Study to Evaluate the Safety, Tolerability, and Efficacy of BGE-175 in Hospitalized Adults With Coronavirus Disease 2019 (COVID-19) That Are Not in Respiratory Failure

This is a randomized, placebo-controlled, parallel-group, multicenter, double-blind study of BGE-175 administered PO or NG in participants ≥ 50 years of age and hospitalized with documented COVID-19 who are not yet in respiratory failure.

After signing informed consent, participants will be screened upon presentation at the hospital. Screening will include full physical examination, vital signs, safety laboratory evaluation, oxygen saturation, pre-diagnostics to measure prostaglandin D2 (PGD2) status, and baseline assessment of World Health Organization (WHO) Ordinal Scale for COVID-19. If confirmed that the participant qualifies for this protocol according to listed inclusion and exclusion criteria, participants will receive the first dose of study medication, PO. The participant will then receive study medication PO or NG (if intubated or unable to swallow medication) once daily, at approximately the same time each day for up to 13 additional days. Study medication will be administered in addition to standard of care deemed appropriate by the treating physician(s). Participants will be randomized to receive BGE-175 or placebo. Participants will be monitored daily for all relevant efficacy outcomes, oxygen saturation, and adverse events. Blood will be drawn periodically for safety laboratory measurements, plasma kinetics, lymphocyte subsets, C-reactive protein, and cytokines. Nasopharyngeal swabs will be collected to measure viral load. Participants will be monitored for 14 days after administration of the last dose (Day 28) and followed through Day 57.

• BGE-175 (Drug): Drug
• Placebo (Other): Placebo

Primary outcomes

• Proportion of Participants Who Have Died or Progressed to Respiratory Failure [First dose date up to Day 28]: Proportion of participants who have died or progressed to respiratory failure as defined by progressing to the need for high-flow nasal cannula O2 delivery, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO) at Day 28. The proportion of participants is represented as a percentage.

