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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Dose Escalation and Proof-of-Concept Study to Evaluate the Safety and Efficacy of Razuprotafib in Hospitalized Subjects With Coronavirus Disease 2019

Conditions
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COVID-19, Acute Respiratory Distress Syndrome (ARDS)

Intervention / Treatment
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* Drug: Razuprotafib Subcutaneous Solution
* Drug: Placebo Subcutaneous Solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to understand and provide informed consent; Males and non-pregnant females 18 years of age or older at the time of Screening; 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; 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; 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: Inability to initiate study drug within 12 hours after randomization; Female of childbearing potential who is unable or unwilling to forego breastfeeding through Day 28; Systolic blood pressure <100 mmHg; In shock or requiring pressor support; 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); Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × the upper limit of normal (ULN); Total bilirubin >2 × ULN; Estimated glomerular filtration rate <30 mL/min or receiving hemodialysis or hemofiltration; Moribund subject not expected to survive 24 hours in the opinion of the treating clinical team; 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; 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. 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); Use of CYP2C8 inhibitors (eg, gemfibrozil, fluvoxamine, or ketoconazole); Participation in another investigational study during the present study through the last visit (Day 28); or Previous randomization in this study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: 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. Although The Data Review Committee (DRC) recommended to continue with the study after the completion of Part 1, Step 1, the Sponsor elected to discontinue the study due to business-related reasons.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Razuprotafib 10 mg<br>Active Comparator | Drug: Razuprotafib Subcutaneous Solution<br>* Up to 3 daily dose levels of Razuprotafib Subcutaneous Solution will be evaluated. Doses will be administered subcutaneously three times daily (Q8H) for 7 days.<br>* Other names: Razuprotafib 10 mg and 20 mg solution;|
| Placebo Comparator: Placebo<br>Placebo Comparator | Drug: Placebo Subcutaneous Solution<br>* Matched vehicle-controlled placebo solution will be administered subcutaneously three times daily (Q8H) for 7 days<br>* Other names: Placebo comparator;|
| Experimental: Razuprotafib 20 mg<br>Active Comparator | Drug: Razuprotafib Subcutaneous Solution<br>* Up to 3 daily dose levels of Razuprotafib Subcutaneous Solution will be evaluated. Doses will be administered subcutaneously three times daily (Q8H) for 7 days.<br>* Other names: Razuprotafib 10 mg and 20 mg solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percent of Subjects Who Were Alive and Free of Respiratory Failure Prior to Day 7 and Day 28 | All results were summarized descriptively by treatment arm and expressed as proportions, along with corresponding 95%CI of the difference between response rates, and p-values using Cochran-Mantel-Haenszel (CMH). The 95% CI will be constructed using the normal approximation method. Respiratory failure was defined as subjects who were on invasive mechanical ventilation; received oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates >20L/min with fraction of delivered oxygen ≥0.5) noninvasive positive pressure ventilation or extracorporeal membrane oxygenation; or had 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).Subjects who died prior to the study timepoint (Day 7 or Day 28) were imputed based on the worst outcome. | Baseline up to Day 7 and Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants in Each Category of the NIAID 8-point Ordinal Scale at Day 7 and Day 28 | Summary of number and percent of subjects in each category (ie, categories 1 to 8) of the NIAID 8-Point Ordinal Scale at baseline, Day 7 and Day 28. The NIAID 8-point ordinal scale includes the following grades: Death; Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); Hospitalized, on noninvasive ventilation or high-flow oxygen devices; Hospitalized, requiring supplemental oxygen; Hospitalized, not requiring supplementation oxygen - requiring ongoing medical care (COVID-19 related or otherwise); Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; Not hospitalized, limitation on activities and/or requiring home oxygen; and Not hospitalized, no limitations on activities. | Baseline, Day 7, and Day 28 | 
| The Number and Percent of Participants Who Experienced All-Cause Mortality at Day 7 and Day 28 | Analysis of the Number and Percent of Participants who Experienced All-Cause Mortality at Day 7 and Day 28 in the Full Analysis Set | Baseline up to Day 7 and Day 28 | 
| Number of Participants Who Improve by Greater or Equal to 2 Categories on the NIAID 8-point Ordinal Scale From Baseline to Day 7 and Day 28 | Analysis of number of participants who improve by >= 2 categories on the NIAID 8-point scale from baseline to Day 7 and Day 28 in the full analysis set.% = 100 x n/N', where N' = number of participants with non-missing values at baseline and the specified post-baseline visit. Participants who died prior to the Day 7 or Day 28 were imputed as 1. | Baseline to Day 7 and Day 28 | 
