
< 70 mm 
Hg 
Dopamine 
≤ 5 
or 
dobutamine 
Dopamine > 5 
Epinephrine 
≤ 0.1 
Dopamine > 15 
Epinephrine > 0.1 
Norepinephrine 
any dose 
Norepinephrine 
> 0.1 
≤ 0.1 
CNS, Glasgow 
Coma Score 
15 
13 – 14 
10 – 12 
6 – 9 
< 6 
Renal, 
Creatinine 
mg/dL 
< 1.2 
1.2 – 1.9 
2.0 – 3.4 
3.5 – 4.9 
> 5.0 
Source: Grissom et al, 2010 
Note: Discharged patients will be assigned a 0 score and dead patients a score of 20. 
 
5.1.3 Other Outcomes: 
• 
Average mSOFA scores at day 7 and day 14, gathered either from in-hospital labs and 
clinical notes for inpatients, or from calling discharged patients 


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• 
Ventilator-free survival at day 7 and day 14, as assessed by the patient’s best score on the 
NIAID-OS on day 7, day 14 and day 28 
• 
Overall survival at day 7, day 14 and day 28 
• 
Proportion of patients with hypotension (MAP <70 mm Hg or requirement for inotropes 
or vasopressors to maintain blood pressure) at day 7 and day 14 
• 
Proportion of patients with acute kidney injury at day 7 and day 14 
• 
Time to hospital discharge 
 
5.2. Assessment of Safety 
• 
Incidence of adverse events (AEs) 
• 
Incidence of serious AEs (SAEs) 
• 
Incidence of thromboembolic events 
• 
Creatinine, bilirubin, AST and ALT, hemoglobin 
 
In addition to the ongoing and final safety assessments through the course of the trial, a detailed 
review of safety by the DSMB will follow the ascertainment of the 14-day outcomes on the first 
30 and 120 patients. After 30 and 120 patients have received treatment and have completed their 
day 14 event, enrollment will be suspended (suspension of enrollment will occur at n = 30, based 
on DSMB recommendation, enrollment will continue during the safety analysis at n = 120). An 
interim blinded safety report will be sent to the DSMB. Enrollment will continue according to 
DSMB recommendations. The DSMB will provide a report to the UTHealth COVID-19 
Research Workgroup and UTHealth IRB to consider further patient screening and enrollment. 
 
5.3. Exploratory Outcomes 
Efficacy of vadadustat to induce known transcriptional targets of HIFs (e.g., erythropoietin, 
extracellular adenosine levels, circulating levels of CD73, VEGF, hypoxia-driven microRNAs that 
dampen lung inflammation) will be explored. 
 
Various laboratory measurements (e.g., serum creatinine, FGF-23, markers of attenuated 
inflammation) will be measured and summarized. 
 
6. Study Population 
 
6.1. Eligibility Criteria 
 
6.1.1. Inclusion Criteria 
1. Men and women ≥ 18 years of age 
2. Laboratory-confirmed diagnosis of COVID-19 by detection of SARS-CoV-2 RNA by RTPCR 
from any specimen respiratory 
3. Admitted to the hospital within 36 hours 
4. For patients admitted WITH respiratory symptoms, enrollment must occur within 36 hours of 
hospital admission. If the patient is admitted to the hospital with normal saturations, but 
develops respiratory symptoms DURING their hospital stay, enrollment may occur within 24 


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13 – VSTAT | Revised December 23, 2021 
 
hours of desaturation to 94% or less on room air. 
5. Oxygen saturation of hemoglobin by pulse oximetry at room air ≤94% 
6. Understands the procedures and requirements of the study and provides written informed 
consent and authorization for protected health information disclosure 
 
6.1.2. Exclusion Criteria 
1. Hypersensitivity to vadadustat or any of its excipients 
2. Placed on mechanical ventilation before randomization 
3. Hemoglobin above the gender-specific upper limit of normal (ULN) at randomization: 16 g/dL 
for females and 18 g/dL for males 
4. Patients who have erythrocytosis or polycythemia vera 
5. Patient taking Probenecid, lopinavir or ritonavir. 
6. Women who are pregnant or breastfeeding, or positive pregnancy test before randomization 
7. Patients not on maintenance dialysis with eGFR< 31ml/min. 
8. Patients who have received a solid organ transplant, heart, kidney, liver or lung 
9. Patients who are prisoners 
10. Patients who are currently Do Not Resuscitate (DNR) or Do Not Intubate (DNI) 
11. Patients with modified Rankin scale of 3 or greater 
12. Patient who are currently enrolled in any other interventional clinical trial 
13. Acute thromboembolism 
14. Home oxygen (O2) 
 
7. Study Drug 
 
7.1. Dosage 
Vadadustat 900 mg or matching placebo 
 
7.2. Route and Form 
Oral 150 mg tablets and matching placebo 
 
7.3. Administration to Intubated Patients 
Tablets can be crushed using a pill crusher and administered to an intubated patient through a 
nasogastric tube. Tablets may be dissolved in warm water after cutting the pill in half. 
 
The research pharmacist or designee will dispense study drug to the patient and maintaining study 
drug accountability as described below. 
 
7.4. Vadadustat 
Refer to the Vadadustat Pharmacy Manual for details on the shipping, dispensing, storage, 
destruction, and accountability of vadadustat tablets. 


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7.4.1. Storage and Supplies 
Vadadustat will be provided as 150 mg, white to off-white, round, biconvex film-coated, debossed 
or non-debossed tablets for oral administration. The tablets and matching placebo will be packaged 
in high density polyethylene bottles with child resistant closures, polypropylene liner, and induction 
seal. 
 
Vadadustat and placebo will be stored per the investigational study drug label in a temperature 
controlled, locked facility, accessible only to authorized study personnel. 
 
7.4.2. Dispensing of Vadadustat or Placebo 
Patients will receive one of the following doses for 14 days, or until their date of discharge, or 
whichever comes first, vadadustat 900 mg (6 tablets once daily) or matching placebo (6 tablets once 
daily) without regard for meals at approximately the same time each day. 
 
7.4.3. Vadadustat Accountability and Destruction 
All vadadustat will be accounted for and all discrepancies explained. The research pharmacy is 
responsible for keeping accurate records of the clinical supplies received from Akebia Therapeutics 
(Akebia) all supplies retained in inventory at the study site, and study drug dispensed to or returned 
from each patient. Records will be maintained that accurately reflect the drug accountability of 
vadadustat. 
 
Drug accountability includes, but is not limited to: 
• 
Monitoring expiration dates. 
• 
Verifying physical inventory matches documented inventory. 
 
Verifying accountability records are completed for all vadadustat received, dispensed, and returned, 
and that all required fields are complete, accurate, and legible. During the study, the research 
pharmacist will be notified of any expiration dates or retest date extensions of study drug. If an 
expiration date notification is received during the study, the study site will complete all instructions 
outlined in the notification, including segregation of expired study drug for return to the Akebia or 
its designee for destruction as specified by the Akebia. 
 
Prior to study site closure and at appropriate intervals during the study, the research pharmacist of 
designee will perform study drug accountability and reconciliation. 
 
At the end of the study, the investigator will retain all original documentation regarding study drug 
accountability, return, and/or destruction, and copies will be sent to the sponsor. 
 
All unused and/or partially used vadadustat will be returned to Akebia or destroyed at the study 
site, as specified by Akebia. Appropriate records of the disposal will be documented and 
maintained. No unused vadadustat may be disposed of until fully accounted for by Akebia or 
designee. Empty containers may be disposed of according to local procedures with the permission 
of Akebia. 


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7.4.4. Dosing rationale 
The planned dosing is a fixed daily dose of 900 mg (supplied as 6-150 mg tablets). We believe that 
the dose and magnitude of HIF stabilization needed to induce the hypothesized beneficial 
pulmonary effects are the same as that needed to induce erythropoiesis. In healthy volunteers who 
received single doses of vadadustat, the median tmax ranged between 3.5 hours for the subjects 
who were administered 900 mg. The peak erythropoietin concentration was reached after 18 hours 
from dosing. In healthy volunteers who received 10 daily doses of vadadustat, the mean change in 
hemoglobin from baseline to day 11 among those who took vadadustat 900 mg was 0.43 g/dL. 
From published literature on COVID‑19 patients, the median duration from onset of illness to 
admission is 7 days and takes a median of additional 3.5 days until ICU admission. In order to 
maximize the benefit of acute HIF stabilization and observe a potential benefit, a dose of 900 mg 
once daily for 14 days is recommended. 
Vadadustat doses of 150-1200 mg per day were tested in healthy volunteers and patients with 
anemia secondary to chronic kidney disease (CKD). A dose of vadadustat 900 mg was administered 
to healthy volunteers and patients with CKD for 10 days without significant adverse effects. In 
healthy volunteers, the most commonly reported AEs (nausea, diarrhea, abdominal pain, flatulence, 
dyspepsia, headache, and dizziness) were generally reported to be mild to moderate in severity. 
There were no SAEs, deaths, or withdrawals due to AEs, and no clinically relevant changes in mean 
laboratory values, vital signs or ECGs. In CKD subjects, the most commonly reported AEs were 
nausea, diarrhea, vomiting, hypertension, hypotension, coronary artery disease, chronic and acute 
renal failure, gastroenteritis, urinary tract infection, and pneumonia. 
8. Study Procedures 
 
8.1. Recruitment 
All COVID-19 patients will be screened for eligibility. If a patient meets screening eligibility, the 
study coordinator will introduce the study to the patient to determine interest. If the patient is 
interested in participating in the study, the study coordinator will introduce the patient to one of the 
study clinicians either in person or virtually utilizing WebEx. Written consent will be obtained for 
all patients interested in study participation. Patients will be randomized if meeting all eligibility 
criteria (as specified in inclusion/exclusion criteria). Initial recruitment will occur at MHH- 
Southwest and MHH-Texas Medical Center for the first 30 patients. After 30 and then 120 patients 
are treated, screening and enrollment will be suspended (suspension of enrollment will occur at n 
= 30, based on DSMB recommendation, enrollment will continue during the safety analysis at n = 
120) to enable an interim blinded safety analyses by the DSMB. The DSMB will provide a report 
to the UTHealth COVID-19 Research Workgroup and UTHealth IRB to consider further patient 
screening and enrollment. 
 
8.2. Concomitant medication 
Probenecid is not allowed as it may increase systemic exposure to vadadustat. Investigators should 
adjust the dose of these concomitant medication as follows: 
 
1. Simvastatin, maximum daily dose of 20 mg 


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2. Rosuvastatin, maximum daily dose of 10 mg 
 
If the patient is currently taking erythropoiesis-stimulating agents or ESA (e.g., epoetin alfa, 
darbepoietin alpha, or methoxy polyethylene glycol-epoetin beta), the medication should be 
discontinued. 
 
Sulfasalazine and other breast cancer resistance protein (BCRP) substrates (imatinib, gefitinib, 
nilotinib, prazosin, glyburide, cimetidine, AZT and lamivudine) should be used with caution as 
vadadustat can increase systemic exposure to these medications. Lopinavir and rotinavir are also 
prohibited due to observed higher LFTs in patients treated with these drugs. 
 
Phosphate binders (iron-containing and non-iron containing) and oral iron supplements should be 
taken at least 2 hours before or after the dose of vadadustat as they can interfere with vadadustat 
absorption. 
 
At enrollment, the study team will notify the treating physician of medications prohibited by the 
study. Study personnel will review the patient’s current medications daily to identify the use of any 
prohibited medications and notify the treating physician when they are prescribed. The study team 
will discuss the use of alternative medications. If the prohibited medication cannot be stopped the 
patient will continue in the study but study medication will be stopped. 
 
 
8.3. Complete Withdrawal from Study Visits/Assessments 
A patient has the right to withdraw consent for participation in the study at any time. Withdrawal 
of consent is a patient’s refusal to continue study treatment, data collection and ALL methods of 
follow-up noted in the informed consent form: procedures, participation in reduced 
procedures/study visits, telephone contact only or alternative contact only, source document or 
designated alternative contact, or access to medical records from alternative sources. 
 
It is important for the Investigator to review options with a patient. The patient may decide to stop 
study medication but still be followed up in the hospital and contacted on Day 7, 14, and 28 after 
discharge to assess safety and efficacy outcomes. Alternatively, the patient may decide to 
completely withdraw consent from the study which entails not receiving study medication, not to 
be followed up in the hospital, and not to be contacted after discharge. 
 
8.4. Data Collection 
Refer to Appendix 1 (Schedule of Activities) for detailed timing and frequency of the below 
activities: 
• 
Informed consent 
• 
Demographic and contact information 
• 
Oxygen saturation by pulse oximetry 
• 
Pregnancy test (collected only at baseline) 
• 


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• 
Hemoglobin, creatinine, liver function test (AST, ALT, Bilirubin) at baseline, day 7, day 14 
and during long term follow up visits at 6mo, 12mo and 24mo (If the patient remains 
hospitalized after 14 days, or the drug is discontinued for any reason, creatinine and 
hemoglobin lab values will be collected for up to 2 days following the last dose, again 
ceasing upon discharge.) 
• 
Height, weight, BMI 
• 
Eligibility, at baseline 
• 
Randomization 
• 
Blood biomarkers (during hospitalization only) o Baseline, Day 7 and Day 14 (10 cc 
each collection) 
• 
Urine biomarkers (during hospitalization only) o Baseline, Day 7 and Day 14 (5 cc each 
collection) 
• 
Medical/Medication history 
• 
Study medication dosing 
• 
AE and SAEs 
• 
Concomitant medications and COVID-19 specific treatment other than vitamins and 
minerals 
• 
Modified SOFA, daily until discharge, & at Day 7, 14, and 28, with discharged patients 
receiving a score of 0 and deceased patients receiving a score of 20. 
• 
NIAID-OS, daily and until discharge and at Day 7, 14, and 28 
• 
For patients who are discharged, before or after completing 14 days of in-hospital treatment, 
a phone visit at day 7, 14, and 28 after randomization will be conducted to collect serious 
adverse events and NIAID-OS score. 
 
8.4.1. Extended Follow Up 
Eligible patients will be asked on the consent form if they would like to consent to participate in an 
extended follow up opportunity which will consist of the following: 
 
• Return to the clinic at 6, 12 and 24 months 
• Complete a quality of life questionnaire 
• Provide a small blood sample (10 ml) 
• Provide a urine sample (10 ml) 
• Perform a pulmonary function test to see how well their lungs are working and a bedside 
echocardiogram to see how their heart is working. 
 
The participant will receive a $100 gift card for each follow up visit completed. In addition, the 
parking and travel expenses will be covered. 
 
To consent to the optional long term follow up, the patient will be asked to check a box and initial. 
 
8.5 Protocol Deviations: Protocol deviations will be recorded in the RedCAP database. The type 
of deviation will be specified. The deviation will be described and corrective actions will be 
recorded. 


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9. Data and Safety Monitoring Board (DSMB) 
A DSMB will be formed. DSMB is a group of external experts who will provide oversight to the 
conduct of the study and provide safety assessment through planned interim analysis. The DSMB 
shall include an odd number of members, minimum of 3, preferably 5. It should include at least one 
of the following: one critical care physician, one physician-trialist and one statistician. 
 
In addition to the ongoing and final safety assessments through the course of the trial, a detailed 
review of safety by the DSMB will follow the ascertainment of the 14-day safety on the first 
30,120 and 400 patients. After 30,120 and 400 patients have received treatment and have 
completed their day 14 event, an interim blinded safety analysis by the DSMB will be completed. 
The DSMB will provide a report to the UTHealth COVID-19 Research Workgroup and 
UTHealth IRB to consider further patient screening and enrollment. In the n=400 safety analysis 
there will be no planned suspension in ongoing recruitment during evaluation of the findings. 
 
10. Discontinuation of study treatment in individual patients (Stopping Criteria) 
Vadadustat must be permanently discontinued if a patient meets one of the following pre-specified 
criteria: 
1. 
Patient completes 14 days of in-hospital treatment since randomization 
2. 
Patient is discharged before 14 days of treatment since randomization 
3. 
If the clinical team deems necessary that the patient receive a medication that was 
previously prohibited, or if the clinical team decides the patient should not receive 
vadadustat. 
4. 
Persistent eGFR decrease (greater than 2 days < 30) 
5. 
Hemoglobin above the gender specific upper limit of normal (ULN): females (16 g/dL) and 
males (18 g/dL) 
6. 
Patient dies 
 
11. Safety Assessment 
11.1. Adverse Events (AEs) 
For the purposes of this study, an AE is any untoward medical occurrence (including an abnormal 
laboratory finding) that occurs in the protocol-specified AE reporting period; the event does not 
necessarily have a causal relationship with that treatment or usage. 
 
