Covid19Phase 3MEDIC-LAUMCNCT04631536
Managing Endothelial Dysfunction in COVID-19 : A Randomized Controlled Trial at LAUMC
A Phase 3 study testing Atorvastatin + L-arginine + Folic acid + Nicorandil + Nebivolol in people with Covid19, run by Lebanese American University Medical Center at 1 site in Lebanon.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Covid19
- What is being tested?
- Atorvastatin + L-arginine + Folic acid + Nicorandil + Nebivolol
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 42 participants
- Where
- 1 siteLebanon
- Study dates
- 10 Jan 2021to 1 Jul 2022
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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.
Show all 16Show fewer
- .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
- Patient refuses to participate
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Managing Endothelial Dysfunction in COVID-19 : A Randomized Controlled Trial at the Lebanese American University Medical Center- Rizk Hospital
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.
Read more
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.
Read the detailed description
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
- Conditions
- Covid19
- Being tested
- Atorvastatin + L-arginine + Folic acid + Nicorandil + Nebivolol, Placebo
- Keywords
- Endothelial dysfunction, Nicorandil, Statin, Nebivolol, L-arginine, Folic acid
- Medical subject headings
- COVID-19
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Atorvastatin + L-arginine + Folic acid + Nicorandil + NebivololDrug
Also called Nicorandil, L-arginine, Folic acid, 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.
PlaceboDrug
Placebo + Standard of Care (dexamethasone, anticoagulation, vitamin c, zinc)
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: Drug: Atorvastatin + L-arginine + Folic acid + Nicorandil + Nebivolol |
| Placebo | Placebo comparator | Placebo + Standard of Care (dexamethasone, anticoagulation, vitamin c, zinc) Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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
assess the patients in need of mechanical ventilation or ICU admission
Measured: Assessment on daily basis for up to 1 month or until hospital discharge/death whichever came first
All cause mortality
All cause mortality
Measured: assessed for up to 1 month
Occurrence of side effects
Occurrence of side effects
Measured: Assessment on daily basis after intervention given for up to 1 month or until hospital discharge/death whichever came first
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Nov 2020
- Study start10 Jan 2021
- Primary completion29 Mar 2022 (estimated)
- Study completion1 Jul 2022 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (18)Papers the sponsor has linked to this study.
- Other trials for Covid19Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Care provider
- Enrolment
- 42 participants (actual)
Sponsor and investigators
- Lead sponsor
- Lebanese American University Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Kamal Matli, Lebanese American University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04631536
- Sponsor's protocol ID
- Lebanese American University
- Acronym
- MEDIC-LAUMC
- Status last verified
- Jan 2022
- First submitted
- 28 Oct 2020
- Last updated
- 14 Feb 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Wu YC, Chen CS, Chan YJ. The outbreak of COVID-19: An overview. J Chin Med Assoc. 2020 Mar;83(3):217-220. doi: 10.1097/JCMA.0000000000000270.
PubMed 32134861Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiology: A review. Clin Immunol. 2020 Jun;215:108427. doi: 10.1016/j.clim.2020.108427. Epub 2020 Apr 20.
PubMed 32325252Mason RJ. Pathogenesis of COVID-19 from a cell biology perspective. Eur Respir J. 2020 Apr 16;55(4):2000607. doi: 10.1183/13993003.00607-2020. Print 2020 Apr.
PubMed 32269085Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020 Apr 7;323(13):1239-1242. doi: 10.1001/jama.2020.2648. No abstract available.
PubMed 32091533Driggin E, Madhavan MV, Bikdeli B, Chuich T, Laracy J, Biondi-Zoccai G, Brown TS, Der Nigoghossian C, Zidar DA, Haythe J, Brodie D, Beckman JA, Kirtane AJ, Stone GW, Krumholz HM, Parikh SA. Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the COVID-19 Pandemic. J Am Coll Cardiol. 2020 May 12;75(18):2352-2371. doi: 10.1016/j.jacc.2020.03.031. Epub 2020 Mar 19.
PubMed 32201335Murthy S, Gomersall CD, Fowler RA. Care for Critically Ill Patients With COVID-19. JAMA. 2020 Apr 21;323(15):1499-1500. doi: 10.1001/jama.2020.3633. No abstract available.
PubMed 32159735Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 May;46(5):846-848. doi: 10.1007/s00134-020-05991-x. Epub 2020 Mar 3. No abstract available.
PubMed 32125452Hu Y, Sun J, Dai Z, Deng H, Li X, Huang Q, Wu Y, Sun L, Xu Y. Prevalence and severity of corona virus disease 2019 (COVID-19): A systematic review and meta-analysis. J Clin Virol. 2020 Jun;127:104371. doi: 10.1016/j.jcv.2020.104371. Epub 2020 Apr 14.
PubMed 32315817Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. doi: 10.1056/NEJMoa2002032. Epub 2020 Feb 28.