| Time to Return to Prehospitalization Oxygen Requirement | Summary of Time to Return to Prehospitalization Oxygen Requirement in the Intent-to-Treat Population | up to 28 days | 
| Summary of The Mean Change From Baseline in D-Dimer at Day 7 and 28 | Mean Change from baseline in systemic biomarkers of vascular leakage and inflammation (ie, D-Dimer) at Day 7 and 28 in the Full Analysis Set | at Day 7 and 28 | 
| Summary of Change From Baseline in C-Reactive Protein (CRP) at Day 7 and 28 | Change from baseline in systemic biomarkers of vascular leakage and inflammation (ie, CRP ) at Day 7 and 28 in the Full Analysis Set | at Day 7 and 28 | 
| Number of Participants Who Improve by at Least 2 Categories on the NIAID 8-point Ordinal Scale From Baseline to Day 7 and Baseline to Day 28 | Analysis of the proportion of participants who improve by >=2 categories on the NIAID 8-point scale from baseline to Day 7. % = 100 x n/N', where N' = number of participants with a non-missing values at baseline and the specified post-baseline visit. Baseline is defined as the last measurement prior to the first dose of study drug. | from baseline to Day 7 and baseline to Day 28 | 
| Number of Participants Who Were Discharged and Free of Respiratory Failure Prior to Day 7 and Day 28 | The number of participants who were discharged and free of respiratory failure at Day 7 and Day 28 were summarized by treatment arm and pooled razuprotafib (10 and 20 mg) group. | Day 7 and Day 28 | 
| Number of Participants Alive and Not Requiring Invasive Mechanical Ventilation at Any Time | Analysis of Number of Participants Alive and Not Requiring Invasive Mechanical Ventilation at Any Time Through Day 28 in the Full Analysis Set | Baseline up to Day 28 | 
| Time to Reach Grade 6, 7, or 8 on the NIAID 8-Point Ordinal Scale | The clinical status of the participants was assessed within 1 hr prior to each dose of study drug, using the NIAID 8-point ordinal scale until Day 28. After the treatment period, clinical status will be assessed once daily until Day 18, unless discharged. If the subject is discharged alive prior to Day 28, clinical status was assessed at the post-treatment observation period telephone visits only. Grade 6=hospitalized, not requiring oxygen and no longer requires ongoing medical care; Grade 7 = not hospitalized, limitation on activities and/or requiring home oxygen; and Grade 8 = not hospitalized, no limitations on activities. | From Screening through the end of the study (up to 28 days) | 
| Change in PaO2:FiO2 Ratio From Baseline to Day 7 and Baseline to Day 28 | Analysis of the change in PaO2:FiO2 ratio from baseline to Day 7 (or discharge) and baseline to Day 28 (or discharge) in the intent-to-treat population. Baseline was defined as the last measurement prior to the first dose of study drug. Baseline PaO2;FiO2 ratio value was not provided for the pooled Razuprotafib group. | Baseline up to Day 7 and Day 28 | 
| Length of Hospitalization and Not Requiring Invasive Mechanical Ventilation From Baseline to Day 7 and Day 28 (or Death) | Analysis of length of hospitalization and not requiring invasive mechanical ventilation from baseline to Day 7 and Day 28 in the intent-to-treat population. Note: The overall number of participants analyzed represents the total number of participants in each treatment group for the ITT Population. The summaries of the mean number of days from baseline included only those participants with available data. Baseline was defined as the last measurement prior to the first dose of study drug. Baseline values were not provided.The length of hospitalization was to include all days that the participant was admitted to the hospital. For participants who were discharged and readmitted to the hospital, the length of hospitalization was to include the days after readmission. Hospitalization days were counted in 24-hour periods; any partial days were counted as a whole day. | Baseline up to Day 7 and Day 28 | 
| Length of Hospitalization From Baseline to Day 7 and Day 28 (or Death) | Analysis of length of hospitalization from baseline to day 7 and day 28 (or death) in the intent-to-treat population. Baseline was defined as the last measurement prior to the first dose of study drug. Baseline values were not provided. The length of hospitalization was to include all days that the participant was admitted to the hospital. For participants who were discharged and readmitted to the hospital, the length of hospitalization was to include the days after readmission. Hospitalization days were counted in 24-hour periods; any partial days were counted as a whole day. | From Baseline to Day 7 or Day 28 (or Death) | 
| Number of Participants Who Worsen by Greater Than or Equal to 2 Categories on The NIAID 8-point Ordinal Scale From Baseline to Day 7 and Day 28 | Analysis of number of participants who worsen by >= 2 categories on the NIAID 8-point ordinal scale from baseline to Day 7 in the Full Analysis Population. % = 100 x n/N', where N' = number of participants with non-missing values at baseline and the specified post-baseline visit. Participants who died prior to the Day 7 or Day 28 were imputed as 1. | From baseline to Day 7 and Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, ARDS, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)