- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04813471
Managing Endothelial Dysfunction in Critically Ill COVID-19 Patients at LAUMCRH
Managing Endothelial Dysfunction in Critically Ill COVID-19 Patients at the Lebanese American University Medical Center- Rizk Hospital
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) is the novel pathogen responsible for coronavirus disease 2019 (COVID-19) first discovered in Wuhan, China [1]. Since its emergence in late December 2019, many pathophysiological mechanisms have been proposed with multiple pathways that involve various organ systems [2, 3]. Although considered at its emergence as a respiratory infection with manifestations ranging from lower respiratory tract infection to pneumonia and advancing to acute respiratory disease syndrome (ARDS) in its final stages, recent evidence has highlighted how disseminated the virus can be affecting almost every organ be it the heart, kidneys, or blood vessels . Recent trends in research have focused on elucidating the cardiovascular dysfunction in COVID-19 patients especially following studies showing that cardiovascular risk factors are among the most common presenting comorbidities and that cardiovascular complications of SARS-CoV-2 are among the most lethal [4-11] . Initial research revealed that the virus makes use of the angiotensin-converting enzyme 2 (ACE-2) receptor, a widely expressed receptor found in multiple cells lining the lung, heart, gastrointestinal tract, kidneys and endothelial cells to infiltrate host cells. Another prominent mechanism of infection is immune system dysregulation manifesting as a cytokine storm and inflammatory response over-activation [12, 13].
Attempts at laying out a comprehensive or unifying pathogenesis of a COVID-19 infection have singled out endothelial dysfunction as a core pathway [14]. The endothelium is a monolayer of squamous endothelial cells lining the inner surface of arteries, veins and microvasculature. The endothelium hence plays a major role in homeostasis with interactive roles in blood pressure regulation, anti-coagulation and immune protection. Moreover, it is relevant to note that the most common comorbidities that present with COVID-19 such as hypertension, diabetes, obesity and old age are all underlined by pre-existing endothelial damage or dysfunction. As such, endothelial dysfunction and oxidative stress and their relation to the manifestation and progression of COVID-19 infections has gained significant traction in recent publications [15]. This breakthrough exposes several causes of endothelial dysfunction which include direct lining attack, hypoxia, cytokine storm and suppressed endothelial nitric oxide synthase (eNOS) with concomitant nitric oxide deficiency [15]. Several studies have emphasized the role of Nitric Oxide (NO) signaling as a major regulator of vascular tone with its antioxidant, anti-inflammatory and antithrombotic activity. For example, augmenting the production of NO and its bioavailability by Nicorandil has been proposed as a potential treatment in patients with COVID 19. Nicorandil is a vasodilatory agent composed of N-[2-hydroxyethyl]-Nicotinamide Nitrate) used among patients with acute heart failure emergencies. However, it has never been tested in patients with cardiovascular complications resulting from COVID 19 [16]. Moreover, statins are cardio-protective in nature with recent reports showing that they can be beneficial in COVID-19 [17]. An important mechanism via which Statins may improve endothelial function include increasing the production of NO and subsequent vasodilation effect, along with its established major anti-inflammatory and anti-oxidant properties [17]. Vitamin B complex will be used because of the role it plays in cell functioning, energy metabolism, and proper immune function. In addition of its assistance in proper activation of the immune response, reducing pro-inflammatory cytokine levels, improving respiratory function, maintaining endothelial integrity, preventing hypercoagulability and reducing the length of stay in hospital. [18-19-20] Furthermore, eNOS overexpression leads to an increase in NO formation only when the BH4 synthase GTP-cyclohydrolase 1 (GCH-1) is also up-regulated. So, Folic Acid and L-arginine will be given to supplement our patients with BH4 (Tetrahydrobiopterin) [21]. We hypothesize that its administration along with the other previously mentioned agents would improve endothelial function in patients suffering from COVID 19 via a cumulative increase in the bioavailability of NO, and thus improving patients' outcomes
Study Type
Enrollment (Anticipated)
Phase
- Phase 3
Contacts and Locations
Study Contact
- Name: Kamal Matli, MD
- Phone Number: +9613439675
- Email: matlikamal@gmail.com
Study Locations
-
-
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Beirut, Lebanon, 000000
- Recruiting
- LAUMCRH
-
Contact:
- Georges Ghanem, MD
- Phone Number: 9611200800
- Email: georges.ghanem@laumcrh.com
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Participants must be 18 years of age or older
- Participants must have a PCR confirming COVID 19 status
- Participants must be classified as critical as per the FDA evidence of critical illness, which is defined as respiratory failure requiring at least one of the following: Endotracheal intubation and mechanical ventilation, oxygen delivered by high- flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates > 20 L/min with fraction of delivered oxygen ≥ 0.5), noninvasive positive pressure ventilation, ECMO, or clinical diagnosis of respiratory failure (i.e., clinical need for one of the preceding therapies, but preceding therapies not able to be administered in setting of resource limitation)
- Eligible for or already taking Statin
Exclusion Criteria:
- Patients who are already on statins or Nicorandil.
