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

• ClinicalTrials.gov Identifier: NCT04573322
• Recruitment Status: Completed
• First Posted: October 5, 2020
• Results First Posted: April 1, 2022
• Last Update Posted: April 14, 2022
• Sponsor: Diffusion Pharmaceuticals Inc
• Information provided by (Responsible Party): Diffusion Pharmaceuticals Inc

Tracking Information

• First Submitted Date: September 29, 2020
• First Posted Date: October 5, 2020
• Results First Submitted Date: March 14, 2022
• Results First Posted Date: April 1, 2022
• Last Update Posted Date: April 14, 2022
• Actual Study Start Date: September 10, 2020
• Actual Primary Completion Date: March 17, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 30, 2022)

• Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) [ Time Frame: Up to 70 days post-study drug administration ]
  Lead-in phase: Overall summary of subjects with TEAEs
• Time to Recovery Through Day 28 [ Time Frame: 28 days ]
  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

  1. Ambulatory - No limitation of activities
  2. Ambulatory - Limitation of activities
  3. Hospitalized, Mild Disease - Hospitalized, no oxygen therapy
  4. Hospitalized, Mild Disease - Oxygen by mask or nasal prongs
  5. Hospitalized Severe Disease - Non-invasive ventilation or high-low oxygen
  6. Hospitalized Severe Disease - Intubation and mechanical ventilation
  7. Hospitalized Severe Disease - Ventilation + additional organ support (pressors, Renal Replacement Therapy (RRT), Extracorporeal Membrane Oxygenation (ECMO)
  8. Dead - Death

Original Primary Outcome Measures (submitted: September 30, 2020)

• Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) [ Time Frame: 5 days ]
  Lead-in phase: Serious adverse events and DLTs, 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: ARDS, Cough, Dyspnea, Hypoxia, Pneumonitis, Pulmonary Edema, Respiratory Failure, or Respiratory, Thoracic and Mediastinal disorders - Other.
• Time to recovery through Day 28 [ Time Frame: 28 days ]
  Randomized 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 0-9, as follows: 0. Uninfected - No clinical or virological evidence of infection

  1. Ambulatory - No limitation of activities
  2. Ambulatory - Limitation of activities
  3. Hospitalized, Mild Disease - Hospitalized, no oxygen therapy
  4. Hospitalized, Mild Disease - Oxygen by mask or nasal prongs
  5. Hospitalized Severe Disease - Non-invasive ventilation or high-low oxygen
  6. Hospitalized Severe Disease - Intubation and mechanical ventilation
  7. Hospitalized Severe Disease - Ventilation + additional organ support (pressors, Renal Replacement Therapy (RRT), Extracorporeal Membrane Oxygenation (ECMO)
  8. Dead - Death

Current Secondary Outcome Measures (submitted: March 30, 2022)

• Change From Baseline in WHO Ordinal Severity Scale as a Categorical Improvement or Worsening [ Time Frame: 7 days ]
  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

  1. Not hospitalized, no limitations on activities
  2. Not hospitalized, limitation on activities
  3. Hospitalized, no requiring supplemental oxygen
  4. Hospitalized, requiring supplemental oxygen
  5. Hospitalized, on non-invasive ventilation or high flow O2
  6. Hospitalized, on invasive mechanical ventilation or ECMO
  7. Death
• Oxygenation - Ventilator Free Days [ Time Frame: 28 days ]
  Lead-in phase: Ventilator free days in the first 28 days (to day 29).
• Hospital Length of Stay [ Time Frame: 28 days ]
  Lead-in phase: Days of treatment during the inpatient period
• Oxygenation - Time to Return to Baseline [ Time Frame: 28 days ]
  Lead-in phase: Time to return to room air or baseline oxygen requirement
• Oxygenation - Pulse Oximetry [ Time Frame: Baseline through Day 10 ]
  Lead-in phase: Blood oxygenation by recorded continuous pulse oximetry (SpO2:FiO2 ratio)

Original Secondary Outcome Measures (submitted: September 30, 2020)

• WHO Ordinal Severity Scale [ Time Frame: 28 days ]
  Proportion of subjects with WHO ordinal severity scale score of 6 or 7 at any time through Day 28
• WHO Ordinal Severity Scale - Time to Improvement [ Time Frame: 28 days ]
  Time to an improvement of one category (i.e., a 1-point improvement) from baseline
• WHO Ordinal Severity Scale - Change from Baseline [ Time Frame: 28 days ]
  • Change from baseline in WHO scale score at days 2, 4, 7, 10, 14 and 28, as a categorical improvement or worsening
  • Mean change in WHO ordinal severity scale score from baseline through days 2, 4, 7, 10, 14 and 28
• National Early Warning Score (NEWS) [ Time Frame: 28 days ]
  • The time to discharge or to a NEWS of ≤ 2 and maintained for 24 hours, whichever occurs first The NEWS score determines the degree of illness of a patient and prompts critical care intervention. The following physiological parameters are assessed on a scale of 0 to 3, with a higher score indicating a more critical condition:

