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

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

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

Study Overview

• Status: Completed
• Conditions: SARS-CoV-2 (Covid19)
• Intervention / Treatment: Drug: Trans Sodium Crocetinate; Drug: Normal saline

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Romania
  • Bucharest, Romania, 021105
    • National Institute of Infectious Diseases- Prof. Dr. Matei Balş

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Hospitalized subjects with confirmed SARS-CoV-2 infection and hypoxemia, defined as SpO2 < 94% on room air or requiring supplemental oxygen
2. 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.
3. WHO ordinal scale score of 3, 4 or 5 at baseline
4. Male or non-pregnant female adult ≥18 years of age at time of enrolment.
5. Subject (or legally authorized representative (LAR)) provides written informed consent prior to initiation of any study procedures.
6. Understands and agrees to comply with planned study procedures.
7. Illness of any duration
8. 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:

1. Intubated and mechanically ventilated at baseline
2. Receiving extracorporeal membrane oxygenation (ECMO) at baseline
3. Severe organ dysfunction (SOFA score > 10)
4. Patient or LAR unable to provide written informed consent
5. ALT/AST > 3 times the upper limit of normal or serum bilirubin > 1.5 times the upper limit of normal
6. Estimated glomerular filtration rate (eGFR) by Modification of Diet in Renal Disease (MDRD) formula < 30 mL/min/1.73 m^2 or on dialysis
7. Pregnancy or breast feeding.
8. Anticipated transfer to another hospital which is not a study site within 72 hours.
9. Allergy to any study medication

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lead-in 0.25 mg/kg; 0.25 mg/kg TSC, administered via IV bolus every 6 hours for up to 15 days	Drug: Trans Sodium Crocetinate; 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; Other Names: TSC
Experimental: Lead-in 0.50 mg/kg; 0.50 mg/kg TSC, administered via IV bolus every 6 hours for up to 15 days	Drug: Trans Sodium Crocetinate; 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; Other Names: TSC
Experimental: Lead-in 1.0 mg/kg; 1.0 mg/kg TSC, administered via IV bolus every 6 hours for up to 15 days	Drug: Trans Sodium Crocetinate; 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; Other Names: TSC
Experimental: Lead-in 1.5 mg/kg; 1.5 mg/kg TSC, administered via IV bolus every 6 hours for up to 15 days	Drug: Trans Sodium Crocetinate; 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; Other Names: TSC
Experimental: Randomized Active TSC; 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; 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; Other Names: TSC
Placebo Comparator: Randomized Placebo; 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; Normal Saline, in an equivalent volume by participant body weight, administered via IV bolus every 6 hours for up to 15 days; Other Names: 0.9% Sodium Chloride (NaCl)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Diffusion Pharmaceuticals Inc
• Investigators: Principal Investigator: Adrian Streinu Cercel, MD, National Institute of Infectious Diseases, Bucharest, Romania

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2020
• Primary Completion (Actual): March 17, 2021
• Study Completion (Actual): April 29, 2021

Study Registration Dates

• First Submitted: September 29, 2020
• First Submitted That Met QC Criteria: September 30, 2020
• First Posted (Actual): October 5, 2020

Study Record Updates

• Last Update Posted (Actual): April 14, 2022
• Last Update Submitted That Met QC Criteria: April 12, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Hypoxia; Hypoxemia
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Protective Agents; Antioxidants; Anticarcinogenic Agents; Trans-sodium crocetinate
• Other Study ID Numbers: 100-303

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes