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Investigating the Involvement of ACE and Angiotensinogen Genes' Polymorphism Along With Other Thrombophilic Genotypes in Severe Forms of COVID-19 With/Without Thrombotic Events (iGenes-COVID19)

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ClinicalTrials.gov Identifier: NCT04519398
Recruitment Status : Recruiting
First Posted : August 19, 2020
Last Update Posted : August 19, 2020
Sponsor:
Information provided by (Responsible Party):
Professor Adrian Covic, Grigore T. Popa University of Medicine and Pharmacy

Brief Summary:

An estimated 22% of the global population is at an increased risk of a severe form of COVID-19, while one in four coronavirus patients admitted to intensive care unit will develop a pulmonary embolism. A major public health question remains to be investigated: why COVID-19 is mild for some, critically severe for others and why only a percentage of COVID-19 patients develop thrombosis, despite the disease's proven hypercoagulable state? Patients' intrinsic characteristics might be responsible for the deep variety of disease forms.

Our study aims to assess the validity of the hypothesis according to which underlining genetic variations might be responsible for different degrees of severity and thrombotic events risks in the novel coronavirus disease.

Moreover, we suspect that prothrombotic genotypes occuring in the genes that encode angiotensin-converting enzyme (ACE-DEL/INS) and angiotensinogen (AGT M235T) are involved in the unpredictable evolution of COVID-19, both in terms of severity and thrombotic events, due to the strong interactions of SARS-CoV-2 with the renin-angiotensin-aldosterone system (RAAS). Therefore, we also aim to assess the validity of the theory according to which there is a pre-existing atypical modulation of RAAS in COVID-19 patients that develop severe forms and/or thrombosis.

Our hypothesis is based on various observations. Firstly, there is a substantial similarity with a reasonably related condition such as sepsis, for which there is a validated theory stating that thrombophilic mutations affect patients' clinical response. Secondly, racial and ethnic genetic differences are responsible for significant dissimilar thrombotic risks among various nations. Thirdly, an increase in stroke incidence has been reported in young patients with COVID-19, without essential thrombosis risk factors, favoring the idea that a genetic predisposition could contribute to increase the thrombotic and thromboembolic risk. Fourthly, the plasminogen activator inhibitor (PAI)-1 4G/5G inherited mutation was found to be responsible for a thrombotic state causing post-SARS osteonecrosis.


Condition or disease Intervention/treatment
Covid19 Corona Virus Infection Thrombosis ARDS Thrombophilia Thromboses, Intracranial Thromboses, Deep Vein RAAS Genetic: Complete thrombophilic profile testing by multiplex PCR

Detailed Description:

The study's protocol will cover the following steps:

• Collected data from COVID-19 patients at admission will include:

  • Descriptive general demographic data
  • Previous pathologies and thrombosis risk factors
  • Routine biological data (the blood routinely collected will also be used for SARS-Cov-2 specific RT-PCR exam)

Complete thrombophilic profile testing by multiplex PCR and reverse hybridization of DNA to assess the presence of prothrombotic genotypes:

  • Factor V Leiden
  • Factor V 4070 A G (Hr2)
  • Factor II G20210A
  • Methylenetetrahydrofolate reductase (MTHFR) C677T
  • MTHFR A1298C
  • Cystathionine β-synthase (CBS) 844ins68
  • PAI-1 4G/5G
  • Glycoprotein IIIa T1565C (HPA-1a/b)
  • ACE-DEL/INS
  • Apolipoprotein E (ApoE)
  • AGT M235T
  • Angiotensin II type 1 receptor (ATR-1) A1166C
  • Fibrinogen - 455 G A
  • Factor XIII Val34Leu SpO2, respiratory rate, PaO2/FiO2 RAAS components

    • Imagistic procedures (chest X-ray or CT)

