Managing Endothelial Dysfunction in COVID-19 : A Randomized Controlled Trial at LAUMC (MEDIC-LAUMC)
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|ClinicalTrials.gov Identifier: NCT04631536|
Recruitment Status : Not yet recruiting
First Posted : November 17, 2020
Last Update Posted : January 8, 2021
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.
|Condition or disease||Intervention/treatment||Phase|
|Covid19||Drug: Atorvastatin + L-arginine + Folic acid + Nicorandil + Nebivolol Drug: Placebo||Phase 3|
Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) is the novel pathogen responsible coronavirus disease 2019 (COVID-19) first discovered in Wuhan, China. Since its emergence in late December 2019, many pathophysiological mechanisms have been proposed with multiple pathways that involve various organ systems . 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 . Initial research revealed that the virus makes use of the angiotensin-converting enzyme 2 (ACE-2) receptor to infiltrate host cells. With the ACE-2 receptor being a widely expressed receptor found in multiple cells lining the lung, heart, gastrointestinal tract, kidneys and endothelial cells. Another prominent mechanism of infection is immune system dysregulation manifesting as a cytokine storm and inflammatory response over-activation.
Attempts at laying out a comprehensive or unifying pathogenesis of a COVID-19 infection have singled out endothelial dysfunction as a core pathway. The endothelium in summary is monolayer lining the 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 thus 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 gain significant traction in recent publications. 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. Several studies have emphasized the role of NO signaling as a major regulator of vascular tone and 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 (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 . Statins are cardioprotective in nature with recent reports showing that they can be beneficial in COVID-19 . 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 . Nebivolol, a cardio-selective beta blocker has also shown non-adrenergic vasodilating properties via the release of NO along with antioxidative and anti-atherosclerotic activities. Furthermore, eNOS overexpression leads to an increase in NO formation only when the BH4 synthase GTP-cyclohydrolase 1 (GCH-1) is alsoup-regulated. So, Folic Acid and L-arginine will be given to supplement our patients with BH4 . 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 Nitric Oxide (NO), and thus improving patients' outcomes
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||80 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Double (Participant, Care Provider)|
|Official Title:||Managing Endothelial Dysfunction in Moderate COVID-19 : A Randomized Controlled Trial at the Lebanese American University Medical Center- Rizk Hospital|
|Estimated Study Start Date :||January 10, 2021|
|Estimated Primary Completion Date :||January 31, 2021|
|Estimated Study Completion Date :||May 1, 2021|
Experimental: Endothelial Dysfunction Protocol
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).
Drug: Atorvastatin + L-arginine + Folic acid + Nicorandil + Nebivolol
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.
Placebo Comparator: Placebo
Placebo + Standard of Care (dexamethasone, anticoagulation, vitamin c, zinc)
Placebo + Standard of Care (dexamethasone, anticoagulation, vitamin c, zinc)
- Clinical Improvement [ Time Frame: 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 ]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.
- Need for invasive mechanical ventilation [ Time Frame: Assessment on daily basis for up to 1 month or until hospital discharge/death whichever came first ]assess the patients in need of mechanical ventilation
- Length of ICU stay [ Time Frame: Assessment on daily basis after the intervention is given for up to 1 month or until hospital discharge/death whichever came first ]Length of ICU stay
- Length of hospital Stay [ Time Frame: Assessment on daily basis after intervention given for up to 1 month or until hospital discharge/death whichever came first ]Length of hospital Stay
- Length of need of mechanical ventilation [ Time Frame: Assessment on daily basis after intervention given for up to 1 month or until hospital discharge/death whichever came first ]Length of need of mechanical ventilation
- All cause mortality [ Time Frame: assessed for up to 1 month ]All cause mortality
- Occurrence of side effects [ Time Frame: Assessment on daily basis after intervention given for up to 1 month or until hospital discharge/death whichever came first ]Occurrence of side effects
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04631536
|Contact: Matli Kamal, MDemail@example.com|