Silymarin in COVID-19 Pneumonia (SCOPE)

Trial of Silymarin in Adults With COVID-19 Pneumonia

A randomized placebo controlled trial to assess the clinical outcome in COVID-19 Pneumonia following administration of Silymarin owing to its role as a p38 MAPK pathway inhibitor and its antiviral, anti-inflammatory and anti-oxidant effects

Study Overview

• Status: Unknown
• Conditions: COVID-19; Viral Pneumonia Human Coronavirus
• Intervention / Treatment: Drug: Placebo; Drug: Silymarin

Detailed Description

To date, there are no drugs or other therapeutics approved by the U.S. Food and Drug Administration (FDA) to prevent or treat COVID-19 that has spread globally resulting in the ongoing pandemic as declared by the World Health Organization (WHO) on 11 March 2020. While the majority of patients have mild symptoms, some progress to viral pneumonia and multi-organ failure (MOF).

Older age, cardiovascular disease, diabetes mellitus, chronic respiratory illness, systemic hypertension, and malignancy are all associated with an increased risk of death in COVID-19.

In fatal cases of human severe acute respiratory syndrome-associated coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-2 infections, patients suffer from severe respiratory distress necessitating mechanical ventilation. Previous studies showed that genetic susceptibility and inflammatory cytokines (Interleukins: IL-6, 8, 10, Tumor Necrosis Factor [TNF] and Vascular endothelial growth factor [VEGF]) are closely related to the occurrence of acute respiratory distress syndrome (ARDS).

Cytokine storm is another life-threatening condition, and likely a leading cause of fatality.

Rapid viral replication and apoptosis together with virus-induced angiotensin-converting enzyme 2 (ACE-2) down-regulation and shedding and antibody-dependent enhancement (ADE) are responsible for aggressive inflammation caused by SARS-CoV-2, which is closely related to SARS-CoV; where both viruses hijack the same entry receptor ACE-2 suggesting the likelihood of the same population of cells being targeted and infected.

A Previous study demonstrated that p38 mitogen-activated protein kinase (p38 MAPK) and its downstream targets are activated in SARS-CoV infected Vero E6 cells and that activation of p38 MAPK enhances the cytopathic effects of SARS-CoV infection.

Interestingly, the p38 MAPK pathway is a key regulator of proinflammatory cytokine synthesis, which may contribute to the chronic low-grade inflammation observed with ageing. Another study hypothesized that ageing up-regulates the activation of p38 MAPK as well as the pro-inflammatory cytokines TNF-α, IL-1β and IL-6 in mouse lung and is accompanied by disturbances in oxidant-antioxidant status.

Furthermore, it was shown that p38 MAPK pathway is involved in the inflammatory response induced by cigarette smoke exposure, endotoxin and oxidative stress, through activation and release of pro-inflammatory cytokines, and it was postulated that inhibition of p38 MAPK prevented allergen-induced pulmonary eosinophilia, mucus hypersecretion and airway hyper-responsiveness.

p38 MAPK was identified as a possible target in vascular cells, which can be activated by high glucose levels and diabetes, where at moderate and commonly encountered levels of hyperglycemia, p38 MAPK appears to be activated by PKC-δ isoform-dependent processes.

Numerous preclinical studies have addressed the role of p38 MAPK in ischemic heart disease, myocardial infarction, and atherosclerosis.

Hence, The investigators of this clinical trial have concluded that p38 MAPK pathway activation could explain the increased risk of death from COVID-19 in older age, diabetes mellitus, cardiovascular disease, systemic hypertension and chronic respiratory diseases. Therefore, p38 MAPK inhibitors may play a promising role in the treatment of SARS-CoV-2 and COVID-19 improving the clinical outcomes.

Silymarin, an extract from the seed of the milk thistle plant (Silybum marianum [S. marianum]) is widely known for its hepatoprotective functions, mainly due to its anti-oxidative, anti-inflammatory, and immunomodulatory effects.

Recent studies documented the antiviral activities of Silymarin against several viruses; including flaviviruses (hepatitis C virus and dengue virus), togaviruses (Chikungunia virus and Mayaro virus), influenza virus, hepatitis B virus and Human Immunodeficiency Virus (HIV); in addition to its anti-oxidative and anti-inflammatory role.

