Study of Varespladib in Patients Hospitalized With Severe COVID-19

This is a 2-part, multi-center, randomized, double-blind, placebo-controlled, phase 2 study designed to evaluate the safety, tolerability, and efficacy of oral varespladib, in addition to standard of care, in patients hospitalized with severe COVID-19 caused by SARS-CoV-2.

The goals of this 2-part, multi-center, randomized, double-blind, placebo-controlled, phase 2 study are to define a safe dose for the population and to assess the safety, tolerability, and efficacy of orally dosed varespladib to improve survival without respiratory failure in patients hospitalized with severe coronavirus disease 2019 (COVID-19), when given in addition to the institutional standard of care therapy.

Mortality rates of COVID-19 are strongly linked to acute respiratory distress syndrome (ARDS) which may be, additionally, correlated with elevations of secretory phospholipase 2 (sPLA2) and widespread loss of functioning lung tissue. Upregulation of sPLA2 is thought to be involved in the dysregulated inflammatory cascade pathways (increased markers of immune activation, also known as cytokine release syndrome) and enzymatic degradation of lung surfactant linked to the development of ARDS. It is believed that treatment with varespladib, a potent inhibitor of sPLA2, might prevent or mitigate progression of pulmonary dysfunction in COVID-19 patients by two mechanisms: suppression of sPLA2-induced inflammation and, uniquely, preservation of pulmonary surfactant by direct inhibition of the enzyme responsible for surfactant phospholipid degradation: sPLA2.

Data from previous phase 2 clinical trials of varespladib suggested it had potential to reduce mortality in severely septic patients with ARDS, particularly when treatment was initiated within 18 hours of identification of organ failure.

The study will be conducted in two parts. Both parts will be randomized and double-blind. Part 1 will be dose-finding in four parallel treatment groups randomized to treatment with varespladib (at 250 mg once daily \[QD\], twice daily \[BID\], or three times daily \[TID\] \[250, 500, or 750 mg/day\]) or placebo in a 5:5:5:3 ratio. After all participants in Part 1 have completed Day 28, a data safety monitoring board (DSMB) will review the safety results from Part 1, including all available safety data through Day 60, and will recommend the dose regimen to be used in Part 2. Part 2 will randomize an additional 72 participants to the dose regimen selected from Part 1 or placebo in a 1:1 ratio.

In both parts of the study, eligible participants will be enrolled and randomized to receive active varespladib or placebo in addition to institutional standard of care for 7 days.

Participants will be assessed daily per standard of care while hospitalized and on a regular basis after discharge. The Day 1, 4, 7, 14, and 28 visits will be performed in person (either at the hospital/site or via a home health provider) to assess safety, obtain blood and urine samples for laboratory tests, and obtain clinical outcome data. The Day 2, 3, 5, 6, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 45, and 60 visits for discharged participants may be conducted by phone or via electronic patient-reported outcome (ePRO) devices.

Efficacy will be assessed by respiratory failure-free survival at Day 28. Safety will be assessed by evaluating adverse events (AEs), vital sign measurements, use of oxygen therapies, changes in levels of biomarkers, clinical laboratory test results, electrocardiograms (ECGs), physical examination findings, and concomitant medications and therapies. A DSMB will evaluate safety data at specified intervals during both parts of the trial.

Pharmacokinetic (PK) samples will be drawn from all participants in Part 1 and in a subset of approximately 14 participants in Part 2 in order to enable estimation of PK parameters in approximately 22 participants receiving active treatment with varespladib.

Eligibility Criteria:
Inclusion Criteria:

1. Participant is hospitalized with severe COVID-19 illness, defined in accordance with the Food and Drug Administration (FDA) Guidance for Industry - COVID-19: Developing Drugs and Biological Products for Treatment or Prevention (May 2020):

   a. Severe illness:

   i. Symptoms suggestive of severe systemic illness with COVID-19, which could include any symptom of moderate illness or shortness of breath at rest, or respiratory distress

   ii. Clinical signs indicative of severe systemic illness with COVID-19, such as respiratory rate ≥30 per minute, heart rate ≥125 per minute, SpO₂ ≤93% on room air at sea level or partial pressure of oxygen PaO₂/fraction of inspired oxygen FiO₂ \<300.
2. Participant has a positive virologic nucleic acid amplification test (NAAT) indicating SARS-CoV-2 infection in a sample collected \<72 hours prior to randomization.
3. Participant is between the ages of 18 and 80 years at the time of enrollment.
4. Participant provides informed consent prior to initiation of any study procedures.
5. Participant agrees to not participate in another clinical trial for the treatment of COVID 19 or SARS-CoV-2 through Day 28.
6. Participant has adequate hematologic status (in the absence of transfusion and growth factor support for at least 28 days), defined as follows:

   1. Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L
   2. Platelet count ≥75 × 10⁹/L
   3. Hemoglobin ≥9 g/dL.
7. Participant has an Eastern Cooperative Oncology Group (ECOG) performance score of 0-2.

