Evaluation of the Safety and Efficacy of Razuprotafib in Hospitalized Subjects With Coronavirus Disease 2019

This was a Phase 2, randomized, double-blind, placebo-controlled, parallel-group, multicenter, dose escalation and proof-of-concept study to evaluate the safety and efficacy of razuprotafib, administered 3 times daily (TID) (every 8 hours \[Q8H\]), in hospitalized subjects with moderate to severe Coronavirus disease 2019 (COVID-19) receiving standard of care therapy.

The study was planned to include 2 parts with Part 1 comprising the dose escalation period of the study and Part 2 comprising the proof-of-concept safety and efficacy period of the study.

Part 1 was to be a 2-step dose escalation that included approximately 60 subjects. Part 1, Step 1 was to include 30 subjects, and Part 1, Step 2 was to include 30 subjects. Part 1 was designed to primarily focus on safety; however, efficacy data was to be collected and analyzed as well.

Despite the Data Review Committee (DRC) recommendation to continue the study, after completion of Part 1, Step 1, the Sponsor elected to discontinue the study due to business-related reasons. Recruitment challenges and slow site startup led to delays in completing the study in a practical timeframe, and were the primary reasons to discontinue the study. No further subjects were recruited after Part 1, Step 1 completion. A full analysis of the data from Part 1, Step 1 was conducted and is presented in this report.

Part 1, Step 2 and Part 2 was not conducted.

Eligibility Criteria:
Inclusion Criteria:

1. Ability to understand and provide informed consent;
2. Males and non-pregnant females 18 years of age or older at the time of Screening;
3. Laboratory-confirmed active SARS-CoV-2 infection within 72 hours prior to randomization, or (if testing results cannot be obtained) by evidence of progressive disease suggestive of ongoing SARS-CoV-2 infection;
4. Females of childbearing potential must be willing to completely abstain or agree to use a highly effective method of contraception through Day 28; and have a negative urine pregnancy test during Screening;
5. Currently hospitalized, receiving standard of care therapy for COVID-19, and meets the criteria for moderate or severe COVID-19, as follows: Moderate = symptoms of moderate illness with COVID-19, which could include any symptom of mild illness or shortness of breath with exertion and with respiratory rate at 20 or greater breaths/min, Peripheral capillary oxygen saturation (SpO2) \>93% on room air at sea level, or heart rate at 90 or greater beats/min; Severe = symptoms suggestive of severe systemic illness with COVID-19, which could include any symptom of moderate illness, shortness of breath at rest, or respiratory distress, and respiratory rate at 30 or greater breaths/min, heart rate at 125 or greater beats/min, or SpO2 \>93% on room air at sea level or (partial pressure of oxygen:fraction of inspired oxygen (PaO2:FiO2) \<300.

Exclusion Criteria:

1. Inability to initiate study drug within 12 hours after randomization;
2. Female of childbearing potential who is unable or unwilling to forego breastfeeding through Day 28;
3. Systolic blood pressure \<100 mmHg;
4. In shock or requiring pressor support;
5. Respiratory failure, defined as subjects who are on mechanical ventilation; are receiving 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 of 0.5 or greater), noninvasive positive pressure ventilation, or extracorporeal membrane oxygenation (ECMO); or have a clinical diagnosis of respiratory failure (ie, clinical need for 1 of the preceding therapies, but preceding therapies not able to be administered in setting of resource limitation);
6. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>3 × the upper limit of normal (ULN);
7. Total bilirubin \>2 × ULN;
8. Estimated glomerular filtration rate \<30 mL/min or receiving hemodialysis or hemofiltration;
9. Moribund subject not expected to survive 24 hours in the opinion of the treating clinical team;
10. Any concurrent serious medical condition (eg, active malignancies on chemotherapy, post organ transplant, end stage congestive heart failure) or not likely to respond to treatment;
11. Decision to withhold life-sustaining treatment; Note: In the event of cardiac arrest, the decision to withhold cardiopulmonary resuscitation only does not fulfill this exclusion criterion.
12. Use of cytochrome P450 (CYP) 2 subfamily C, polypeptide 8 (2C8) substrates (eg, repaglinide, paclitaxel, or cerivastatin) or CYP3A4 substrates (eg, amlodipine, budesonide, dasabuvir, enzalutamide, imatinib, lopinavir, loperamide, saquinavir, sildenafil, midazolam, or montelukast);
13. Use of CYP2C8 inhibitors (eg, gemfibrozil, fluvoxamine, or ketoconazole);
14. Participation in another investigational study during the present study through the last visit (Day 28); or
15. Previous randomization in this study.