PubMed 32109013Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, Wang H, Wan J, Wang X, Lu Z. Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. 2020 Jul 1;5(7):811-818. doi: 10.1001/jamacardio.2020.1017.
PubMed 32219356Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020 Apr;46(4):586-590. doi: 10.1007/s00134-020-05985-9. Epub 2020 Mar 3. No abstract available.
PubMed 32125455Liu PP, Blet A, Smyth D, Li H. The Science Underlying COVID-19: Implications for the Cardiovascular System. Circulation. 2020 Jul 7;142(1):68-78. doi: 10.1161/CIRCULATIONAHA.120.047549. Epub 2020 Apr 15.
PubMed 32293910Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004 Jun;203(2):631-7. doi: 10.1002/path.1570.
PubMed 15141377Jung F, Kruger-Genge A, Franke RP, Hufert F, Kupper JH. COVID-19 and the endothelium. Clin Hemorheol Microcirc. 2020;75(1):7-11. doi: 10.3233/CH-209007.
PubMed 32568187Libby P, Luscher T. COVID-19 is, in the end, an endothelial disease. Eur Heart J. 2020 Sep 1;41(32):3038-3044. doi: 10.1093/eurheartj/ehaa623.
PubMed 32882706
Study at a glance
From the registry record, last updated by the sponsor on 14 Feb 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Managing Endothelial Dysfunction in COVID-19 : A Randomized Controlled Trial at the Lebanese American University Medical Center- Rizk Hospital
- ClinicalTrials.gov ID
- NCT04631536
- Acronym / sponsor ID
- MEDIC-LAUMC / Lebanese American University
- Conditions
- Covid19
- Keywords
- Endothelial dysfunction, Nicorandil, Statin, Nebivolol, L-arginine, Folic acid
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 42 participants (actual)
- Lead sponsor
- Lebanese American University Medical CenterUniversity, hospital or other
- Study start
- 10 Jan 2021 (actual)
- Primary completion
- 29 Mar 2022 (estimated)
- Study completion
- 1 Jul 2022 (estimated)
- First posted
- 17 Nov 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, care provider)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Endothelial Dysfunction Protocol | Experimental | Drug: Atorvastatin + L-arginine + Folic acid + Nicorandil + NebivololOur 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 |
| Placebo | Placebo comparator | Drug: PlaceboPlacebo + Standard of Care (dexamethasone, anticoagulation, vitamin c, zinc) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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.
Key exclusion criteria (16 listed)
- Participant in another RCT
- Myocarditis
- Patients who are already on beta-blockers
- Patients already on Nicorandil.
- . Patients taking PDE5 inhibitors or Riociguat
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Atorvastatin + L-arginine + Folic acid + Nicorandil + NebivololAlso: Nicorandil, L-arginine, Folic acid, Nebivololactive 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. | Drug | Endothelial Dysfunction Protocol |
| PlaceboPlacebo + Standard of Care (dexamethasone, anticoagulation, vitamin c, zinc) | Drug | Placebo |
Primary outcome
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
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
3 secondary outcomes
Need for ICU admission or invasive mechanical ventilation
Time frame: Assessment on daily basis for up to 1 month or until hospital discharge/death whichever came first
All cause mortality
Time frame: assessed for up to 1 month
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
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Feb 2022.
- Background: PubMed 32134861Wu YC, Chen CS, Chan YJ. The outbreak of COVID-19: An overview. J Chin Med Assoc. 2020 Mar;83(3):217-220. doi: 10.1097/JCMA.0000000000000270.
- Background: PubMed 32325252Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiology: A review. Clin Immunol. 2020 Jun;215:108427. doi: 10.1016/j.clim.2020.108427. Epub 2020 Apr 20.
- Background: PubMed 32269085Mason RJ. Pathogenesis of COVID-19 from a cell biology perspective. Eur Respir J. 2020 Apr 16;55(4):2000607. doi: 10.1183/13993003.00607-2020. Print 2020 Apr.
- Background: PubMed 32091533Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020 Apr 7;323(13):1239-1242. doi: 10.1001/jama.2020.2648. No abstract available.
- Background: PubMed 32201335Driggin E, Madhavan MV, Bikdeli B, Chuich T, Laracy J, Biondi-Zoccai G, Brown TS, Der Nigoghossian C, Zidar DA, Haythe J, Brodie D, Beckman JA, Kirtane AJ, Stone GW, Krumholz HM, Parikh SA. Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the COVID-19 Pandemic. J Am Coll Cardiol. 2020 May 12;75(18):2352-2371. doi: 10.1016/j.jacc.2020.03.031. Epub 2020 Mar 19.
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- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Atorvastatin + L-arginine + Folic acid + Nicorandil + Nebivolol in people with Covid19, run by Lebanese American University Medical Center at 1 site in Lebanon.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 14 Feb 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Lebanon. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04631536, which also lists 18 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Feb 2022.