Secondary outcomes

• Proportion of Participants Experiencing Treatment-emergent Adverse Events [First dose of treatment through study Day 57]: Proportion of participants experiencing treatment-emergent adverse events as measured by the Common Terminology Criteria for Adverse Events (CTCAE) v 5.0. The proportion of participants is represented as a percentage.
• Survival [Baseline through Day 57; at Day 14, Day 28 and Day 57]: Proportion of participants surviving at Day 14, Day 28, and Day 57. The proportion of participants is represented as a percentage.
• Proportion of Subjects Who Survive Without Progression to Respiratory Failure Through Day 28 [First dose of treatment through Day 14, Day 28]: Proportion of subjects who survive without progression to respiratory failure at Day 28. The proportion of participants is represented as a percentage.
• Time to Two Successive Negative Viral Titers in Nasopharyngeal Swabs [Baseline through Day 28]: Kaplan-Meier Estimate of Time to Two Successive Negative Viral Titers in Nasopharyngeal Swab (median)
• Time to Clinical Worsening From Baseline Value (Defined by Time to ≥ 1-point Worsening on WHO Ordinal Scale for COVID-19) [First dose date up to Day 57]: Kaplan-Meier Estimate of Time to Clinical Worsening from Baseline Value. Time to clinical worsening from baseline value (defined by time to ≥ 1-point worsening on World Health Organization (WHO) Ordinal Scale for COVID-19). The ordinal scale is an assessment of the clinical status at a given day. Each day, the worst score from the previous day will be recorded. The scale is as follows: 0.) Uninfected 1.) Ambulatory with no limitation of activities 2.) Ambulatory with limitation of activities 3.) Hospitalized, mild disease with no oxygen therapy 4.) Hospitalized, mild disease with oxygen by mask or nasal prongs 5.) Hospitalized, severe disease with noninvasive ventilation or high-flow oxygen 6.) Hospitalized, severe disease with intubation and mechanical ventilation 7.) Hospitalized, severe disease with ventilation and additional organ support (pressors, renal retention therapy, extracorporeal membrane oxygenation) 8.) Death. A higher score means a worse outcome.
• Proportion of Patients Who Develop Critical COVID-19 Illness [First dose date up to Day 57]: Proportion of patients who develop critical COVID-19 illness as defined by at least one of the following: A. RF defined based on resource utilization requiring at least one of the following: Endotracheal intubation and mechanical ventilation, oxygen delivered by high-flow nasal cannula (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, clinical diagnosis 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) B. Hemodynamic compromise (defined by systolic blood pressure < 90 mm Hg, or diastolic blood pressure < 60 mm Hg or requiring vasopressors) C. Multi-organ dysfunction/failure The proportion of participants is represented as a percentage.
• Time to Clinical Improvement From Baseline Value (Defined by Time to ≥ 1-point Improvement on WHO Ordinal Scale for COVID-19 Score - Must be Maintained Through Day 28) [First dose date up to Day 28]: Kaplan-Meier Estimate of Time to Clinical Improvement from Baseline Value. Time to clinical improvement defined by time to ≥ 1-point improvement on World Health Organization (WHO) Ordinal Scale for COVID-19 - must be maintained through Day 28. The ordinal scale is an assessment of the clinical status at a given day. Each day, the worst score from the previous day will be recorded. The scale is as follows: 0.) Uninfected 1.) Ambulatory with no limitation of activities 2.) Ambulatory with limitation of activities 3.) Hospitalized, mild disease with no oxygen therapy 4.) Hospitalized, mild disease with oxygen by mask or nasal prongs 5.) Hospitalized, severe disease with noninvasive ventilation or high-flow oxygen 6.) Hospitalized, severe disease with intubation and mechanical ventilation 7.) Hospitalized, severe disease with ventilation and additional organ support (pressors, renal retention therapy, extracorporeal membrane oxygenation) 8.) Death. A higher score means a worse outcome.
• Mean Change From Baseline in WHO Ordinal Scale for COVID-19 Score [Day 14/End of Treatment, Day 28, Day 57]: Mean change from baseline in WHO Ordinal Scale for COVID-19 score World Health Organization (WHO) Ordinal Scale for COVID-19. The ordinal scale is an assessment of the clinical status at a given day. Each day, the worst score from the previous day will be recorded. The scale is as follows: 0.) Uninfected 1.) Ambulatory with no limitation of activities 2.) Ambulatory with limitation of activities 3.) Hospitalized, mild disease with no oxygen therapy 4.) Hospitalized, mild disease with oxygen by mask or nasal prongs 5.) Hospitalized, severe disease with noninvasive ventilation or high-flow oxygen 6.) Hospitalized, severe disease with intubation and mechanical ventilation 7.) Hospitalized, severe disease with ventilation and additional organ support (pressors, renal retention therapy, extracorporeal membrane oxygenation) 8.) Death. A higher score means a worse outcome.
• Number of Patients Who Had Intubation During the Study [First dose date up to Day 57]: Proportion of Patients who had Intubation during the study defined as proportion of patients who had any documented intubation during the study.
• Duration of Intubation [First dose date up to Day 57]: Duration of Intubation (first post-dosing intubation)
• Time to Discharge From Hospital Intensive Care Unit [First dose date up to Day 57]: Time from intensive care unit admission to the recorded time of intensive care unit discharge
• Number of Patients Who Had Supplemental Oxygen Administration [First dose date up to Day 57]: Proportion of patients who had any documented post-dosing supplemental O2 administration during the study.
• Duration of Supplemental Oxygen Administration [First dose date up to Day 57]: Duration of participants receiving supplemental oxygen
• Number of Patients Who Had Noninvasive Ventilation or High-flow Nasal Cannula O2 Administration [First dose date up to Day 57]: Proportion of patients who had any documented post-dosing noninvasive ventilation or high-flow nasal cannula O2 administration.
• Duration of Noninvasive Ventilation by Nonrebreather Mask or High-flow Nasal Cannula [First dose date up to Day 57]: Duration of participants receiving noninvasive ventilation by nonrebreather mask or high-flow nasal cannula
• Number of Patients Who Had Mechanical Ventilation. [First dose date up to Day 57]: Proportion of patients who had any documented post-dosing mechanical ventilation.
• Duration of Mechanical Ventilation [First dose date up to Day 57]: Duration of participants receiving mechanical ventilation
• Number of Patients Who Had Mechanical Ventilation Plus Additional Organ Support Using Vasopressors, and/or Renal Replacement Therapy and/or ECMO. [First dose date up to Day 57]: Proportion of patients who had any documented post-dosing mechanical ventilation plus additional organ support using vasopressors, and/or renal replacement therapy and/or ECMO.
• Duration of Mechanical Ventilation Plus Additional Organ Support Using Vasopressors, and/or Renal Replacement Therapy and/or ECMO [First dose date up to Day 57]: Duration of participants receiving mechanical ventilation plus additional organ support using vasopressors, and/or renal replacement therapy and/or ECMO
• Daily Ratio of Oxygen Saturation (SpO2) to Fractional Inspired O2 (SpO2/FiO2) [First dose date up to Day 28]: Daily ratio of participants' oxygen saturation (SpO2) to fractional inspired O2 (SpO2/FiO2)
• Time to Discharge From the Hospital [First dose date up to Day 57]: Length (in days) of the time of hospitalization until medical discharge
• Number of Patients With Re-hospitalization [First dose date up to Day 57]: Proportion of patients who are hospitalized again after the discharge of first hospitalization.
• Proportion of Participants Requiring Intensive Care Unit Admission [First dose date up to Day 57]: Proportion of participants admitted to hospital intensive care unit post randomization. The proportion of participants is represented as a percentage.