Exclusion Criteria:

1. Participant has mild, moderate, or critical COVID-19 defined in accordance with the FDA Guidance for Industry:

   a. Mild COVID-19:

   i. Symptoms of mild illness with COVID-19 that could include fever, cough, sore throat, malaise, headache, muscle pain, gastrointestinal symptoms, without shortness of breath or dyspnea

   ii. No clinical signs indicative of moderate, severe, or critical severity

   b. Moderate COVID-19:

   i. Symptoms of moderate illness with COVID-19, which could include any symptom of mild illness (fever, cough, sore throat, malaise, headache, muscle pain, gastrointestinal symptoms) or shortness of breath with exertion

   ii. Clinical signs suggestive of moderate illness with COVID-19, such as respiratory rate ≥20 breaths per minute, peripheral oxygen saturation (SpO₂) \>93% on room air at sea level, heart rate ≥90 beats per minute

   iii. No clinical signs indicative of severe or critical illness

   c. Critical COVID-19:

   i. Respiratory failure defined based on resource utilization requiring at least one of the following:
   * Endotracheal intubation and mechanical ventilation
   * Oxygen delivered by high-flow nasal cannula (\[HFNC\] heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates \>20 L/min with fraction of delivered oxygen ≥0.5)
   * Noninvasive positive pressure ventilation
   * ECMO, or
   * Clinical diagnosis of respiratory failure (i.e., clinical need for one of the preceding therapies, but preceding therapies not able to be administered in setting of resource limitation)

   ii. Shock (defined by systolic blood pressure \<90 mmHg, or diastolic blood pressure \<60 mmHg or requiring vasopressors)

   iii. Multi-organ dysfunction/failure.
2. Participant has taken investigational medications within 7 days or 5 half-lives prior to enrollment, whichever is shorter.
3. Participant has required any new form of sedation, anxiolysis or central nervous system (CNS) depressant within the 48 hours prior to enrollment that would interfere with neurologic assessments at enrollment.
4. Has history of cerebrovascular accident or intracranial bleeding of any kind, acute coronary syndrome, myocardial infarction, or severe pulmonary hypertension.
5. Participant has chronic respiratory failure not associated with COVID-19, defined as prior need for home oxygen, need for home noninvasive positive-pressure ventilation (NIPPV) for reasons other than isolated sleep apnea, or other signs of chronic respiratory failure, in the investigator's judgment.
6. Upper gastrointestinal (GI) bleed evidenced by hematemesis, "coffee-ground" emesis or nasogastric aspirate, or hematochezia thought to originate from upper GI tract.
7. Participant has abnormal liver function defined as any 2 of the following at screening:

   1. Total bilirubin ≥2 × ULN
   2. Alanine aminotransferase (ALT) ≥3 × ULN
   3. Aspartate aminotransferase (AST) ≥3 × ULN
   4. Alkaline phosphatase (ALP) \>3 × ULN
   5. Gamma-glutamyl transferase (GGT) \>3 × ULN
8. Participant has an estimated glomerular filtration rate (eGFR) \<60 mL/min.
9. Participant has a known allergy or significant adverse reaction to varespladib-methyl or related compounds.
10. Participant is considered by the investigator to be unable to comply with protocol requirements due to geographic considerations, psychiatric disorders, or other compliance concerns; or has any serious medical condition or clinically significant laboratory, ECG, vital sign, or physical examination abnormality that would prevent study participation or place the participant at significant risk, as judged by the Investigator.
11. Participant is breast-feeding, pregnant, has a positive serum hCG pregnancy test, or is not willing to use a highly effective method of contraception for 14 days after treatment. Highly effective methods of contraception are as follows:

    1. Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal)
    2. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable)
    3. Intrauterine device, intrauterine hormone-releasing system
    4. Bilateral tubal occlusion
    5. Vasectomized partner
    6. Sexual abstinence
    7. Double-barrier method (condoms, sponge, diaphragm, with spermicidal jellies, or cream).