An AE includes medical conditions, signs, and symptoms not previously observed in the subject 
that emerge during the protocol-specified AE reporting period, including signs or symptoms 
associated with pre-existing underlying conditions that were not present prior to the AE reporting 
period. 


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AEs therefore include the following: 
• 
All AEs, whether suspected to be causally related to study drug or otherwise. 
• 
All AEs secondary to any medication overdose, medication error, abuse, withdrawal, 
sensitivity, or toxicity. 
• 
Illnesses apparently unrelated to study drug, including the worsening of a pre-existing 
illness (see paragraph below on Pre-existing Conditions). 
• 
Injury or accidents. Note that if a medical condition is known to have caused the injury or 
accident (for example, a fall secondary to dizziness), the medical condition (dizziness) and 
the accident (fall) will be reported as 2 separate AEs. 
• 
Abnormalities in physiological testing or physical examination findings that require clinical 
intervention or further investigation (beyond ordering a repeat [confirmatory] test). 
• 
Laboratory abnormalities that require clinical intervention or further investigation (beyond 
ordering a repeat [confirmatory] test) unless they are associated with an already reported 
clinical event. Laboratory abnormalities associated with a clinical event reported as an AE 
(for example, elevated liver enzymes in a subject with jaundice) will be described under 
‘Comments’ on the report of the clinical event rather than reported as separate AEs. 
 
The following guidelines are to be used when reporting AEs for this study: 
• 
Medical Diagnoses – Whenever possible, a medical diagnosis term will be used to report 
AEs instead of signs and symptoms due to a common etiology, as determined by qualified 
medical study staff. For example, pneumonia will be the reported AE term, instead of fever, 
dyspnea, etc., when the diagnosis has been established. Signs and symptoms will be reported 
as event terms only when the medical diagnosis remains unknown and revised to a medical 
diagnosis term once it has been established. 
• 
Procedures – Diagnostic and therapeutic noninvasive and invasive procedures, such as 
surgery, will not be reported as AEs. However, the medical condition for which the 
procedure was performed will be reported if it meets the definition of an AE. For example, 
an acute appendicitis that begins during the AE reporting period will be reported as the AE 
and the resulting appendectomy noted under “Comments.” 
• 
Preplanned therapeutic procedures not associated with a new medical condition or 
worsening pre-existing condition will not be reported as AEs. 
• 
Pre-existing Conditions – In this study, a pre-existing condition (i.e., a disorder present 
before the AE reporting period started and noted on the pretreatment medical 
history/physical examination form) will not be reported as an AE unless the condition 
worsens, or episodes increase in frequency during the AE reporting period. 
• 
Abnormal Test Findings – All laboratory test results will be reviewed by the research 
team. The research team will utilize his/her judgment in determining if out of range 
laboratory values are clinically significant. Laboratory tests that are considered clinically 
significant will be reported as AEs, either separately or as part of a description of a 
symptomatic AE. If there are significant changes in a laboratory report from a previous 
result that are determined to be clinically significant, these will also be reported as AEs. 
Any abnormal laboratory value, which requires treatment or further diagnostic testing or 
results in discontinuation from study will be reported as AEs. An expected laboratory 


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abnormality from a condition that is part of the medical history is not considered clinically 
significant for the purposes of the study unless it represents a worsening of the condition. 
 
Special daily safety monitoring for the risk of thrombosis and proinflammatory state is planned in 
this trial. This will be achieved by daily review of electronic medical records for clinical evaluation 
of thromboembolic events. Furthermore, all patients will be managed according to local 
institutional anticoagulation protocols. 
 
Thrombo-embolic events (complications) including: 
• 
Deep vein thrombosis—catheter associated or spontaneous 
• 
Pulmonary embolism 
• 
Ischemic stroke 
• 
Systemic arterial thrombosis 
• 
Acute coronary syndrome/myocardial infarction. 
 
11.2. Serious adverse events (SAEs) 
SAEs are AEs that meet one or more of the following criteria/outcomes: 
• 
Death 
• 
Life-threatening 
• 
In-patient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant disability/incapacity 
• 
Congenital anomaly/birth defect 
• 
Is considered a medically important event not meeting the above criteria, but which may 
jeopardize a patient, or may require medical or surgical intervention to prevent one of the criteria 
listed in this definition 
 
Serious also includes any other event that the investigator judges to be serious. If there is any doubt 
whether the information constitutes an AE or SAE, the information is to be treated as an SAE. 
 
Life threatening – Defined as any event in which the subject was at risk of death at the time of the 
event. ‘Life threatening’ does not refer to an event which hypothetically might have caused death 
if it were more severe. For example, drug-induced hepatitis that resolved without evidence of 
hepatic failure would not be considered life threatening, even though drug-induced hepatitis of a 
more severe nature can be fatal. 
 
Hospitalization – Defined as an overnight admission with observation of a minimum of 24 hours. 
A hospitalization planned before the start of the study for a preexisting condition that has not 
worsened during the AE reporting period does not constitute an SAE unless an untoward event 
occurs related to the procedure (e.g., elective hospitalization for a total knee replacement due to a 
pre-existing condition of osteoarthritis of the knee that has not worsened during the study). 
 
Disability – Defined as a substantial disruption in a person’s ability to conduct normal life functions. 


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In addition to the above criteria for classifying AEs as serious, the following situations will be also 
be classified as serious for purposes of this study: 
 
Malignancies – If a subject develops basal cell carcinoma of skin, squamous cell carcinoma of skin, 
or cervical carcinoma in situ during the study, or has worsening of these events from baseline, the 
investigator will determine if the event is reported as an AE or SAE. Newly diagnosed malignancies 
or a recurrence of a malignancy will be reported as an SAE with the seriousness criterion “medically 
important” if no other seriousness criteria are met. 
 
All cardiac events will be specifically elicited and followed. Troponins ordered by the clinical 
team will be recorded in the Daily lab section of the CRF. Troponin levels are not required, but 
will be recorded when available. Recent data using vadadustat in the PROTECT2 study showed 
an increase rate of major adverse cardiac events (MACE) in some study participants. This 
increase in MACE events occurred in patients who were not on dialysis, were treated outside the 
US and were treated for more than 6 months with vadadustat. This risk as not seen in dialysis 
patients and was not seen in study participants in the US. The DSMB was notified of these 
results. Based on the above data, the DSMB recommended that all cardiac events be tracked and 
troponins be recorded when ordered by the treating team. 
 
Any SAE, regardless of causal relationship, must be reported to the sponsor within 24 hours after 
the Investigator becomes aware of the SAE. Compliance with this time requirement is essential so 
that sponsor may comply with its regulatory obligations. 
 
11.3. Eliciting Adverse Event Information 
The investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
patient. Patients will be questioned daily about AEs if they are able to respond, and then followed 
through the duration of the study. 
 
11.4. Reporting 
Each AE is to be classified by the investigator as serious or non-serious. 
 
All AEs that occur in study subjects during the AE reporting period specified in the protocol must 
be reported, whether or not the event is considered to be related to study drug. 
 
11.4.1. Reporting Period 
The AE reporting period for this study begins upon initiation of study drug and ends up to 16 days 
after randomization (14 days of drug dosage plus two days), while SAEs will be continued to be 
reported up to Day 28, and will be assessed via follow-up, or through the patient’s chart. However, 
AEs considered secondary to protocol mandated procedures should be reported post signing of the 
informed consent form (ICF), whether or not they occur before or after initiation of study drug. 
Subjects discharged from the hospital will be contacted on day 7, 14, and 28 to assess for SAEs. In 
addition, SAEs that occur during the protocol-defined AE reporting period that the investigator 
assesses as unexplained and related to the study drug will also be reported as an SAE to the 
UTHealth IRB and the FDA. AEs and SAEs that occur after the protocol-defined period that the 


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investigator assesses as related to the study drug will also be reported as an AE to UTHealth. If the 
event is serious, related, and unexpected, the event will be reported to the investigator IRB and the 
FDA. 
 
11.4.2. Reporting AEs 
All AEs (serious and non-serious) are to be reported on the AE CRF in the clinical database during 
the AE reporting period as described in Section 11.1. 
 