Sex: All, ages: 50 Years to any

Inclusion Criteria:

* Ability to voluntarily provide informed consent that is documented per local requirements
* An understanding, ability, and willingness to fully comply with study procedures and restrictions
* Hospitalized subjects with a confirmed SARS-CoV-2 infection
* Laboratory (polymerase chain reaction \[PCR\]) confirmed infection with SARS-CoV-2
* Age ≥ 50 years
* COVID-19 illness of any duration, and oxygen saturation measurements ≤ 94% over 5 minutes on room air (Note: low flow oxygen is permitted, but room air oxygen saturation must be ≤ 94%)
* Not in respiratory failure as defined by at least one of the following:

  1. Respiratory failure defined by requiring at least one of the following:

     * Endotracheal intubation and mechanical ventilation
     * Oxygen delivered by high-flow nasal cannula at flow rates > 20 L/min with fraction of delivered oxygen ≥ 0.5)
     * NIPPV
     * ECMO
     * Clinical diagnosis of respiratory failure (i.e., need for one of the preceding therapies, but preceding therapies are not being administered because it is unavailable in the current setting)
  2. Hemodynamic compromise (defined by systolic blood pressure < 90 mm Hg, or diastolic blood pressure < 60 mm Hg) or requiring vasopressors
  3. Multi-organ dysfunction/failure
* Females subjects of childbearing potential must have a negative pregnancy test at screening or pre-treatment on Day 1
* Male and female subjects of childbearing potential must agree to use methods of contraception that are consistent with local regulations for those participating in clinical studies

Exclusion Criteria:

* Participation in any other randomized, controlled clinical trial of an experimental treatment for COVID-19 (uncontrolled, compassionate use trials are allowed)
* In the opinion of the investigator, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatments
* Currently participating in a vaccination trial for SARS-CoV-2
* Known positive test for influenza A or influenza B at the time of screening
* Positive for human immunodeficiency virus (HIV) that is not controlled with current treatment
* Hepatitis B surface antigen, or Hepatitis C positive at the time of screening. Subjects who are positive for Hepatitis C but have Hepatitis C virus (HCV) RNA below the limit of quantitation may be enrolled. Subjects with Hepatitis B, but with undetectable viral load, may be enrolled.
* Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 × the upper limit of normal (ULN)
* Stage 4 severe chronic kidney disease (i.e., estimated glomerular filtration rate \[eGFR\] < 30 mL/min) or acute renal failure resulting in eGFR < 30 mL/min
* Serious comorbidity, including:

  1. Myocardial infarction (within the last month)
  2. Moderate or severe heart failure (New York Heart Association \[NYHA\] class III or IV)
  3. Acute stroke (within the last month)
  4. Uncontrolled malignancy. Uncontrolled malignancy would include cancers that are not considered in remission, or solid tumor or hematological malignancies with evidence of disease progression in the past 3 months (i.e., there is evidence of disease progression by Response Evaluation Criteria in Solid Tumours \[RECIST\] or equivalent relevant criterion for the type of malignancy), and are not considered effectively managed with ongoing treatment as determined by the investigator
  5. Recent severe thromboembolic disease or evidence of severe thromboembolic disease defined as a current large vessel thromboembolic event or a thromboembolic event within the past 3 months (e.g., deep vein thrombosis \[DVT\], pulmonary embolism, ischemic stroke, transient ischemic attack) requiring interventional treatment. This exclusion does not prohibit prophylaxis for thromboembolic events, including those considered possible with concurrent SARS-CoV-2 infection.
* History of severe allergic or anaphylactic reactions or hypersensitivity to the study drug
* Consideration by the investigator, for any reason, that the subject is an unsuitable candidate to receive study treatment

