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Silymarin in COVID-19 Pneumonia (SCOPE)

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ClinicalTrials.gov Identifier: NCT04394208
Recruitment Status : Not yet recruiting
First Posted : May 19, 2020
Last Update Posted : July 14, 2020
Sponsor:
Information provided by (Responsible Party):
Khaled Mohammed Korany Salem, Cairo University

Tracking Information
First Submitted Date  ICMJE May 15, 2020
First Posted Date  ICMJE May 19, 2020
Last Update Posted Date July 14, 2020
Estimated Study Start Date  ICMJE August 1, 2020
Estimated Primary Completion Date September 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 16, 2020)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 16, 2020)
  • Clinical outcome [ Time Frame: 7-14 days ]
    Clinical status as assessed with the seven-category ordinal scale on days 7 and 14
  • 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
  • Hospitalization [ Time Frame: Randomization till hospital discharge or death whichever came first, assessed up to 28 days ]
    Total days of hospitalization
  • Virologic Response [ Time Frame: Randomization till discharge, up to 28 days ]
    number of days patient remained with positive RT-PCR SARS-CoV-2 swab
  • Adverse events [ Time Frame: Randomization till hospital discharge, up to 28 days ]
    Any adverse events whether related to medication or not
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Silymarin in COVID-19 Pneumonia
Official Title  ICMJE Trial of Silymarin in Adults With COVID-19 Pneumonia
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
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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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
Condition  ICMJE
  • COVID-19
  • Viral Pneumonia Human Coronavirus
Intervention  ICMJE
  • Drug: Silymarin
    Silymarin Oral at a dose of 420 mg/day in 3 divided doses.
  • Drug: Placebo
    Placebo comparator
Study Arms  ICMJE
  • Placebo Comparator: Group 1
    Patients with COVID-19 pneumonia receiving standard of care as per Ministry of Health Protocol of Treatment plus placebo
    Intervention: Drug: Placebo
  • 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
    Intervention: Drug: Silymarin
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: May 16, 2020)
50
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 30, 2020
Estimated Primary Completion Date September 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Khaled Salem, MSc +201113451163 ext 6415 khaledsalem@kasralaimy.edu.eg
Contact: Mostafa Alfishawy, Consultant +201550079112 malfishawy@kasralainy.edu.eg
Listed Location Countries  ICMJE Egypt
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04394208
Other Study ID Numbers  ICMJE CairoU COVID-19 Study Group
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Supporting Materials: Analytic Code
Responsible Party Khaled Mohammed Korany Salem, Cairo University
Study Sponsor  ICMJE Cairo University
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Cairo University
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP