Randomized, Comparative, Clinical Trial to Evaluate Efficacy and Safety of PNB001 in Moderate COVID-19 Patients

  1. Eric Lattmann
  2. Pradnya Bhalerao
  3. BL ShashiBhushan
  4. Neeta Nargundkar
  5. Pornthip Lattmann
  6. K Sadasivan Pillai
  7. PN Balaram

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Abstract

Objective

To evaluate the efficacy and safety of PNB001 a CCK-A agonist and CCK-B antagonist, a new chemical entity with anti-inflammatory and immune stimulation properties, along with Standard of Care (SOC) in patients with moderate COVID-19 infection.

Design

Multi-center, randomized, parallel group, comparative, open label study.

Setting

Two tertiary-care hospitals in India.

Participants

Patients with laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (PCR) within 2 days of randomization, having pneumonia with no signs of severe disease (severe disease means SpO2≤94% on room air), and any two of the following signs or symptoms suggestive of COVID-19: fever, cough, dyspnea, or hypoxia.

Interventions

Patients were randomized 1:1 to receive PNB001 at an oral dose of 100 mg three times daily for 14 days with Standard of Care (PNB001+SOC) or only SOC.

Main outcome measures

The primary endpoints were mean change in the 8-point WHO Ordinal Scale score from baseline by Day 14 and mortality rate by Day 28. The key secondary endpoints were percentage of patients showing change in clinical status using the ordinal scale, improvement in inflammatory segments in X-ray chest, reduction of days of hospitalization, duration of supplemental oxygen use, days to negative PCR for COVID-19 and change in inflammation markers Interlukin-6 (IL6) and C-reactive protein (CRP) from baseline by Day 14.

Results

A total of 40 (20 in PNB 001+SOC arm and 20 in SOC arm) patients were randomized and received treatment. The primary endpoint showed significant clinical improvement from baseline to Day 14 with PNB001+SOC (0.22 Vs 1.12; P=0.0421). One patient in PNB001+SOC arm and two patients in SOC arm died (1 Vs 2; HR: 2.0 [95%CI=0.18, 22.05]; P=0.5637) by Day 28. At the end of the treatment by Day 14, more patients achieved zero ordinal scale in PNB001+SOC arm (17 Vs 12; P=0.0766). In the PNB001+SOC arm, change in mean chest X-ray score showed significant improvement (2.05 Vs 1.16; P=0.0321), and more patients quickly showed complete improvement (10 Vs 7; HR: 1.48 [95%CI=0.64, 3.44]; P=0.4309). In the PNB001+SOC arm, patients needed shorter duration of hospitalization in days (9.45 Vs 9.80) and more patients attained earlier discharge from the hospital (19 Vs 15; P=0.0486) with respect to days. The mean duration of supplemental oxygen requirement in days was shorter (5.45 Vs 7.10) and complete withdrawal from supplemental oxygen was more frequent with PNB001+SOC compared to SOC by Day 14 (17 Vs 13; P=0.1441). All patients in both the arms had negative PCR by the end of the study (18 Vs 17; P=0.6265) by similar time (7.6 Vs 7.0). Exploratory analysis done for IL-6, CRP, Neutrophil-Lymphocyte-Ratio (NLR), Platelet-Lymphocyte-Ratio (PLR) and Erythrocyte Sedimentation Rate (ESR) showed statistically significant reduction by Day 14 demonstrating PNB001’s anti-inflammatory and immunomodulatory properties. Lymphocyte and neutrophil counts also improved by Day 14. 11 adverse events (AE) in 8 patients were observed with PNB001+SOC compared to 13 AEs in 10 patients with SOC; none of the AEs in PNB001+SOC arm were related to PNB001. The most common AE were tachycardia and acute respiratory distress syndrome; there were isolated cases of hepatic enzyme elevation and hyperglycemia. Overall, safety profile was similar between PNB001+SOC and SOC arms.

Conclusions

PNB001 with standard of care showed significant clinical improvement in moderate COVID-19 patients when compared to standard of care and was well tolerated by moderate COVID-19 patients.

Trial Registration

CTRI/2020/10/028423

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  1. ScreenIT

    SciScore for 10.1101/2021.04.16.21255256: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: The study protocol was approved by independent ethics committee.
    Consent: All the patients provided written informed consent prior to study enrolment.
    RandomizationStudy Design and Conduct: This was a multi-center, randomized, parallel group, comparative, open label, clinical study to evaluate efficacy and safety of PNB001 in patients with moderate COVID-19 infection.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    All the statistical analyses were performed using SAS 9.2 or higher version software.
    SAS
    suggested: (SASqPCR, RRID:SCR_003056)

    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: We detected the following sentences addressing limitations in the study:
    Strengths and limitations of this study: This randomized clinical study assessed the comparative efficacy and safety PNB001+SOC versus SOC using comprehensive clinical endpoints in moderate COVID-19 patients. We consider that our findings are of high significance as the screened patients underwent randomization, and the baseline characteristics were similar between the treatment arms. All assessed parameters showed significant benefit or favored PNB001+SOC arm. There were a few limitations to the study. The total number of patients enrolled in the study was low, however the number was based on regulatory recommendation during approval. Study was designed as an open label study however since open label was the requirement from the regulatory agency and since endpoints were mostly objective it is unlikely to have biased the endpoint assessment. Three patients (one in treatment and two in control) had to be discontinued due to worsening of clinical condition while another 2 withdrew after randomization into the study, however, this was essential to comply with the protocol.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    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.

    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 10.1101/2021.04.16.21255256 on medRxiv
  3. Version published to 10.23880/mjccs-16000297