Managing Endothelial Dysfunction in COVID-19 : A Randomized Controlled Trial at LAUMC

NCT04631536 | Unknown Phase 3 DMC

• 1 other identifier: Lebanese American University
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

Brief Summary

COVID-19 infection was shown to cause endothelial dysfunction . At the level of the endothelium the pathophysiological mechanisms have been hypothesized and were divided into pro-coagulant, pro-inflammatory, anti-fibrinolytics, impaired barrier function, vasoconstrictor and pro-oxidant. So far, the pro-coagulant and pro-inflammatory pathways have been studied and as a result dexamethasone and anticoagulation became part of the standard therapies for the disease. However, so far, no RCT has been evaluated on targeting the vasoconstrictive and antioxidant pathways with an aim of revealing clinical benefit. So, with this trial we intend to provide a regiment composed of several medications we hypothesize will act on several downstream pathways that would improve endothelial function primarily via the increase in NO production and release. At the time of this proposal there has been no randomized trials evaluating or testing the use of cardiovascular drugs targeting endothelial dysfunction in COVID-19 patients. As previously noted there has been a call to study these drugs and their effect after a strong research regarding their theorized effectiveness. For evidence, there was a recently published meta-analysis evaluating the role of statins in COVID-19 with preliminary findings suggested a reduction in fatal or severe disease by 30% and discredited the suggestion of harm, that emphasized on the need of well-designed randomized controlled trial to confirm the role of statins in COVID-19 patients. Our study would help determine the potential therapeutic effect of the endothelial protocol as adjunct to mainstream management. This study seeks to further our knowledge in treating COVID-19 to ultimately improve clinical outcomes and reduce complications.

Conditions

Covid19

Keywords

Endothelial dysfunction; Nicorandil; Statin; Nebivolol; L-arginine; Folic acid

Outcome Measures

Primary Outcomes (1)

• Clinical Improvement

  The primary outcome was the time to recovery, defined as the first day, during the 28 days after enrollment, on which a patient met the criteria for category 1, 2, or 3 on the eight-category ordinal scale. The categories are as follows: 1, not hospitalized and no limitations of activities; 2, not hospitalized, with limitation of activities, home oxygen requirement, or both; 3, hospitalized, not requiring supplemental oxygen and no longer requiring ongoing medical care (used if hospitalization was extended for infection-control or other nonmedical reasons); 4, hospitalized, not requiring supplemental oxygen but requiring ongoing medical care (related to Covid-19 or to other medical conditions); 5, hospitalized, requiring any supplemental oxygen; 6, hospitalized, requiring noninvasive ventilation or use of high-flow oxygen devices; 7, hospitalized, receiving invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); and 8, death

  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

Secondary Outcomes (3)

• Need for ICU admission or invasive mechanical ventilation

  Assessment on daily basis for up to 1 month or until hospital discharge/death whichever came first

• All cause mortality

  assessed for up to 1 month

• Occurrence of side effects

  Assessment on daily basis after intervention given for up to 1 month or until hospital discharge/death whichever came first

Study Arms (2)

Endothelial Dysfunction Protocol

EXPERIMENTAL

Our study will evaluate the impact of the endothelial treatment protocol (atorvastatin, nicorandil, l-arginine, folic acid and nebivolol) in patients already on optimal medical therapy for the treatment of COVID0-19 virus. Endothelial dysfunction protocol + Standard of Care (dexamethasone, anticoagulation, vitamin c, zinc). 1. Atorvastatin or continue home statin Atorvastatin will be provided as a 40 mg tablet to be given PO once daily. This dose was suggested because high intensity statin has been associated with a better endothelial profile (Int J Cardiol 2017 Oct 1;244:112-118.-- Eur J Clin Pharmacol 2014 Oct;70(10):1181-93) 2. Nicorandil Nicorandil 10 mg PO BID as the recommended dose for coronary vasodilatation by the manufacturer 3. Nebivolol Nebivolol 2.5-5 mg PO ONCE daily while keeping Heart Rate (HR) between 50-90 bpm 4. Folic Acid Folic Acid 5 mg po once daily 5. L-Arginine L-Arginine 1 g po TID