      • All patients with a positive SARS-CoV-2 PCR test will be included
      • Patients will be divided into three groups depending on disease severity and the presence of thrombotic state:
    • 1st group includes COVID-19 patients with proved
  • venous thrombosis (deep vein thrombosis, pulmonary embolism or venous thrombosis occurring in more atypical places such as in the veins of the brain, liver, kidney, mesenteric vein and the veins of the arms)
  • or arterial thrombosis (heart attacks, strokes)

    • 2nd group encompasses asymptomatic patients and those with mild or moderate disease, according to current guidelines, without thrombosis: no symptoms or evidence of lower respiratory disease by clinical assessment or imaging and a SpO2 ≥ 94%
    • 3rd group includes severe disease, according to current guidelines, without thrombosis: respiratory frequency > 30 breaths per minute, SpO2 < 94%, PaO2/FiO2 < 300 mmHg, or lung infiltrates >50%

      • Statistical methods will be employed to check for significant differences between prothrombotic mutations frequency and RAAS components levels for the three groups

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Study Type : Observational
Estimated Enrollment : 60 participants
Observational Model: Ecologic or Community
Time Perspective: Prospective
Official Title: Investigating the Involvement of ACE and Angiotensinogen Genes' Polymorphism Along With Other Thrombophilic Genotypes in Severe Forms of COVID-19 With/Without Thrombotic Events
Actual Study Start Date : August 18, 2020
Estimated Primary Completion Date : February 17, 2021
Estimated Study Completion Date : August 18, 2021


Group/Cohort Intervention/treatment
COVID-19 patients with proved venous thrombosis

1st group includes COVID-19 patients with proved

  • venous thrombosis (deep vein thrombosis, pulmonary embolism or venous thrombosis occurring in more atypical places such as in the veins of the brain, liver, kidney, mesenteric vein and the veins of the arms)
  • or arterial thrombosis (heart attacks, strokes)
Genetic: Complete thrombophilic profile testing by multiplex PCR

Complete thrombophilic profile testing by multiplex PCR and reverse hybridization of DNA to assess the presence of prothrombotic genotypes:

  • Factor V Leiden
  • Factor V 4070 A>G (Hr2)
  • Factor II G20210A
  • Methylenetetrahydrofolate reductase (MTHFR) C677T
  • MTHFR A1298C
  • Cystathionine β-synthase (CBS) 844ins68
  • PAI-1 4G/5G
  • Glycoprotein IIIa T1565C (HPA-1a/b)
  • ACE-DEL/INS
  • Apolipoprotein E (ApoE)
  • AGT M235T
  • Angiotensin II type 1 receptor (ATR-1) A1166C
  • Fibrinogen - 455 G>A
  • Factor XIII Val34Leu

Asymptomatic COVID-19 & those with mild or moderate disease
2nd group encompasses asymptomatic patients and those with mild or moderate disease, according to current guidelines, without thrombosis: no symptoms or evidence of lower respiratory disease by clinical assessment or imaging and a SpO2 > 94%
Genetic: Complete thrombophilic profile testing by multiplex PCR

Complete thrombophilic profile testing by multiplex PCR and reverse hybridization of DNA to assess the presence of prothrombotic genotypes:

  • Factor V Leiden
  • Factor V 4070 A>G (Hr2)
  • Factor II G20210A
  • Methylenetetrahydrofolate reductase (MTHFR) C677T
  • MTHFR A1298C
  • Cystathionine β-synthase (CBS) 844ins68
  • PAI-1 4G/5G
  • Glycoprotein IIIa T1565C (HPA-1a/b)
  • ACE-DEL/INS
  • Apolipoprotein E (ApoE)
  • AGT M235T
  • Angiotensin II type 1 receptor (ATR-1) A1166C
  • Fibrinogen - 455 G>A
  • Factor XIII Val34Leu

Severe disease, according to Guidelines, without thrombus
3rd group includes severe disease, according to current guidelines, without thrombosis: respiratory frequency > 30 breaths per minute, SpO2 < 94%, PaO2/FiO2 < 300 mmHg, or lung infiltrates >50%
Genetic: Complete thrombophilic profile testing by multiplex PCR