11.4.3. Reporting SAEs 
Any SAE, regardless of causal relationship, will be reported to the sponsor’s designee within 24 
hours after the investigator becomes aware of the SAE. Compliance with this time requirement is 
essential so that the sponsor may comply with its regulatory obligations. Additionally, it may be 
necessary for UTHealth (or designee) to directly communicate with the investigator if additional 
information is required. 
 
The initial SAE report should be completed as fully as possible but will contain, at a minimum 
item number 1 to 6: 
1. Subject number/ID, sex, and age 
2. The date of report 
3. Name of the reporter 
4. Name of the suspected medicinal product 
5. A description of the event, including event term(s), seriousness criteria, and a clinical 
summary of the event 
6. Causality assessment 
 
The investigator will assess the relationship to each specific component of the study treatment. A 
SAE Report Form will be sent to the sponsor or its designee via email or the investigator will call 
the sponsor or its designee SAE hotline within 24 hours of being made aware of the SAE. 
 
Refer to the SAE Report Form and SAE Report Form Guidelines for more details on SAE reporting, 
including timelines, and email for reporting and the contact information for any questions regarding 
SAE reporting. 
 
The investigator must report follow-up information relating to an SAE to the study safety monitor 
as it becomes available by submitting a REDCAP SAE Report Form. The subject will be observed 
and monitored carefully until the condition is resolved or stabilizes. 
 
All deaths are to be thoroughly investigated and reported to the UTHealth IRB. Autopsy reports 
and death certificates are to be obtained, if possible. In-hospital deaths will be investigated via 
electronic medical records (EMR). Out-of-hospital deaths will be investigated by calling their 
family, and reviewing available death certificates. 


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In addition to the sponsor’s responsibility for reporting SAEs to all applicable regulatory agencies, 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC), and investigators within 
the required timeline, UTHealth and/or its designee are responsible for reporting SAEs to all 
applicable regulatory agencies, central ethics committees, and investigators as well within the 
required timeline. 
 
11.5. Relationship to Study Drug 
The investigator must provide an assessment of causality (relationship to study drugs) at the time 
of the report. If causality is difficult to determine, for example, due to incomplete clinical 
information at the time of the report, the investigator must use clinical judgment under consideration 
of the criteria outlined below and provide a causality assessment. It is also good practice to include 
a rationale for the causality assessment. 
The assessment of causal relationship to study drug will be evidence-based, and not based on the 
premise that all AEs are possibly causally related to study drug until proven otherwise. 
Examples of evidence that would suggest a causal relationship between the study drug and the AE 
include the occurrence of an AE that is uncommon and known to be strongly associated with drug 
exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome), or an AE that is 
uncommon in the population exposed to the drug. 
 
The site investigator, on the basis of his or her clinical judgment and the following definitions, 
determines the relationship of the AE to the protocol intervention as one of the following: 
 
Algorithm to Determine Relatedness of Adverse Event in Study Agent 
Unrelated 
The temporal relationship between treatment exposure and the adverse even is 
unreasonable or incompatible and/or adverse event is clearly due to extraneous causes 
(e.g. underlying disease, environment). 
Unlikely 
Must have both of the following two (2) conditions, but may have reasonable or only 
tenuous temporal relationship to intervention: 
1. Could readily have been produced by the subject’s clinical state, 
environmental, or other interventions. 
2. Does not follow known pattern of response to intervention. 
Reasonable Possibility 
Must have at least two (2) of the following three (3) conditions: 
1. Has a reasonable temporal relationship to intervention 
2. Could not have readily been produced by the subject’s clinical state or 
environmental or other interventions 
3. Follows a known pattern of response to intervention. 
Definitely 
Must have all three (3) of the following conditions: 
1. Has a reasonable temporal relationship to intervention 
2. Could not possibly have been produced by the subject’s clinical state or 
have been due to environmental or other interventions 
3. Follows knows pattern of response to intervention. 
Default assessments using the ‘related’ category without supportive evidence for a causal 
relationship to study drug is generally uninformative and does not contribute meaningfully to the 
development of the safety profile of the drug or to subject protection. 


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Investigators are encouraged to choose the most plausible cause for the event(s) from the following 
list: medical history, lack of efficacy/worsening of treated condition, study treatment, other 
treatment (concomitant, or previous), withdrawal of study treatment, administration error, protocol- 
related procedure, others (specify). 
 
11.6. Severity 
The investigator will assess each AE using the CTCAE guidelines to describe the maximum severity 
of the AE: 
• 
Grade 1 Mild – asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2 Moderate – minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental ADL. 
• 
Grade 3 Severe or medically significant but not immediately life threatening – 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self care 
ADL. 
• 
Grade 4 Life threatening consequences – urgent intervention indicated. 
• 
Grade 5 Death related to AE. 
 
Note that a severe AE is not necessarily a serious AE. For example, a headache may be severe in 
intensity, but would not be classified as serious unless it met one of the criteria for serious events 
listed above, see Section 11.4.3. 
 
11.7. Emergency Unblinding: 
A representative of the study leadership will always be available using 24-hour telephone number 
for communication with investigators and healthcare providers caring for the patient. 
 
If a clinician requests emergency unblinding of study drug in response to a clinical event, the study 
representative will discuss the clinical utility of unblinding with the clinician. Emergency 
unblinding will only occur if the clinical and investigator agree that it is necessary to treat the 
patient. Emergency unblinding should be rare as there is no antidote to the drug, and it is given 
orally. All requests for emergency unblinding will be reported to the study safety officer. The safety 
officer will then determine if the patient should continue to receive study medication. 
 
11.7.1 Non-Emergency Un-blinding 
At times the sponsor or designee may request un-blinding of safety events in accordance with their 
reporting responsibilities. In these cases, if the treatment team does not need to be un-blinded, the 
database manager will un-blind the sponsor or their designee but will not un-blind the clinical or 
research team. 
 
11.8 Follow-up of Unresolved Events 
All AEs will be followed until they are resolved, or the investigator assesses them as chronic or 
stable or the subject’s participation in the study ends (i.e., until a final report is completed for that 


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subject). 
 
All SAEs and non-serious events that are ongoing at the time a subject’s participation in the study 
ends and that are assessed by the investigator as related to the study drug, will continue to be 
followed until they resolve or until the investigator assesses them as “chronic” or “stable”. Follow- 
up information will be reported to UTHealth on the appropriate CRF or paper SAE Report Form if 
EDC is unavailable. 
 
More details of the study safety plan are described in the study Manual of Procedures. 
 
12. Sample Size and Power Calculation 
The trial will investigate the superiority of vadadustat 900 mg per day to placebo for the prevention 
and treatment of ARDS among COVID-19 patients, defined by the proportion of patients at day 14 
who are dead (8) or hospitalized, on invasive mechanical ventilation or ECMO (7) or hospitalized, 
on noninvasive ventilation or high flow oxygen devices (6) on the NIAID-OS (i.e. decrease in the 
proportion of participants with NIAID-OS < 6 at day 14). 
 
Anticipated sample size for the current study is N = 650. An evaluation by the DSMB will occur 
following ascertainment of 14-day safety outcomes for the first 30 patients that are randomized and 
dosed, and a second at the first 120 (i.e. n = 60 receiving Vadadustat). 
 
Bayesian analysis for superiority will occur following ascertainment of outcome at fourteen days 
after randomization of N = 650 patients. We stipulate that a posterior probability of a > 2.5% 
decrease in the proportion of NIAID-OS > 6 as a function of treatment that is > 0.85 constitutes 
sufficient evidence to declare that the active treatment condition is superior to placebo. The prior 
distribution for analysis will be ~Beta(a= 1, b = 1), or in the presence of covarying for stratification 
factors ~Normal (µ=0, σ2=1 x 10) for the coefficients in the log-form of the appropriate generalized 
linear model. 
 
We anticipate a decrease in the proportion of NIAID-OS > 6 participants due to treatment will be 
approximately 15%, with preliminary data suggesting a rate of 25.1% in the placebo condition. 
Assuming this effect, K = 1000 Monte Carlo clinical trial simulations, for N = 650 participants and 
the previously stated decision rules resulted in detection of a > 2.5% decrease in NIAID-OS > 6 
due to the active treatment 99.1% of the time with a Type I Error rate of 3.5%. For more modest 
effects, 12.5% and 10% decreases in NIAID-OS > 6, the current sample and decision rules will lead 
to detection 96.1% and 86.3% of the time with Type I Error rates of 4.8% and 3.7% respectively. 
 
13. Statistical Analysis 
 
13.1. Specific Statistical Hypothesis Primary 
Outcome 
Among adult hospital admissions with lab-confirmed diagnosis of COVID-19, vadadustat 900 mg 
will demonstrate superiority to placebo as defined by a lower probability, at treatment day 14, of 


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death (8) or hospitalization, on invasive mechanical ventilation or ECMO (7) or hospitalization, on 
non-invasive ventilation or high flow oxygen devices (6) on the NIAID-OS. Generalized linear 
modeling will evaluate the probability of patients demonstrating this status at day fourteen of 
treatment as a function of treatment condition after covarying for stratification variables. 
Secondary Outcome 
 
Among adult hospital admissions with lab-confirmed diagnosis of COVID-19, vadadustat 900 mg 
will demonstrate superiority to placebo as defined by a higher probability, at treatment day 14, of 
recovery on the MSOFA scale (MSOFA = 0). Generalized linear modeling will evaluate the 
probability of patients demonstrating an MSOFA = 0 at day fourteen of treatment as a function of 
treatment condition after covarying for stratification variables. 
13.2. Bayesian Modeling Strategy 
Initial analyses examining group differences for baseline variables will use cross-tabulation, 
ANOVA’s, and examination of correlations between baseline variables and specified outcomes. 
For the purposes of evaluating the comparability of groups, a posterior probability of > 95% will 
constitute evidence for statistically reliable differences. Baseline or demographic variables on 
which group differences are detected, and which are correlated with outcomes, meet the definition 
of confounders (Assmann et al 2005, Pocock et al 2002) and will result in two sets of analyses: one 
in which the relevant variable is included as a covariate and one in which it is not. This will permit 
determination of the degree to which any group differences might confound conclusions regarding 
treatment. 
 
Broadly, the data analytic strategy will use generalized linear and multilevel models (R v. 3.6, and 
Stan 2.17) for both discrete and continuous outcomes (SAS Institute 2002-2012, R Core Team 2017, 
Carpenter et al 2017). Multilevel generalized linear modeling to account for clustering of patients 
within site and repeated observations within patients will evaluate continuous, dichotomous, and 
count data. All analyses will apply intention-to-treat principles with missingness addressed via joint 
modeling of observed outcomes and the missing data, an approach robust to ignorable missingness 
(i.e., MCAR and MAR) (Best & Thomas 2000). Sensitivity analyses will evaluate robustness of 
analytic conclusions to missing data. Non-ignorable missing data patterns will be addressed through 
pattern-mixture modeling methods (Fitzmaurice & Laird 2000). Evaluation of posterior 
distributions will permit statements regarding the probability that effects of varying magnitudes 
exist, given the data. Specification of diffuse, neutral priors will reflect the initial uncertainty 
regarding effect sizes. For all generalized linear models, priors for regression coefficients will be 
specified as ~Normal (µ=0, σ2=1 x 10), level one and two error variances will be specified as ~Half- 
Normal (µ=0, σ2=1 x 103). The choice of prior distribution for level two variances will follow 
Gelman’s recommendations (Gelman 2006). Priors for the comparison of proportions will be 
specified as ~Beta (α=1.0, β=1.0). 
 
14. Ethics 
The protocol titled “Vadadustat for the prevention and treatment of acute respiratory distress 
syndrome (ARDS) in hospitalized patients with Coronavirus Disease 2019 (COVID-19) will be 


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submitted to the local Institutional Review Board (IRB). 
 
The protocol will be reviewed by: 
The Committee for the Protection of Human Subjects 
The University of Texas Health Science Center at Houston  
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The study will be reviewed, approved and conducted in accordance with regulations mandated by 
The University of Texas Health Science Center at Houston Institutional Review Board. In addition, 
the study will be conducted according to the College of American Pathologists standards that meet 
Good Clinical Practice (GCP). These standards respect the following guidelines: 
• 
GCP: Consolidated Guideline (International Conference on Harmonization ICH of 
Technical Requirements for the Registration of Pharmaceuticals for Human Use, May 1996) 
• 
Integrated Addendum to ICH E6 (R1): Guideline for Good Clinical Practice, E6 (R2); 
Current step 4 version dated 9 November 2016. 
• 
United States (US) Code of Federal Regulations (CFR) dealing with clinical studies (21 
CFR Parts 50, 54, 56, 312, 314, and 511) 
• 
Declaration of Helsinki, concerning medical research in humans (“Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects,”) Helsinki 1964, 
amended Tokyo 1975, Venice 1983, Hong Kong 1989 and revised version of Somerset 
West, Republic of South Africa, October, 1996, Note of Clarification added by the WMA 
World Medical Association General Assembly, Washington 2002, Note of Clarification 
added by the WMA General Assembly, Tokyo 2004 


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15. Informed Consent 
Potential subjects are to receive a thorough explanation of study details and procedures and 
provided time to ask any questions. All subjects must sign the IRB approved informed consent form 
before performing any study-related activity (including screening activities). Due to COVID-19 to 
prevent cross contamination, the original signed consent form is given to the patient. A photograph 
using HIPAA compliant Tiger Connect will be captured of the signature page and will be placed in 
the subject’s study file. In the case where an adult is incapable of making an informed decision, 
they will be excluded from study participation. 
 
16. Data handling and record keeping 
16.1. CRFs/EDC 
This study will utilize an electronic data capture (EDC) system to manage data collection during 
this trial. The system is fully Code of Federal Regulations 21 part 11 compliant. This EDC will 
reside behind the Zone 100 UTHealth firewall with Shibboleth-based user-access and identification. 
Patients will be assigned a unique ID number. A master key file will be stored on the shared password 
protected drive at UTHealth. Only Co-investigators at UTHealth and their staff (to be added through 
amendment at a later date when hired) will have access to this master key file. 
The EDC in this study will utilize the REDcap system maintained on secure UTHealth servers. This 
database possesses a graphical user interface to facilitate data entry, capability of tracking data 
management and user activity, a data validation element to check user data (e.g. impermissible/out- 
of-range or missing values), and a reporting function to assist with the review and analysis of data. 
The data base will utilize a relational structure to avoid so-called “orphan records” with staff 
password protected and access to and modification of data tables restricted based on their 
operational roles. Clinical Research Forms (CRF’s) available through this system are required and 
will be completed for each randomized subject. Any data from the electronic system are the sole 
property of the sponsor and will not be made available in any form to third parties, except for 
authorized representatives of the sponsor or appropriate regulatory authorities, without written 
permission from the sponsor. The investigator has ultimate responsibility for the accuracy, 
authenticity, and timely collection and reporting of all clinical, safety, and laboratory data entered 
in the EDC or any other data collection forms. The CRFs will be signed electronically by the 
investigator to attest that the data contained on the CRFs are true. 
In most cases, the source documents are contained in the subject’s chart at the hospital, dialysis or 
research clinic, or the physician's office. In these cases, data collected on the CRFs will match the 
data in those charts. 
16.2. Record Retention 
To enable evaluations and/or audits from regulatory authorities or the sponsor, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient information to 
link records, e.g., CRFs and hospital records), all original signed informed consent forms, copies 
of all CRFs, SAE forms, source documents, detailed records of drug disposition, and adequate 
documentation of relevant correspondence (e.g., letters, meeting minutes, and telephone calls 
reports). The records will be retained by the investigator according to the International Conference 


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of/Council for Harmonisation (ICH) of Technical Requires for Pharmaceuticals for Human Use 
local regulations, or as specified in the Clinical Study Agreement, whichever is longer. 
If the investigator becomes unable for any reason to continue to retain study records for the required 
period (e.g., retirement and relocation), the sponsor will be prospectively notified. The study 
records will be transferred to a designee acceptable to the sponsor, such as another investigator, 
another institution, or to the sponsor. The investigator will obtain sponsor’s written permission 
before disposing of any records, even if retention requirements have been met. 
17. Quality control and assurance 
17.1. Manufacture and Storage 
Drug to be tested: Vadadustat is manufactured by Akebia and contains microcrystalline cellulose 
(MCC), sodium starch glycolate, hydroxypropyl methylcellulose (HPMC), colloidal silicon 
dioxide, and magnesium stearate, and a nonfunctional film coat in addition to vadadustat. Placebo: 
Placebo is manufactured by Akebia and contains MCC, colloidal silicon dioxide, magnesium 
stearate, and a nonfunctional film coat. Vadadustat and placebo are stored at room temperature. 
 
