Safety and Efficacy of Trans Sodium Crocetinate (TSC) in SARS-CoV-2 (COVID-19) Infected Subjects

Study Overview
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Brief Summary
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This study will assess the safety and efficacy of TSC as a treatment for participants who are infected with SARS-CoV-2 (COVID-19).

Detailed Description
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This trial has two phases. The first phase is an open-label, pharmacokinetic, pharmacodynamic, ascending dose, safety and tolerability lead-in. The second phase is a single-center, randomized, placebo-controlled, double-blind, adaptive, safety and efficacy, pilot. The lead-in phase will study 4 doses of TSC and enroll 24 participants. Each TSC dose will be administered as an IV bolus injection to 6 unique participants per dose level administered four times per day (every 6 hours) for 5 days. Participants will be assigned in groups of 3, and a Safety Monitoring Committee (SMC) will review Dose Limiting Toxicities (DLTs) after each group of 3 participants. The first group of 3 participants will receive TSC at a dose of 0.25 mg/kg. If there are no DLTs, 3 additional subjects will be studied at 0.25 mg/kg. If there are 0 or 1 DLT among the 6 participants studied at 0.25mg/kg, 3 additional participants will be studied at the next higher dose, 0.5 mg/kg. If there are no DLTs an additional 3 participants will be studied at 0.5 mg/kg. If there are 0 or 1 DLTs among the 6 subjects studied at 0.5 mg/kg, 3 additional participants will be studied at the next higher dose, 1.0 mg/kg. The study will continue in this fashion seeking an observed toxicity rate that is < 0.33 among 6 participants at any one dose level, or TSC at 1.5 mg/kg proves to be safe and tolerable. As participants complete the initial 5 days of treatment they will continue at their assigned TSC dose four times per day (every 6 hours) for up to 15 days. Participants will be assigned to dose levels in ascending order. The dose range is as follows. 0.25 mg/kg TSC + Standard of Care 0.50 mg/kg TSC + Standard of Care 1.00 mg/kg TSC + Standard of Care 1.50 mg/kg TSC + Standard of Care At the completion of the lead-in the Safety Monitoring Committee (SMC) will examine the resultant safety and blood oxygenation (S:F) data for all participants and determine the optimum, safe and tolerable dose of TSC for use in the pilot study. Dose Limiting Toxicity (DLT) is defined as any study drug related grade 3 or 4 adverse event during the treatment period, with the exception of pulmonary events in the CTCAE that are known complications of SARS-CoV-2 infection: Acute Respiratory Distress Syndrome (ARDS), Cough, Dyspnea, Hypoxia, Pneumonitis, Pulmonary Edema, Respiratory Failure, or Respiratory, Thoracic and Mediastinal disorders - Other. The SMC will apply clinical judgement in their review of adverse events (particularly abnormal laboratory results). The two arm, randomized pilot will enroll up to 200 participants, and will be overseen by a Data Safety Monitoring Board (DSMB). TSC dosing will be at the selected optimum, safe and tolerable biologic dose with an active to placebo ratio of 2:1 toward providing the maximum potential benefit to participants. If two doses of TSC are to be studied in the randomized pilot the active to placebo ratio will be 2:2:1. Randomization will be stratified by disease severity, age and presence of pre-specified comorbidities. The treatment arms are as follows. TSC + Standard of Care Placebo + Standard of Care Each TSC dose will be administered as an IV bolus injection 4 times per day (every 6 hours) for up to 15 days. Participants randomized to placebo will receive an IV bolus injection of an equivalent volume by participant weight of Normal Saline four times per day (every 6 hours) for up to 15 days. All study drug administration will be performed by unblinded medical staff. Participants, investigators and caregivers will not see the injection or injection site or be aware of randomization. Blood oxygenation will be measured via recorded continuous pulse oximetry and the SpO2:Fraction of Inspired Oxygen (FiO2) ratio calculated. All participants will undergo safety and efficacy assessments including laboratory assays, blood sampling on days 1 through day 15 (while hospitalized) and day 29 by return clinic visit or if still hospitalized. All participants, whether a part of the lead-in phase or randomized pilot, will be assessed for survival, serious adverse events and adverse events by requested return to the clinic on Day 60.

Official Title
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Open-label, Pharmacokinetic, Pharmacodynamic, Ascending Dose Safety lead-in Followed by a Single-center, Placebo-controlled, Double-blind, Adaptive, Safety and Efficacy, Pilot Study of Trans Sodium Crocetinate (TSC) in SARS-CoV-2 Infected Subjects

Conditions
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SARS-CoV-2 (Covid19)

Intervention / Treatment
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* Drug: Trans Sodium Crocetinate
* Drug: Normal saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hospitalized subjects with confirmed SARS-CoV-2 infection and hypoxemia, defined as SpO2 < 94% on room air or requiring supplemental oxygen Laboratory-confirmed SARS-CoV-2 infection as determined by PCR, or other commercial or public health assay in any specimen < 72 hours prior to enrollment. WHO ordinal scale score of 3, 4 or 5 at baseline Male or non-pregnant female adult ≥18 years of age at time of enrolment. Subject (or legally authorized representative (LAR)) provides written informed consent prior to initiation of any study procedures. Understands and agrees to comply with planned study procedures. Illness of any duration Women of childbearing potential must have a negative blood pregnancy test at the screening/baseline visit (Day 1) and agree to use a double method of birth control through 30 days after the last dose of study drug. Exclusion Criteria: Intubated and mechanically ventilated at baseline Receiving extracorporeal membrane oxygenation (ECMO) at baseline Severe organ dysfunction (SOFA score > 10) Patient or LAR unable to provide written informed consent ALT/AST > 3 times the upper limit of normal or serum bilirubin > 1.5 times the upper limit of normal Estimated glomerular filtration rate (eGFR) by Modification of Diet in Renal Disease (MDRD) formula < 30 mL/min/1.73 m^2 or on dialysis Pregnancy or breast feeding. Anticipated transfer to another hospital which is not a study site within 72 hours. Allergy to any study medication

