Trans Sodium Crocetinate (TSC) to Improve Oxygenation in COVID-19

  1. Anca Streinu-Cercel
  2. Oana Săndulescu
  3. Victor Daniel Miron
  4. Alina-Alexandra Oană
  5. Maria Magdalena Motoi
  6. Christopher D. Galloway
  7. Adrian Streinu-Cercel

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Abstract

Trans Sodium Crocetinate (TSC) is a bipolar synthetic carotenoid under development as a drug to enhance oxygenation to hypoxic tissue in addition to standard of care. TSC acts via a novel mechanism of action, improving the diffusivity of oxygen in blood plasma. Thus, it is based on physical-chemical principles, unlike most drugs which are based on biochemistry-based mechanisms. We explored the use of escalating doses and multiple daily dosing of TSC as a potential therapeutic for patients suffering from hypoxemia due to SARS-CoV-2 infection.

Methods

Individuals ≥18 years who were hospitalized with confirmed SARS-CoV-2 infection and hypoxemia, defined as SpO 2 < 94% on room air or requiring supplemental oxygen, WHO ordinal scale 3 through 7 (exclusive of Extra Corporeal Membrane Oxygenation [ECMO]) were enrolled in cohorts of six subjects, each of whom received the same dose (0.25, 0.5, 1.0, or 1.5 mg/kg) of TSC via intravenous bolus every 6 hours in addition to standard of care (SOC).

This report describes the safety and efficacy results from the lead-in phase of the study and the population pharmacokinetics (PK) analyses. Safety was assessed as the number of serious adverse events and dose-limiting toxicities (DLTs) observed with each dose. Several efficacy parameters were examined in the lead-in phase and descriptive statistics of efficacy parameters are provided. No formal statistical analyses were performed. The population PK analyses were based on previous analyses and examination of the concentration profiles, and two-compartment linear pharmacokinetic models were evaluated and validated. Covariates, including body size, age, sex, organ function, and dose level, were evaluated for inclusion into the model.

Results

TSC was well tolerated. There were no treatment emergent adverse events (TEAEs) reported. There were 2 serious adverse events (SAEs) reported during the study, neither were considered treatment-related. A total of 24 (96%) subjects survived. One subject (4.0%) died during the study as a result of an SAE (respiratory failure), and that event was determined to be due to COVID-19 complications and not related to study drug.

There was an observed reduction in the time to improvement in WHO Ordinal Scale with increasing dose. The median time to 1-point reduction in subjects receiving 0.25 mg/kg was 11.5 days versus 7.5 days in the 1.5 mg/kg treatment cohort. The overall range across all doses was 1 day to 28 days. A total of 36.0% of subjects had a 1-point improvement in WHO Ordinal Scale to Day 7. The 1.5 mg/kg dose resulted in observed superior outcomes for multiple secondary clinical outcomes: time to 1-point WHO Ordinal Score improvement through Day 29/discharge, 1-point improvement by Day 7, days to return to room air, and hospital length of stay.

The PK results showed that the two-compartment model fit the data well. Clearance decreased with increasing dose level and there was no evidence that clearance was affected by covariates other than dose level.

Conclusions

These findings suggest that TSC administration every 6 hours at doses up to 1.5 mg/kg for up to 15 days is safe and well tolerated with predictable pharmacokinetics and demonstrated an observed clinical benefit in the treatment of COVID-19-related hypoxemia.

( ClinicalTrials.gov number, NCT04573322 )

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  1. ScreenIT

    SciScore for 10.1101/2021.10.08.21264719: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIRB: Ethics Statement: The study was conducted in accordance with the general ethical principles as enunciated in the Declaration of Helsinki (1996) and in conformance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidance and applicable Health Authority and local requirements regarding Institutional Review Boards, Independent Ethics Committees, informed consent, and other statutes or regulations related to the rights and welfare of human subjects participating in biomedical research.
    Consent: Ethics Statement: The study was conducted in accordance with the general ethical principles as enunciated in the Declaration of Helsinki (1996) and in conformance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidance and applicable Health Authority and local requirements regarding Institutional Review Boards, Independent Ethics Committees, informed consent, and other statutes or regulations related to the rights and welfare of human subjects participating in biomedical research.
    Sex as a biological variablenot detected.
    RandomizationTrial Design: The study was designed to have two phases: an open-label lead-in phase and a randomized placebo-controlled phase.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    The analyses were conducted with NONMEM software.
    NONMEM
    suggested: (NONMEM, RRID:SCR_016986)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04573322RecruitingSafety and Efficacy of Trans Sodium Crocetinate (TSC) in SAR…

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • No funding statement was detected.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2021.10.08.21264719v1 on medRxiv