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

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.