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: Parallel Assignment
Interventional Model Description: Open-label, pharmacokinetic, pharmacodynamic, ascending dose, safety and tolerability lead-in Single-center, randomized, placebo-controlled, double-blind, adaptive, safety and efficacy pilot
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lead-in 0.25 mg/kg<br>0.25 mg/kg TSC, administered via IV bolus every 6 hours for up to 15 days | Drug: Trans Sodium Crocetinate<br>* TSC, at the optimum safe and tolerable dose determined in the lead-in phase, administered via IV bolus every 6 hours for up to 15 days<br>* Other names: TSC;|
| Experimental: Lead-in 0.50 mg/kg<br>0.50 mg/kg TSC, administered via IV bolus every 6 hours for up to 15 days | Drug: Trans Sodium Crocetinate<br>* TSC, at the optimum safe and tolerable dose determined in the lead-in phase, administered via IV bolus every 6 hours for up to 15 days<br>* Other names: TSC;|
| Experimental: Lead-in 1.0 mg/kg<br>1.0 mg/kg TSC, administered via IV bolus every 6 hours for up to 15 days | Drug: Trans Sodium Crocetinate<br>* TSC, at the optimum safe and tolerable dose determined in the lead-in phase, administered via IV bolus every 6 hours for up to 15 days<br>* Other names: TSC;|
| Experimental: Lead-in 1.5 mg/kg<br>1.5 mg/kg TSC, administered via IV bolus every 6 hours for up to 15 days | Drug: Trans Sodium Crocetinate<br>* TSC, at the optimum safe and tolerable dose determined in the lead-in phase, administered via IV bolus every 6 hours for up to 15 days<br>* Other names: TSC;|
| Experimental: Randomized Active TSC<br>TSC, at the optimum safe and tolerable dose determined in the lead-in phase, administered via IV bolus every 6 hours for up to 15 days | Drug: Trans Sodium Crocetinate<br>* TSC, at the optimum safe and tolerable dose determined in the lead-in phase, administered via IV bolus every 6 hours for up to 15 days<br>* Other names: TSC;|
| Placebo Comparator: Randomized Placebo<br>Normal Saline, in an equivalent volume by participant body weight, administered via IV bolus every 6 hours for up to 15 days | Drug: Normal saline<br>* Normal Saline, in an equivalent volume by participant body weight, administered via IV bolus every 6 hours for up to 15 days<br>* Other names: 0.9% Sodium Chloride (NaCl);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Lead-in phase: Overall summary of subjects with TEAEs | Up to 70 days post-study drug administration | 
| Time to Recovery Through Day 28 | Lead-in phase: Time to achieve (and maintain through Day 28) a World Health Organization (WHO) ordinal COVID-19 severity scale score of 1, 2 or 3 with a minimum 1-point improvement from baseline. The scale assesses clinical status and the range is 0-8, as follows: 0. Uninfected - No clinical or virological evidence of infection Ambulatory - No limitation of activities Ambulatory - Limitation of activities Hospitalized, Mild Disease - Hospitalized, no oxygen therapy Hospitalized, Mild Disease - Oxygen by mask or nasal prongs Hospitalized Severe Disease - Non-invasive ventilation or high-low oxygen Hospitalized Severe Disease - Intubation and mechanical ventilation Hospitalized Severe Disease - Ventilation + additional organ support (pressors, Renal Replacement Therapy (RRT), Extracorporeal Membrane Oxygenation (ECMO) Dead - Death | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in WHO Ordinal Severity Scale as a Categorical Improvement or Worsening | Lead-in phase: Number and percentage of patients by WHO Severity Scale change from baseline through Day 7 World Health Organization (WHO) Ordinal Severity Scale Not hospitalized, no limitations on activities Not hospitalized, limitation on activities Hospitalized, no requiring supplemental oxygen Hospitalized, requiring supplemental oxygen Hospitalized, on non-invasive ventilation or high flow O2 Hospitalized, on invasive mechanical ventilation or ECMO Death | 7 days | 
| Oxygenation - Ventilator Free Days | Lead-in phase: Ventilator free days in the first 28 days (to day 29). | 28 days | 
| Hospital Length of Stay | Lead-in phase: Days of treatment during the inpatient period | 28 days | 
| Oxygenation - Time to Return to Baseline | Lead-in phase: Time to return to room air or baseline oxygen requirement | 28 days | 
| Oxygenation - Pulse Oximetry | Lead-in phase: Blood oxygenation by recorded continuous pulse oximetry (SpO2:FiO2 ratio) | Baseline through Day 10 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypoxemia, Hypoxia