- Patients labeled as having mild, moderate or severe COVID-19 infection as per the FDA definitions.
- Patients with shock as defined by SBP<90 for more than 30 minutes not responding to IV fluids with evidence of end organ damage.
- Severe hepatic impairment (Child-Pugh class C) or active liver disease are absolute reasons not to be included especially those with unexplained persistent elevations of serum transaminases.
- Pregnancy or breastfeeding
- Hypersensitivity to any of the above-mentioned medications
- On Levodopa.
- Patients on PDE5 inhibitors, Riociguat
- Acute pulmonary edema
- Hypovolemia
- Leber's disease
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Endothelial Dysfunction Protocol
Experimental: Endothelial Dysfunction Protocol Our study will evaluate the impact of the endothelial treatment protocol (atorvastatin(or home statin), nicorandil, l-arginine, folic acid and vitamin B complex) in critically Ill patients already on optimal medical therapy for the treatment of COVID-19 virus. Protocol will be given for a total of 14 days or until discharge from the hospital Patients already on home statin will continue their medication or if the are eligible for statins they will recieve 40 mg tablet to be given PO once daily. Nicorandil Nicorandil 10 mg PO BID for the first 7 days and then if no contraindications escalated to 20 mg PO BID for the remaining 7 days Folic Acid Folic Acid 5 mg po once daily L-Arginine L-Arginine 1 g po TID Vitamin B complex (Becozyme) 1 ampoule IV daily |
Endothelial Protocol
Other Names:
|
No Intervention: Standard of care
Standard of Care
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Clinical Improvement
Time Frame: will followed up for a total of 28 days
|
Clinical improvement was defined as improvement of at least two points from the baseline from date of intervention administration until the date of discharge from hospital or date of death from any cause, whichever came first, assessed up to 1-month status on the six-category ordinal scale.
This scale contains the subsequent categories: (1) death (2) hospital admission requiring invasive mechanical ventilation (3) hospital admission, requiring non-invasive positive pressure ventilation (4) hospital admission, requiring oxygen (5) hospital admission, not requiring oxygen (6) discharge
|
will followed up for a total of 28 days
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Need for invasive mechanical ventilation
Time Frame: F/up for 28 days
|
F/up for 28 days
|
Length of ICU stay
Time Frame: F/up for 28 days
|
F/up for 28 days
|
Length of hospital Stay
Time Frame: F/up for 28 days
|
F/up for 28 days
|
Length of need of mechanical ventilation
Time Frame: F/up for 28 days
|
F/up for 28 days
|
All cause mortality
Time Frame: F/up for 28 days
|
F/up for 28 days
|
Occurrence of side effects
Time Frame: F/up for 28 days
|
F/up for 28 days
|
Collaborators and Investigators
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Coronavirus Infections
- Coronaviridae Infections
- Nidovirales Infections
- RNA Virus Infections
- Virus Diseases
- Infections
- Respiratory Tract Infections
- Respiratory Tract Diseases
- Pneumonia, Viral
- Pneumonia
- Lung Diseases
- COVID-19
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Arrhythmia Agents
- Antihypertensive Agents
- Vasodilator Agents
- Enzyme Inhibitors
- Antimetabolites
- Micronutrients
- Anticholesteremic Agents
- Hypolipidemic Agents
- Lipid Regulating Agents
- Hydroxymethylglutaryl-CoA Reductase Inhibitors
- Vitamins
- Hematinics
- Atorvastatin
- Folic Acid
- Vitamin B Complex
- Nicorandil
Other Study ID Numbers
- LAUMCRH
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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