17.2. Active Dose 
Subjects will receive 900 mg as 6 x 150 mg tablets once daily. 
 
17.3. Dispense and Handling of Study Drug 
The research pharmacist or designee will dispense 6 tablets of vadadustat or placebo daily for each 
study patient. Administration to the study patients will follow the local institution’s procedures. 
 
18. Protocol Amendment 
 
18.1 Long-Term Follow-up 
 
The purpose of this amendment is to characterize the long-term effects on COVID-19 survivors who 
were hospitalized with SARS-CoV-2 and treated with either a HIF activator vadadustat or placebo. 
Specifically, we will 1) characterize the occurrence of long-term COVID-19 sequelae in  a well-
described patient cohort and 2) address the hypothesis that vadadustat would attenuate or prevent 
the long-term disease sequelae of SARS-CoV-2. 
 
18.2 
Study Objectives. 
 
Primary: Evaluation of pulmonary capacity as a function of treatment, time and the interaction 
of treatment and time. 
 
Secondary: Evaluate cardiac, hepatic and renal outcomes, quality of life, and long-term 
neurocognitive impairment of COVID-19 patients treated with either vadadustat or placebo 


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18.3 
Study Diagram. 
 
 
 
 
 
18.4 
Study Population. 
 
Eligibility Criteria 
 
18.4.1 Inclusion Criteria 
• Male or Female age ≥ 18. 
• Previously enrolled in the vadadustat study and agreed for an extended follow-up. 
• Patients who Speak/Write in English or Spanish 
 
18.4.2 Exclusion Criteria 
• Patients who were enrolled in the vadadustat study but withdrew before taking the 1st 
dose of the study drug. 
• Patients who were enrolled in the vadadustat study but did not consent for an extended 
follow-up. 
• Patients who do not speak English or Spanish. 
 
18.5 
Data Collection. 
 
The following will be collected on the 6th, 12th and 24th month follow-up. 
• Informed consent for the extended follow-up shall be referenced to the IRB approved ICF 
of vadadustat study starting February 5, 2021 wherein patients have agreed to participate 
in this long-term study. 
For those patients consented prior to February 5, 2021, please refer to Section 18.9 of the 
study protocol for the reconsenting process. 
• Body Mass Index, height, weight 
• Medication History 
• Tobacco use 
• Past Medical History 
• Laboratory Tests: ALT, AST, Total Bilirubin, Creatinine, and Hemoglobin. 
• Cardiac, Renal and Lung Biomarkers (Blood and urine) 


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Pulmonary Function test 
• Transthoracic echocardiography (TTE) 
• Lung ultrasound 
• PROMIS Scale v1.2 Global Health Survey 
• MoCA Test (Montreal Cognitive Assessment) 
 
 
18.6 
Study Procedures. 
 
Each study participant will undergo the following procedures on 6th, 12 and 24th month follow-  up. 
There is a one (1) month window to complete each follow up appointment once a patient reaches their 
long term follow up due date. This one-month window provides flexibility to schedule and 
accommodate both the patient and the clinical teams’ availability. If a patient cannot be scheduled 
within one month of their follow up date, this will be deemed a loss to follow up and documented 
in RedCAP accordingly. 
 
18.6. 
1 Sample collection processing 
 
Blood and urine samples will be collected at our Clinical Research Unit (CRU) and processed using 
standard protocols. Blood specimens will be collected from the patient (biomarkers and laboratory 
specific tests) and urine over the course of the visit. Universal precautions and institutional biosafety 
procedures will be followed. 
 
18.6.2 Transthoracic Echocardiography (TTE) 
 
This test is the primary noninvasive imaging modality for quantitative and qualitative evaluation of 
cardiac anatomy and function using an ultrasound. This test will be performed by physicians, 
fellowship-trained in ultrasonography. 
 
The study currently evaluates pulmonary function and cardiac function as part of the long term 
follow up protocol. There is currently no lung imagining as part of the follow up process. Previous 
literature has shown ultrasound is as accurate as computed tomography for interstitial lung disease, 
without the cost or ionizing radiation. We are adding lung ultrasound as a seamless addition to the 
echo portion of the long term follow up study. We anticipate this exam will add approximately five 
minutes to the ultrasound portion of the protocol. There are no known harms associated with lung 
ultrasound. 
 
C60 probe using abdominal preset. Axial images obtained via cranial caudal sweep of the right and 
left hemi-thorax in the mid-clavicular, mid-axillary, and peri-scapular. De-identified video clips of 
each location will be saved. We will make notation of any unusual signature with particular attention 
to previously described findings in COVID lung disease including B lines and sub-pleural 
consolidations. 
Data Collection Sheet: 


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R Midclav 
L Midclav 
R Midax 
L Midax 
R Periscap 
L Periscap 
3+ B lines 
Confluent B 
Lines 
Sub-pleural 
Conolidation 
Pleural 
Effusion 
Check mark indicates present of the finding 
 
 
 
18.6.3 
Pulmonary Function Tests 
 
Participants will be subjected to a pulmonary testing using spirometry. Briefly, spirometry is used 
to measure forced expiratory flow rates and volumes. It is the most commonly used pulmonary 
function test and is useful in the evaluation of patients with respiratory symptoms (e.g., dyspnea, 
cough, wheeze) or risk factors for respiratory diseases. Specifically, we will be measuring FVC, 
FEV, FEV/FVC ratio. 
 
 
18.6.4 
Study Questionnaires 
 
The PROMIS Global Health assess an individual’s physical, mental and social health. The measures 
are generic, rather than disease-specific, and often use an ‘In General’ item context as it is intended 
to globally reflect individuals’ assessment of their health. The adult PROMIS Global Health 
measure produces two scores: physical health and mental health. The Montreal Cognitive 
Assessment (MoCA) is a tool to assess short memory, visuospatial abilities, executive functions, 
attention, concentration and working memory, language and orientation to time and place. 
 
 
18.6.5 
Visit Compensation 
 
Each time a patient completes follow up, she/he will receive a $100 gift card, (up to a maximum of 
$300 for completion of 3 follow-up in 24 months). Patients will be provided with a $100 SPA Card 
at the end of each visit. Additionally, the study team will arrange round trip transportation of the 
patient from and to their home or destination. Should they choose to drive, the research team will 
provide patients with parking validation. 
Other findings: 


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18.6.6 Study Dissemination 
 
Study clinicians will review any results found outside of expected ranges for the Transthoracic 
Echocardiography, pulmonary function test, lung ultrasound, labs and/or MoCA. Participants will 
be notified via mail to follow up with their PCP. 
 
 
18.7 
Withdrawal from Follow-up Visits 
 
A patient can withdraw from participating in the long-term follow-up at any point for any reason. If 
possible, reasons for discontinuation or refusal will be documented. 
 
18.8 
Statistics 
 
18.8.1 Specific Statistical Hypothesis of Primary Outcome 
 
The primary outcome analysis will model pulmonary capacity as a function of time, treatment and 
the interaction of time and treatment after controlling for stratification variables (i.e. site and 
MSOFA < 4 or > 4). 
 
18.8.2 Sample Size and Power Calculation 
 
For the purpose of sample size justification, we assume a small between-groups effect (Cohen’s d 
= 0.2) unfolding in linear fashion over time (6, 12, and 24 months). Estimation will focus on the 
interaction of treatment and time to ascertain the degree to which the two group’s trajectories of 
change differ. We further assume that pulmonary function will exhibit with subject autocorrelation 
of r = 0.3 for every six-month time lag with this correlation diminishing by 50% for every additional 
six-month time lag. We anticipate enrolling N = 200 participants, and assume attrition will be 
approximately 10% resulting in a final sample of n = 180. Stipulating a posterior probability of 0.80 
for the existence of an interaction effect (i.e. there is an 80% chance that there are differential 
trajectories of change for the treatments, K = 1000 Monte Carlo simulations identify an interaction 
term 92% of the time. 
 