  1. Respiration rate
  2. Oxygen saturation (SpO2)
  3. Air or oxygen
  4. Systolic blood pressure
  5. Pulse rate
  6. Level of consciousness or new confusion
  7. Temperature
• National Early Warning Score (NEWS) - Change from Baseline [ Time Frame: 28 days ]
  Change from baseline through days 2, 4, 7, 10, 14 and 28 in NEWS
• Mechanical Ventilation [ Time Frame: 28 days ]
  Ventilator free days in the first 28 days (to day 29).
• Mechanical Ventilation - Duration [ Time Frame: 28 days ]
  Incidence and duration of new mechanical ventilation use during the trial
• Hospitalization [ Time Frame: 28 days ]
  • Hospital length of stay by Day 29
  • ICU length of stay by Day 29
• Oxygenation [ Time Frame: 28 days ]
  • Oxygenation free days in the first 28 days from start of therapy
  • Days on extracorporeal membrane oxygenation (ECMO)
• Oxygenation - New Oxygen Use [ Time Frame: 28 days ]
  Incidence and duration of new oxygen use during the trial
• Oxygenation - Advanced Therapies [ Time Frame: 28 days ]
  Proportion on mechanical ventilation, ECMO, noninvasive ventilation and high-flow nasal cannula oxygen delivery and return to room air or baseline oxygen requirement
• Oxygenation - Time to Return to Baseline [ Time Frame: 28 days ]
  Time to return to room air or baseline oxygen requirement
• Oxygenation - Pulse Oximetry [ Time Frame: 28 days ]
  Blood oxygenation by recorded continuous pulse oximetry (SpO2:FiO2 ratio)
• Oxygenation - ABG Measurements [ Time Frame: 28 days ]
  Blood oxygenation by serial arterial blood gas measurements collected prior to the first dose of TSC and at 1 minute, 10 minutes, 30 minutes, 1.5 hours, 3 hours and 6 hours post TSC administration by calculated PaO2:FiO2 ratios
• Mortality [ Time Frame: Up to 60 days ]
  • 15-day mortality
  • 28-day mortality
  • All-cause mortality at day 29
  • In hospital mortality
  • Mortality at Day 60

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety and Efficacy of Trans Sodium Crocetinate (TSC) in SARS-CoV-2 (COVID-19) Infected Subjects
• Official Title: 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
• Brief Summary: 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

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
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Lead-in: no masking. Randomized pilot: The participants, care providers, investigators, and outcomes assessors are masked. The pharmacist, unblinded clinical research associate, and unblinded study drug administrator are not masked.

Primary Purpose: Treatment

• Condition: SARS-CoV-2 (Covid19)

Intervention

• 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 Name: TSC
• 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 Name: 0.9% Sodium Chloride (NaCl)

Study Arms

• Experimental: Lead-in 0.25 mg/kg
  0.25 mg/kg TSC, administered via IV bolus every 6 hours for up to 15 days
  Intervention: Drug: Trans Sodium Crocetinate
• Experimental: Lead-in 0.50 mg/kg
  0.50 mg/kg TSC, administered via IV bolus every 6 hours for up to 15 days
  Intervention: Drug: Trans Sodium Crocetinate
• Experimental: Lead-in 1.0 mg/kg
  1.0 mg/kg TSC, administered via IV bolus every 6 hours for up to 15 days
  Intervention: Drug: Trans Sodium Crocetinate
• Experimental: Lead-in 1.5 mg/kg
  1.5 mg/kg TSC, administered via IV bolus every 6 hours for up to 15 days
  Intervention: Drug: Trans Sodium Crocetinate
• 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
  Intervention: Drug: Trans Sodium Crocetinate
• 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
  Intervention: Drug: Normal saline

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 27, 2021): 25
• Original Estimated Enrollment (submitted: September 30, 2020): 224
• Actual Study Completion Date: April 29, 2021
• Actual Primary Completion Date: March 17, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Romania

Administrative Information

• NCT Number: NCT04573322
• Other Study ID Numbers: 100-303
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Diffusion Pharmaceuticals Inc
• Original Responsible Party: Same as current
• Current Study Sponsor: Diffusion Pharmaceuticals Inc
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Adrian Streinu Cercel, MD; National Institute of Infectious Diseases, Bucharest, Romania

• PRS Account: Diffusion Pharmaceuticals Inc
• Verification Date: April 2022