Furthermore, a recent study demonstrated the role of Silymarin in attenuating cigarette smoke extract-induced inflammation via simultaneous inhibition of autophagy and extracellular signal-regulated kinase/p38 mitogen-activated protein kinase (ERK/ p38 MAPK) pathway in human bronchial epithelial cells, as well as attenuating up-regulation of pro-inflammatory cytokines TNF-α, IL-6 and IL-8 and concluded that Silymarin might be an ideal agent treating inflammatory pulmonary diseases.

This clinical trial aim at evaluating the role of Silymarin in the treatment of adults with COVID-19 Pneumonia

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 3

Contacts and Locations

Study Locations

• Egypt
  • Cairo
    • Giza, Cairo, Egypt, 12613
      • Recruiting
      • Cairo University
      • Contact: Khaled Salem, MSc; Phone Number: +201113451163; Email: khaledsalem@kasralainy.edu.eg
      • Principal Investigator: Khaled Salem, Msc
      • Sub-Investigator: Mostafa Alfishawy, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• COVID-19 patients with CT Chest-proven viral pneumonia with any degree of severity.

Exclusion Criteria:

• Patients < 18 years of age.
• Patients with mild symptoms (as per WHO criteria) of SARS-CoV-2

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Group 1; Patients with COVID-19 pneumonia receiving standard of care as per Ministry of Health Protocol of Treatment plus placebo	Drug: Placebo; Placebo comparator
Experimental: Group 2; patients with COVID-19 pneumonia receiving standard of care as per Ministry of Health Protocol of Treatment + Silymarin Oral 420mg/day in 3 divided doses	Drug: Silymarin; Silymarin Oral at a dose of 420 mg/day in 3 divided doses.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to clinical improvement	Defined as the time from randomization to an improvement of two points (from the status of randomization) on seven category ordinal scale or live discharge from the hospital, whichever comes first.	7-28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical outcome	Clinical status as assessed with the seven-category ordinal scale on days 7 and 14	7-14 days
Duration of Mechanical Ventilation	Time in days patient was intubated	Randomization till hospital discharge or death whichever came first, assessed up to 28 days
Hospitalization	Total days of hospitalization	Randomization till hospital discharge or death whichever came first, assessed up to 28 days
Virologic Response	number of days patient remained with positive RT-PCR SARS-CoV-2 swab	Randomization till discharge, up to 28 days
Adverse events	Any adverse events whether related to medication or not	Randomization till hospital discharge, up to 28 days

Collaborators and Investigators

• Sponsor: Cairo University

Publications and helpful links

General Publications

• Liu CH, Jassey A, Hsu HY, Lin LT. Antiviral Activities of Silymarin and Derivatives. Molecules. 2019 Apr 19;24(8):1552. doi: 10.3390/molecules24081552.
• Li D, Hu J, Wang T, Zhang X, Liu L, Wang H, Wu Y, Xu D, Wen F. Silymarin attenuates cigarette smoke extract-induced inflammation via simultaneous inhibition of autophagy and ERK/p38 MAPK pathway in human bronchial epithelial cells. Sci Rep. 2016 Nov 22;6:37751. doi: 10.1038/srep37751.

Study record dates

Study Major Dates

• Study Start (Actual): August 16, 2020
• Primary Completion (Anticipated): January 30, 2021
• Study Completion (Anticipated): February 28, 2021

Study Registration Dates

• First Submitted: May 15, 2020
• First Submitted That Met QC Criteria: May 16, 2020
• First Posted (Actual): May 19, 2020

Study Record Updates

• Last Update Posted (Actual): August 18, 2020
• Last Update Submitted That Met QC Criteria: August 16, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: SARS-CoV-2; Treatment; COVID-19; Viral Pneumonia; Drug; Silymarin; p38 MAPK Inhibitor
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; COVID-19; Pneumonia; Pneumonia, Viral; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Antioxidants; Silymarin
• Other Study ID Numbers: CairoU COVID-19 Study Group

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code

Drug and device information, study documents

• 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.: No