Clinical and Non-clinical Proof of Concept Supporting the Development of RJX As an Adjunct to Standard of Care Against Severe COVID-19
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (ScreenIT)
Abstract
Background
The identification of effective strategies capable of reducing the case mortality rate of high-risk COVID-19 is an urgent and unmet medical need. We recently reported the clinical safety profile of RJX, a well-defined intravenous GMP-grade pharmaceutical formulation of anti-oxidant and anti-inflammatory vitamins as active ingredients, in a Phase 1 study in healthy volunteers ( ClinicalTrials.gov Identifier: NCT03680105 ) (Uckun et al., Front. Pharmacol. 11, 594321. 10.3389/fphar.2020.594321). Here we report data from a pilot clinical study (RPI-015) which examined the safety, tolerability, and feasibility of using RJX in combination with clinical standard of care (SOC) in hospitalized COVID-19 patients with pneumonia ( ClinicalTrials.gov Identifier: NCT04708340 ). In addition to our early clinical proof of concept (POC) data, we also present non-clinical POC from a mouse model of CRS and ARDS that informed the design of the reported clinical study.
Methods
13 patients, who were hospitalized with COVID-19 pneumonia and abnormally elevated serum inflammatory biomarkers markers ≥3 months prior to the identification of the first confirmed U.S case of the Omicron variant, were treated with IV RJX (daily x 7 days) plus SOC. Non-clinical POC study examined the ability of RJX plus dexamethasone (DEX) to improve the survival outcome in the lipopolysaccharide (LPS)-Galactosamine (GalN) mouse model of fatal cytokine release syndrome (CRS), sepsis and acute respiratory distress syndrome (ARDS).
Findings
In the Phase 1 clinical study, none of the 13 patients developed a treatment-related DLT, SAE, or Grade 3-5 AEs. Nine (9) of the 12 evaluable patients, including 3 patients with hypoxemic respiratory failure, showed rapid clinical recovery. In the non-clinical POC study in LPS-GalN challenged mice, the combination of RJX plus DEX was more effective than RJX alone or DEX alone, reversed the CRS as well as inflammatory tissue damage in the lungs and liver, and improved the survival outcome. Taken together, these findings provide the early clinical and non-clinical POC for the development of RJX as an adjunct to the SOC in the multi-modality management of high-risk COVID-19.
Article activity feed
-
SciScore for 10.1101/2022.02.12.22270748: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: One Cohort 2 patient withdrew consent on day 4 and was replaced with a new patient to have a total of 6 patients evaluable for response.
IRB: The study protocol was approved by the WCG-Central Institutional Review Board (IRB) (OHRP/FDA Parent Organization number: IORG0000432; OHRP/FDA IRB registration number: IRB00000533).
IACUC: The study was approved by the Animal Care and Use Committee of Firat University (Number: 420629).Sex as a biological variable Thirteen hospitalized adult patients with severe or critical COVID-19, including 8 males and 5 females with a median age of 46 years (Range: 24-72 years) of whom 11 were White (Hispanic or Latino) and 2 were Asian (not Hispanic or … SciScore for 10.1101/2022.02.12.22270748: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: One Cohort 2 patient withdrew consent on day 4 and was replaced with a new patient to have a total of 6 patients evaluable for response.
IRB: The study protocol was approved by the WCG-Central Institutional Review Board (IRB) (OHRP/FDA Parent Organization number: IORG0000432; OHRP/FDA IRB registration number: IRB00000533).
IACUC: The study was approved by the Animal Care and Use Committee of Firat University (Number: 420629).Sex as a biological variable Thirteen hospitalized adult patients with severe or critical COVID-19, including 8 males and 5 females with a median age of 46 years (Range: 24-72 years) of whom 11 were White (Hispanic or Latino) and 2 were Asian (not Hispanic or Latino) were enrolled in one of the 2 cohorts of the clinical study within 0-11 days (Median: 4 days; Mean ± SE=4.5±1.0) days after initial COVID-19 diagnosis (Table S2). Randomization Study Design and Eligibility Criteria: The safety, tolerability, and feasibility of using RJX in combination with clinical standard of care for hospitalized COVID-19 patients were evaluated in an open-label pilot study that was Part 1 of an ongoing double-blind, randomized, Phase 1/2 Study (ClinicalTrials.gov Identifier: NCT04708340). Blinding As in previous studies, we applied the concealment of treatment allocation and blind outcome assessment to reduce the risk of bias [26]. Power Analysis not detected. Table 2: Resources
Experimental Models: Organisms/Strains Sentences Resources LPS-GalN model of fatal cytokine storm and sepsis: The therapeutic activities of RJX, DEX, and RJX plus DEX were compared side by side in the LPS-GalN model of fatal CRS, sepsis and ARDS using male BALB/c mice, as previously described [26]. BALB/csuggested: RRID:IMSR_ORNL:BALB/cRl)Software and Algorithms Sentences Resources Statistical analysis of Non-Clinical Data: Statistical analyses were performed using standard methods and the SPSS statistical program (IBM, SPPS Version 21), as previously reported [26]. SPSSsuggested: (SPSS, RRID:SCR_002865)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:
Identifier Status Title NCT03680105 Completed A Safety and Tolerability Study of RJX Drug Product in Healt… NCT04708340 Active, not recruiting Tolerability and Efficacy of RJX in Patients With COVID-19 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.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
-