Participant flow

Outcome results

• Proportion of Participants Who Have Died or Progressed to Respiratory Failure (Primary), Count of participants, Participants: Asapiprant (BGE-175) 31; Placebo 26 (p 0.3312)
• Proportion of Participants Experiencing Treatment-emergent Adverse Events (Secondary), Count of participants, Participants: Asapiprant (BGE-175) 73; Placebo 71
• Survival (Secondary), Count of participants, Participants: Asapiprant (BGE-175) 89; Placebo 93 (p 0.4561)
• Proportion of Subjects Who Survive Without Progression to Respiratory Failure Through Day 28 (Secondary), Number, percentage of participants: Asapiprant (BGE-175) 69.5 (59.1 to 77.7); Placebo 78.6 (69.0 to 85.5) (p 0.2687)
• Time to Two Successive Negative Viral Titers in Nasopharyngeal Swabs (Secondary), Median, days: Asapiprant (BGE-175) 29 (29 to NA); Placebo 29 (29 to NA) (p 0.3977)
• Time to Clinical Worsening From Baseline Value (Defined by Time to ≥ 1-point Worsening on WHO Ordinal Scale for COVID-19) (Secondary), Median, days: Asapiprant (BGE-175) NA (NA to NA); Placebo NA (NA to NA) (p 0.2229)
• Proportion of Patients Who Develop Critical COVID-19 Illness (Secondary), Count of participants, Participants: Asapiprant (BGE-175) 34; Placebo 28 (p 0.2941)
• Time to Clinical Improvement From Baseline Value (Defined by Time to ≥ 1-point Improvement on WHO Ordinal Scale for COVID-19 Score - Must be Maintained Through Day 28) (Secondary), Median, days: Asapiprant (BGE-175) 8 (6.0 to 10.0); Placebo 6 (5.0 to 9.0) (p 0.3325)
• Mean Change From Baseline in WHO Ordinal Scale for COVID-19 Score (Secondary), Mean, score on a scale: Asapiprant (BGE-175) -1.2 +/- 2.17; Placebo -1.8 +/- 1.76 (p 0.0254)
• Number of Patients Who Had Intubation During the Study (Secondary), Count of participants, Participants: Asapiprant (BGE-175) 18; Placebo 10 (p 0.0919)
• Duration of Intubation (Secondary), Mean, Days: Asapiprant (BGE-175) 11.8 +/- 5.32; Placebo 7.8 +/- 7.96 (p 0.749)
• Time to Discharge From Hospital Intensive Care Unit (Secondary), Mean, days: Asapiprant (BGE-175) 15.7 +/- 7.67; Placebo 12.1 +/- 8.55 (p 0.1769)
• Number of Patients Who Had Supplemental Oxygen Administration (Secondary), Count of participants, Participants: Asapiprant (BGE-175) 86; Placebo 92 (p 0.2621)
• Duration of Supplemental Oxygen Administration (Secondary), Mean, days: Asapiprant (BGE-175) 14.7 +/- 17; Placebo 11.7 +/- 14.81 (p 0.2265)
• Number of Patients Who Had Noninvasive Ventilation or High-flow Nasal Cannula O2 Administration (Secondary), Count of participants, Participants: Asapiprant (BGE-175) 26; Placebo 23 (p 0.5497)
• Duration of Noninvasive Ventilation by Nonrebreather Mask or High-flow Nasal Cannula (Secondary), Mean, days: Asapiprant (BGE-175) 11.1 +/- 13.27; Placebo 5.4 +/- 7 (p 0.1172)
• Number of Patients Who Had Mechanical Ventilation. (Secondary), Count of participants, Participants: Asapiprant (BGE-175) 9; Placebo 10 (p 0.853)
• Duration of Mechanical Ventilation (Secondary), Mean, days: Asapiprant (BGE-175) 10.9 +/- 4.99; Placebo 7.7 +/- 4.88 (p 0.1991)
• Number of Patients Who Had Mechanical Ventilation Plus Additional Organ Support Using Vasopressors, and/or Renal Replacement Therapy and/or ECMO. (Secondary), Count of participants, Participants: Asapiprant (BGE-175) 14; Placebo 4 (p 0.0166)
• Duration of Mechanical Ventilation Plus Additional Organ Support Using Vasopressors, and/or Renal Replacement Therapy and/or ECMO (Secondary), Mean, days: Asapiprant (BGE-175) 8.7 +/- 5.85; Placebo 3 +/- 1.41 (p 0.1297)
• 4 more outcome measures not shown.

Adverse events

Time frame: From first dose of treatment through Study Day 57

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2021-09-07)
• Statistical Analysis Plan (PDF, 2022-06-01)

• Richard G Wilkerson, MD, Principal investigator, University of Maryland, Baltimore