Complete thrombophilic profile testing by multiplex PCR and reverse hybridization of DNA to assess the presence of prothrombotic genotypes:

  • Factor V Leiden
  • Factor V 4070 A>G (Hr2)
  • Factor II G20210A
  • Methylenetetrahydrofolate reductase (MTHFR) C677T
  • MTHFR A1298C
  • Cystathionine β-synthase (CBS) 844ins68
  • PAI-1 4G/5G
  • Glycoprotein IIIa T1565C (HPA-1a/b)
  • ACE-DEL/INS
  • Apolipoprotein E (ApoE)
  • AGT M235T
  • Angiotensin II type 1 receptor (ATR-1) A1166C
  • Fibrinogen - 455 G>A
  • Factor XIII Val34Leu




Primary Outcome Measures :
  1. Number of patients with thrombophilic profile alterations [ Time Frame: One year ]
    The difference of prothrombotic genotypes frequency between the three groups


Secondary Outcome Measures :
  1. Number of patients with RAAS components alterations [ Time Frame: One year ]
    The differences of RAAS components levels between the three groups


Biospecimen Retention:   Samples With DNA
Blood with complete thrombophilic profile testing and RAAS components assessment through PCR (multiplex PCR and reverse hybridization of DNA to assess the presence of prothrombotic genotypes)


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
All patients with COVID-19 and thrmbotic events or, Patients with COVID-19 & no thrombotic events but with a severe form Patients with COVID-19 & no thrombotic events and no or mild symptoms
Criteria

Inclusion Criteria:

  • All hospitalized patients with cough, fever, myalgia - with confirmed COVID-19 infection • All patients with a positive SARS-CoV-2 PCR test

Exclusion Criteria:

  • Patient refusal
  • Uncertain tests results
  • Children

Information from the National Library of Medicine

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): NCT04519398


Contacts
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Contact: Alexandru Burlacu, MD, PhD 00407444488580 alexandru.burlacu@umfiasi.ro
Contact: Radu Crisan-Dabija, MD, PhD radu.dabija@umfiasi.ro

Locations
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Romania
University of Medicine and Pharmacy Gr T. Popa Iasi, Romania Recruiting
Iasi, Romania, 700503
Contact: Adrian Covic, Professor       accovic@gmail.com   
Contact: Radu Crisan-Dabija, Lecturer       radu.dabija@umfiasi.ro   
Principal Investigator: Alexandru Burlacu, Lecturer         
Principal Investigator: Radu Crisan-Dabija, Lecturer         
Sub-Investigator: Iolanda Popa, MD, PhD         
Sponsors and Collaborators
Grigore T. Popa University of Medicine and Pharmacy
Investigators
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Study Chair: Adrian Covic, Professor Gr T Popa University of Medicine and Pharmacy Iasi ROMANIA
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Responsible Party: Professor Adrian Covic, MD, PhD, Professor, Grigore T. Popa University of Medicine and Pharmacy
ClinicalTrials.gov Identifier: NCT04519398    
Other Study ID Numbers: GTP0051
First Posted: August 19, 2020    Key Record Dates
Last Update Posted: August 19, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Professor Adrian Covic, Grigore T. Popa University of Medicine and Pharmacy:
Covid-19
COVID-19 severity
Thrombosis
Thrombophilia
thrombophylic profile
Renin-angiotensin-aldosterone system alterations
Additional relevant MeSH terms:
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Coronavirus Infections
Severe Acute Respiratory Syndrome
Intracranial Thrombosis
Thrombosis
Venous Thrombosis
Thrombophilia
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Virus Diseases
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Respiratory Tract Infections
Respiratory Tract Diseases
Hematologic Diseases
Intracranial Embolism and Thrombosis
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Thromboembolism