Drug: Atorvastatin + L-arginine + Folic acid + Nicorandil + Nebivolol

Placebo

PLACEBO COMPARATOR

Placebo + Standard of Care (dexamethasone, anticoagulation, vitamin c, zinc)

Drug: Placebo

Interventions

Atorvastatin + L-arginine + Folic acid + Nicorandil + Nebivolol DRUG

active Comparator: Endothelial dysfunction protocol + Standard of Care (dexamethasone, anticoagulation, vitamin c, zinc). Treatment to be continued until 14 days or discharge/death whichever occurs first. It includes: Nebivolol 5 mg PO daily, Sigmart 10 mg PO twice daily, Atorvastatin 40 mg PO daily, Folic Acid 5 mg PO daily, L-arginine 1000 mg PO 3 times daily.

Also known as: Nicorandil, L-arginine, Folic acid, Nebivolol

Endothelial Dysfunction Protocol

Placebo DRUG

Placebo + Standard of Care (dexamethasone, anticoagulation, vitamin c, zinc)

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults 18 years of age and above admitted for inpatient treatment of COVID-19 infection
• PCR-confirmed COVID-19 classified as mild, moderate or with severe disease as per the FDA.
• With mild being a positive testing by standard RT-PCR assay or equivalent test and symptoms of mild illness with COVID-19 that could include fever, cough, sore throat, malaise, headache, muscle pain, gastrointestinal symptoms, without shortness of breath or dyspnea. No clinical signs indicative of Moderate, Severe, or Critical Severity.
• Moderate defined as positive testing by standard RT-PCR assay or equivalent testing and symptoms of moderate illness which could include any symptom of mild illness or shortness of breath with exertion. Clinical signs suggestive of moderate illness with COVID-19, such as respiratory rate ≥ 20 breaths per minute, saturation of oxygen (SpO2) \> 93% on room air at sea level, heart rate ≥ 90 beats per minute. No clinical signs indicative of Severe or Critical Illness Severity.
• Severe symptoms could include any symptom of moderate illness or shortness of breath at rest, or respiratory distress. Clinical signs indicative of severe systemic illness with COVID-19, such as respiratory 468 rate ≥ 30 per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on room air at sea level or 469 PaO2/FiO2 \< 300.
• No criteria for Critical Severity.
• Eligible for or taking statin

You may not qualify if:

• Participant in another RCT
• Myocarditis
• Patients who are already on beta-blockers
• Patients already on Nicorandil.
• Patients taking PDE5 inhibitors or Riociguat
• Shock as defined by SBP\<90 for more than 30 minutes not responding to IV fluids with evidence of end organ damage.
• Severe bradycardia (\<50 bpm).
• Heart block greater than first-degree (except in patients with a functioning artificial pacemaker).
• Decompensated heart failure.
• Sick sinus syndrome (unless a permanent pacemaker is in place).
• Severe hepatic impairment (Child-Pugh class C) or active liver disease.
• Unexplained persistent elevations of serum transaminases.
• Pregnancy or breastfeeding.
• Hypersensitivity to any of the medications.
• Can't take medications orally

Sponsors & Collaborators

• Lebanese American University Medical Center: lead

Study Sites (1)

LAUMCRH

Beirut, 000000, Lebanon

Location

Related Publications (18)

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MeSH Terms

Conditions

COVID-19

Interventions

Atorvastatin; Arginine; Folic Acid; Nicorandil; Nebivolol

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heptanoic Acids; Fatty Acids; Lipids; Amino Acids, Basic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Diamino; Amino Acids, Essential; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Nitrates; Organic Chemicals; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Pyridines; Ethanolamines; Amino Alcohols; Alcohols; Amines; Benzopyrans; Pyrans

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Cardiology Fellow

Study Record Dates

• First Submitted: October 28, 2020
• First Posted: November 17, 2020
• Study Start: January 10, 2021
• Primary Completion: March 29, 2022
• Study Completion: July 1, 2022
• Last Updated: February 14, 2022

Record last verified: 2022-01

Data Sharing

• IPD Sharing: Will not share

Locations

LE (1)