Silymarin in COVID-19 Pneumonia (SCOPE)

• ClinicalTrials.gov Identifier: NCT04394208
• Recruitment Status: Unknown
• First Posted: May 19, 2020
• Last Update Posted: August 18, 2020
• Sponsor: Cairo University
• Information provided by (Responsible Party): Khaled Mohammed Korany Salem, Cairo University

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
COVID-19; Viral Pneumonia Human Coronavirus	Drug: Silymarin; Drug: Placebo	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Group 1 (Control): Includes 25 patients with COVID-19 pneumonia receiving standard of care as per Ministry of Health Protocol of Treatment + placebo Group 2 (Intervention): Includes 25 patients with COVID-19 pneumonia receiving standard of care as per Ministry of Health Protocol of Treatment + Silymarin Oral at a dose of 420 mg/day in 3 divided doses.
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Treatment
• Official Title: Trial of Silymarin in Adults With COVID-19 Pneumonia
• Actual Study Start Date: August 16, 2020
• Estimated Primary Completion Date: January 30, 2021
• Estimated Study Completion Date: February 28, 2021

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Time to clinical improvement [ Time Frame: 7-28 days ]
   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.

Secondary Outcome Measures :

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

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Contacts

Contact: Khaled Salem, MSc; +201113451163 ext 6415; khaledsalem@kasralaimy.edu.eg

Contact: Mostafa Alfishawy, Consultant; +201550079112; malfishawy@kasralainy.edu.eg

Locations

Egypt

Cairo University; Recruiting

Giza, Cairo, Egypt, 12613

Contact: Khaled Salem, MSc +201113451163 khaledsalem@kasralainy.edu.eg

Principal Investigator: Khaled Salem, Msc

Sub-Investigator: Mostafa Alfishawy, MD

Sponsors and Collaborators

Cairo University

More Information

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.

• Responsible Party: Khaled Mohammed Korany Salem, Assistant Lecturer, Cairo University
• ClinicalTrials.gov Identifier: NCT04394208
• Other Study ID Numbers: CairoU COVID-19 Study Group
• First Posted: May 19, 2020
• Last Update Posted: August 18, 2020
• Last Verified: August 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code

• 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

Keywords provided by Khaled Mohammed Korany Salem, Cairo University:

COVID-19; SARS-CoV-2; Viral Pneumonia; Drug; Silymarin; Treatment; p38 MAPK Inhibitor

Additional relevant MeSH terms:

COVID-19; Pneumonia; Pneumonia, Viral; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Silymarin; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents; Physiological Effects of Drugs