18.8.3 
Linear Multilevel Models 
 
Analyses will focus on longitudinal trajectories of change for outcomes specified in objectives 1-3. 
Generalized linear multilevel models will evaluate change as a function of time, treatment, and the 
interaction of treatment and time after controlling for stratification variables (i.e. site and baseline 
severity as measured by the MSOFA < 4 or > 4). Analyses will utilize Bayesian inference. Prior 
distributions will be neutral (centered on the null hypothesis) and weakly informative as described 
by Gabry and Goodrich (2020). This will have the benefit of regularizing any parameter estimates 
and render more conservative estimates of effect size. Regarding priors essentially as a set of 
assumptions, we will evaluate the robustness of our analytic conclusions to alternative prior 
specifications with varying degrees of regularization/skepticism (Gelman, 2007; Spielgelhalter, 
2004). 


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18.9 
Informed Consent 
Patients enrolled in the vadadustat study after February 5, 2021 have had the option to participate 
in the extended follow-up. Only patients who provided consent for extended follow-up will be 
included in this study. 
 
Patients who were enrolled to the vadadustat study prior to February 5, 2021 will be reconsented in 
order to participate. For these patients, an IRB approved letter was sent out to inform them of an 
opportunity to participate in the long-term follow-up. One week later, a study coordinator contacted 
these patients and provided additional information. For those patients that agreed to be part of the 
study, an electronic consent via RedCap was sent to the patient’s email. Patients have the 
opportunity to review the informed consent form, provide personal information and sign. 
 
19. Publication Plan 
No publication or disclosure of study results will be permitted, except under the terms and 
conditions of a separate, written agreement between The University of Texas Health Science Center 
at Houston (the Sponsor) and the investigator and/or the investigator’s institution. The Sponsor will 
have the opportunity to review and approve all proposed abstracts, manuscripts, or presentations 
regarding this study prior to submission for publication/presentation. Akebia will have the 
opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 
prior to submission for publication/presentation. Any information identified by the Sponsor and 
Akebia as confidential will be deleted prior to submission. 
 
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including: Section II - “Ethical Considerations 
in the Conduct and Reporting of Research” of the Uniform Requirements for Manuscripts 
Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, established by the 
International Committee of Medical Journal Editors. 


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ICF_001.pdf: 
IRB APPROVAL DATE: 01/20/2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VSTAT COVID: Vadadustat Study Targeting ARDS Therapy in COVID and VSTAT-LoTuS: A 
Long- Term Follow Up Study of COVID-19 Patients treated with either vadadustat or 
placebo. 
 
NCT04478071 
 
Version Date: 01/20/2022 
 
 


IRB APPROVAL DATE: 01/20/2022 
 
 
CONSENT TO TAKE PART IN RESEARCH 
HSC-MS-20-0395 
 
Simple Study Title: 
VSTAT-LoTuS 
 
Full Study Title: 
VSTAT COVID: Vadadustat Study Targeting ARDS Therapy in COVID and VSTAT-LoTuS: A Long- 
Term Follow Up Study of COVID-19 Patients treated with either vadadustat or placebo. 
Study Sponsor: 
McGovern Medical School at UTHealth 
 
Principal Investigator: 
Bentley J. Bobrow MD 
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 
 
Study Contact: 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||  
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 
 
Purpose: 
The purpose of this study is to assess how well an oral drug called vadadustat given once a day for 14 days 
works for the prevention and treatment of acute respiratory distress syndrome (ARDS) in patients 
hospitalized with COVID-19 infection. This is a voluntary study and if you choose to participate, you will 
be asked to sign this consent form that you agree to be part of the study. If you have any questions at any 
time or need clarification on anything, or would like a language translator, please ask ||||||||||||||||  |||||||||||||||| 
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||  |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||  
 
The goal of this study is to see how well vadadustat the drug to be tested, works at preventing and treating 
people with COVID-19 infection, your current condition. This drug is not yet approved by the Food and 
Drug Administration (FDA); therefore, it is called an investigational drug. The study is funded through 
Akebia Therapeutics Inc. located in Cambridge, MA. Akebia is paying UTHealth for their work on this 
study. The Department of Defense (DoD) is also supporting this study. 
 
A description of this clinical trial is available on http://www.clinicaltrials.gov, as required by law. Your 
name or any personal information will not be publicly available. After the study has ended, the website will 
include a summary of the results. You can search this website at any time. 
 
In this study, a drug called vadadustat or placebo will be given to you by mouth each day with the goal of 
decreasing inflammation in your lungs and to reduce the chance you may need a ventilator due to the 
COVID-19 infection. The total amount of time you will be in this study is 28 days. This will include the 
time you are in the hospital and then after you go home. On day 28 you will be contacted by the research 
team for follow up. If you agree and are able to take part in this study you will undergo the following 
procedures: 
 
Contact Name: |||||||||||||||||||||||||||||||||||||||||||||||| 
Revised 12/23/2021 
 
 
IRB NUMBER: HSC-MS-20-0395 


Informed Consent Effects of Vadadustat on COVID-19 Induced Acute Respiratory Distress Syndrome 
Page 2 
Contact Name: |||||||||||||||||||||||||||||||||||||||||||||||| 
Revised 12/23/2021 
IRB NUMBER: HSC-MS-20-0395 
IRB APPROVAL DATE: 01/20/2022 
 
 
• 
As part of the study procedure, a small sample of blood (10 ml) will be drawn prior to starting the 
drug, then again on day 7 and on day 14. 
• 
The study drug, vadadustat or a placebo, will be administered every day for 14 days by mouth or if 
you are placed on a ventilator through a nasogastric tube that your doctor will position. You will 
be given six small tablets (each about the size of a baby aspirin), a total of 900 mg once a day. 
• 
You will be followed carefully and assessed to see whether your COVID-19 infection worsens or 
improves and how quickly that happens. 
 
Risks: 
There are potential risks involved with this study that are described in this document. There are both risks 
and benefits to taking part in this study. It is important for you to think carefully about these as you make 
your decision. 
 
Some known risks include: 
• 
If you choose to take part in this study, there is a risk that the vadadustat may not be helpful in 
treating your condition. 
• 
There is a small risk of having a bruise, bleeding or discomfort at the site of the needle stick for 
drawing blood, although we will be taking this blood at the same time as your other blood tests are 
performed, so this will be unlikely. 
• 
The most commonly known side effect of vadadustat is gastrointestinal upset such as nausea and 
vomiting which is usually mild. 
• 
Patients who have COVID-19 are at increased risk for abnormal blood clotting. While this has not 
been detected in clinical studies, there is a theoretical risk that taking vadadustat may increase the 
risk of abnormal blood clotting. If your physician deems appropriate, you may receive a blood 
thinner. 
• 
As we will need to collect some information about your healthcare and blood test results, there are 
possible risks from loss of confidentiality that may arise from taking part in the study. Please be 
assured that we will take every precaution to protect your health information in compliance with 
all hospital, state, and federal regulations and we are committed to preventing this from happening. 
You will also be monitored for any serious adverse effects (SAEs) by your physician and the UTHealth 
Research Team. 
 
Benefits: 
We are doing this study because UTHealth physician-scientists believe that there is a strong chance that the 
drug vadadustat given to patients with COVID-19 could help prevent and/or treat acute respiratory distress 
syndrome (ARDS) which occurs when the lungs become inflamed and cannot function properly. We also 
are doing this study because we believe that some very important information will be discovered which 
may help the medical team treating you. However, even if this drug does not ultimately help patients with 
COVID-19, the information from this study may show us how to better help future patients who are 
receiving treatment for ARDS. 
 
Alternatives: You may choose not to take part in this study. Participation in this research study is 
completely voluntary. You may also choose to stop the research study at any time. Your decision will not 
in any way affect the clinical care you receive. If you are interested in participating, please continue to read 
below. 
 
Who is being asked to take part in this study? 


Informed Consent Effects of Vadadustat on COVID-19 Induced Acute Respiratory Distress Syndrome 
Page 3 
Contact Name: |||||||||||||||||||||||||||||||||||||||||||||||| 
Revised 12/23/2021 
IRB NUMBER: HSC-MS-20-0395 
IRB APPROVAL DATE: 01/20/2022 
 
 
You are being asked to take part in this research study because you have COVID-19 and are at risk for 
developing worsening acute respiratory distress syndrome (ARDS). This study is being conducted by 
physician scientists at UTHealth for patients in the Memorial Hermann Health and Harris Health System. 
Up to 650 adults will take part in the study. 
 
What will happen if I take part in this study? 
You agree to be part of the study to treat ARDS due to the COVID-19. As part of the study procedure, small 
samples of blood (10 ml) will be drawn prior to the drug delivery and urine will be collected at time of 
enrollment, day 7 and at day 14. Blood and urine are being collected for analysis of organ and cell function. 
The study drug, vadadustat or placebo, will be administered every day for 14 days by mouth or if needed, 
through a nasogastric tube. 
 
If randomized to a treatment: 
If you agree to take part in this study you will be randomized (similar to flipping a coin) to receive either 
the study drug vadadustat or the placebo (a tablet that contains no active ingredient). It is not known whether 
vadadustat will be of benefit. For this reason, some study participants must receive a placebo. This will 
allow a careful comparison to study the benefits and side effects of the investigational drug. There is a 50% 
chance you will receive vadadustat and a 50% chance that you will receive placebo. Neither you nor your 
doctor will know if you are receiving vadadustat or placebo, as both will look the same. 
 
Exams, tests, and procedures, including but not limited to blood tests, need to be done as part of this study 
to monitor your safety and health, but may not be included in the usual care. We will use them to carefully 
follow the effects of the study treatment, including preventing and managing side effects. 
 
How long will you be in the study? 
If you agree to take part, your participation will last for 14 days (hospitalization) and 14 days follow-up. 
You will receive a phone follow-up call after you go home on day 28 from when you first came to the 
hospital. 
 
Additionally there is an opportunity to participate in an extended follow up period to determine the impact 
of COVID-19 and the trial on your health. If you choose to participate in this portion of the study you will 
be asked to: 
 
• 
return to the clinic at 6, 12 and 24 months and during each visit: 
• 
complete a quality of life questionnaire 
• 
complete a cognitive questionnaire 
• 
provide a blood sample (10 ml) 
• 
provide a urine sample (10 ml) 
• 
a nurse will perform a pulmonary function test and a doctor will perform a lung ultrasound to see 
how well your lungs are working, in addition to an ultrasound to see how your heart is working 
 
 
If you would like to participate in the extended follow up, please check the box and initial below under the 
signature line. 


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IRB NUMBER: HSC-MS-20-0395 
IRB APPROVAL DATE: 01/20/2022 
 
 
What choices do you have other than this study? 
Your options are to participate in the study or not to participate in this study either way you will still be 
treated. You may decide to stop taking part in the study at any time. To withdraw from the study, please 
contact 
 
 
 
Your doctor or the UTHealth Research Team can stop the study at any time. Your doctor or the UTHealth 
Research Team may stop your participation in the study if: 
 
• 
your condition worsens 
• 
the study is stopped 
• 
the study drug is no longer available 
• 
you do not meet all the requirements of the study, 
• 
or the study is not in your best interest. 
 
If your participation in the study is stopped, your doctor will discuss other options for your treatment. 
If you stop participating in this study, the information already collected about you will still be used in the 
data analysis. However, no further information will be collected without your permission. 
 
While taking part in this study, the study team will notify you of new information that may become available 
and could affect your willingness to stay in the study. 
 
Research participation is voluntary. Vaccines do exist but are not a cure and many people have not been 
able to receive vaccinations. COVID-19 ARDS has significant morbidity and mortality for high risk 
patient populations. 
 
What happens if you are injured during the study? 
In the event of injury resulting from this research, UTHealth, Memorial Hermann System and/or the Harris 
Health system (Lyndon B. Johnson Hospital) are not able to offer financial compensation nor to absorb the 
costs of medical treatment. However, necessary facilities, emergency treatment and professional services 
will be available to you, just as they are to the general community. If you are injured or have any harmful 
effects during the course of the research study, treatment will be available to you. You or your insurance 
company will be billed for any treatment. You should report any such injury to |||||||||||||||||||||||||||  ||||||||||||||||||||||||||| 
|||||||||||||||||||||||||||||||||||  ||||||||||||||||||||||||||||||||||| You will not give up any of your legal rights by signing this consent form. 
 
DoD will not provide compensation for any injury occurring during the study. DoD does not have a 
mechanism to provide compensation for study-related injury. 
 
If you are inured, please report to the PI (Bentley Bobrow, MD at |||||||||||||||  |||||||||||||||) and to the Committee 
for the Protection of Human Subjects at |||||||||||||||  |||||||||||||||. You will not give up any of your legal rights by 
signing this consent form. 
 
What are the costs of taking part in this study? 
If you decide to take part in this research study, you will not incur any additional costs. 
 
Upon completion of the D28 follow up call, a $50 gift card will be mailed to you as a small token of 
appreciation. 
 
If you choose to participate in the extended follow up, you will receive a $100 gift card for each completed 
follow up visit. Parking and travel expenses will also be covered. 


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IRB NUMBER: HSC-MS-20-0395 
IRB APPROVAL DATE: 01/20/2022 
 
 
 
The UTHealth will pay for the special tests and examinations that are required by this study and not 
otherwise part of your standard medical care. 
 
However, many of the tests, procedures, and exams you will receive are believed to be part of standard 
medical care, and may or may not be covered by your medical insurance. If your medical insurance does 
not pay for your care you will be responsible for the cost of the medical care related to your condition 
including laboratory tests, deductibles, co-payments, physician and clinic fees, hospitalization and 
procedures. 
 
 
How will privacy and confidentiality be protected? 
Your privacy is important and your participation in this study will be kept confidential. However, absolute 
confidentiality cannot be guaranteed. 
 
If you sign this document, you give permission to UTHealth, Memorial Hermann Healthcare System and/or 
Harris Health system to use and disclose (release) your health information. The health information that we 
may use or disclose for this research includes all information in a medical record, results of physical 
examinations, medical history, lab tests, or certain health information indicating or relating to a particular 
condition. Please understand that health information used and disclosed may include information relating 
to HIV infection, drug abuse, alcohol abuse, behavioral health, and psychiatric care. 
 
If you sign this document, you give permission to UTHealth and/or Memorial Hermann Health System, 
and/or Harris Health System to use and disclose (release) your health information. Representatives of 
the organizations listed below will see your name and other personal identifiers when they review your 
research records and medical records for the purposes of verifying study data: 
 
• 
Representatives of UTHealth and/or Memorial Hermann Health System and/or Harris Health 
System 
• 
Representatives from the U.S.Food and Drug Administration (FDA) 
• 
IQVIA 
• 
AKEBIA 
• 
The Department of Defense (DoD) 
• 
Representatives of the sponsor for this research including contract research organizations 
• 
Members of the Data and Safety Monitoring Boards (an independent group of experts that 
reviews this study’s data to make sure participants are safe and re research data is reliable) 
• 
Companies engaged with the UTHealth for the commercialization of the results of the research 
study 
If you receive a bill that you believe is related to your taking part in this research study, please 
contact: ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||, 
 
 


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Contact Name: |||||||||||||||||||||||||||||||||||||||||||||||| 
Revised 12/23/2021 
IRB NUMBER: HSC-MS-20-0395 
IRB APPROVAL DATE: 01/20/2022 
 
 
If you sign this document, you give permission to the researchers to obtain health information from the 
following health care providers: 
 
Name of Provider 
Address of Provider 
Fax Number of Provider 
 
Personal identifiers such as your name and medical record number will be removed from the information 
and samples collected in this study. After we remove all identifiers, the information or samples may be 
used for future research or shared with other researchers without your additional informed consent. 
 
Whom can you contact if you have questions about the study? 
If you have questions at any time about this research study, please feel free to contact the Dr. Bentley 
Bobrow MD. 
 as he will be glad to answer your questions. You can contact 
the study team to discuss problems, report injuries, voice concerns, obtain information in addition to asking 
questions about the research. 
 
The Committee for Protection of Human Subjects at the University of Texas Health Science Center has 
reviewed this research study. You may contact them for any questions about your rights as a research 
subject, and to discuss any concerns, comments, or complaints about taking part in a research study at 
 
 
 
SIGNATURES 
Sign below only if you understand the information given to you about the research and you choose to take 
part in this research study. Make sure that all your questions have been answered. If you decide to take 
part in this research study, a copy of this signed consent form will be given to you. 
 
 
 
Printed Name of Subject 
Signature of Subject 
Date 
Time 
 
 
 
 
 
Printed Name of LAR 
Signature of LAR 
Date 
Time 
 
 
 
 
 
 
 
Printed Name of Person 
Obtaining Informed Consent 
Signature of Person Obtaining 
Informed Consent 
Date 
Time 
 
 
 
  
Please check this box and initial if you would like to participate in the extended follow up.