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Recombinant Bacterial ACE2 Receptors -Like Enzyme of B38-CAP Could be Promising Treatment for COVID-19 Infection- and Its Inflammatory Complications Better Than Recombinant Human ACE2 (Bacterial ACE2)

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ClinicalTrials.gov Identifier: NCT04375046
Recruitment Status : Not yet recruiting
First Posted : May 5, 2020
Last Update Posted : June 9, 2021
Sponsor:
Collaborator:
Foshan University Laboratory of Emerging Infectious Disease Institute of Translational Medicine The First Hospital of Jilin University China
Information provided by (Responsible Party):
Mahmoud Ramadan mohamed Elkazzaz, Kafrelsheikh University

Study Description
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Brief Summary:

Recombinant Bacterial ACE2 receptors -like enzyme of B38-CAP could be promising treatment for COVID-19 infection- and Its inflammatory complications better than recombinant human ACE2

Mahmoud ELkazzaz(1),Tamer Haydara(2),Yousry Abo-amer(3), Quan Liu(4)

  1. Department of chemistry and biochemistry, Faculty of Science, Damietta University, Egypt.
  2. Department of Internal Medicine, Faculty of Medicine, Kafrelsheikh University, Egypt
  3. Hepatology,Gastroenterology and Infectious Diseases Department, Mahala Hepatology Teaching Hospital, Egypt
  4. School of Life Sciences and Engineering, Foshan University, Foshan, Guangdong Province; Laboratory of Emerging Infectious Disease, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China.

Abstract

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 100 million people causing over 2.4 million deaths over the world, and it is still expanding. There is an urgent need for targeted and effective COVID-19 treatments which has put great pressure on researchers across the world for developing effective drugs. This paper reviews the possibility of using Recombinant Bacterial ACE2 Receptors -Like Enzyme of B38-CAP to treat SARS-CoV-2 based on the intracellular mechanism of SARS-CoV-2 transmission and consequences caused. Angiotensin-converting enzyme 2 (ACE2) plays a key role in cardiovascular physiology and pathology, and it's being currently being investigated as a potential covid-19 and acute lung failure treatment through several clinical trials.. The SARS-CoV2 binding site was identified as ACE2, a part of the RAAS, which is known to protect the lung from injuries. it has been postulated that SARS-CoV-2 binding to ACE2 may attenuate residual ACE2 activity, skewing the ACE/ACE2 balance to a state of heightened angiotensin II activity leading to inflammatory and oxidative organ damage, as well as pulmonary vasoconstriction, which can lead to acute lung injury.. Therefore, treatment with recombinant soluble ACE2 protein and drugs that up regulate ACE2 may alleviate pulmonary complication. In animal models including heart failure, acute lung injury, and diabetic nephropathy, recombinant human ACE2 protein (rhACE2), which is devoid of its membrane-anchored domain thus soluble, has been shown to have beneficial effects. Despite its positive effects, rhACE2 is a glycosylated protein, which necessitates a time- and cost-intensive protein expression system using mammalian or insect cells, which may be inconvenient in drug production and medical economics. Moreover, we hypothesis that treating COVID-19 patients with recombinant soluble ACE2 protein may induce autoantibodies and T cells to cellular ACE2.Furthermore, rhACE2 may interact with spike protein based vaccine and worsen its effect . These autoantibodies may generated by enforced presentation of the soluble Angiotensin-converting enzyme 2 (ACE2) protein in a complex with COVID-19 Spike protein in fragment crystallizable (FC) Receptor positive Antigen Presenting Cells in the blood The development of autoantibodies might make injury and damage to the host epithelial cells and hamper their ACE2 dependent function in lungs, intestine and testes which express ACE2. In addition to inducing platelet aggregation and thrombosis . Although it has been stated that immune response associated with the chronic infusion of rhACE2 resulting in the degradation of rhACE226, this was not the case with B38-CAP; no antibodies against B38-CAP were detected in the serum of mice infused with B38-CAP for two weeks... In this case we suggest that bacterial engineering could be used to develop better protein drugs for COVID-19 treatment... B38-CAP is an ACE2-like enzyme derived from bacteria that reduces hypertension and cardiac dysfunction. Angiotensin-converting enzyme 2 (ACE2) plays a key role in cardiovascular physiology and pathology, and it is currently being studied in clinical trials to treat acute lung failure. In mice, B38-CAP treatment prevented angiotensin II-induced hypertension, cardiac hypertrophy, and fibrosis. B38-CAP is an ACE2-like enzyme derived from bacteria, demonstrating that evolution has shaped a bacterial carboxypeptidase (B38-CAP) to a human ACE2-like enzyme. As a result, we think that treating COVID-19-infected patients with Bacterial ACE2 like enzymes, rather than human ACE2, may be preferable because it will perform the same role as human ACE2 and may not be recognized by COVID-19 spike protein

Keywords: COVID 2019 ,Infection, B38-CAP , Bacterial ACE2 receptors -like enzyme , rhACE226.


Condition or disease Intervention/treatment Phase
COVID-19 Drug: Recombinant Bacterial ACE2 receptors -like enzyme of B38-CAP (rbACE2) Phase 1

Detailed Description:

Recombinant Bacterial ACE2 receptors -like enzyme of B38-CAP could be promising treatment for COVID-19 infection- and Its inflammatory complications better than recombinant human ACE2

This is a small pilot study investigating whether there is any efficacy signal that warrants a larger Phase 2B trial, or any harm that suggests that such a trial should not be done. It is not expected to produce statistically significant results in the major endpoints. The investigator will examine all of the biologic, physiological, and clinical data to determine whether a Phase 2B trial is warranted.

Primary efficacy analysis will be carried only on patients receiving at least 4 doses of active drug. Safety analysis will be carried out on all patients receiving at least one dose of active drug.

It is planned to enroll more than or equal to 24 subjects with COVID-19. It is expected to have at least 12 evaluable patients in each group.

Experimental group: 0.4 mg/kg rbACE2 IV BID and standard of care Control group: standard of care Intervention duration: up to 7 days of therapy No planned interim analysis.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Recombinant Bacterial ACE2 Receptors -Like Enzyme of B38-CAP Could be Promising Treatment for COVID-19 Infection- and Its Inflammatory Complications Better Than Recombinant Human ACE2
Estimated Study Start Date : July 2021
Estimated Primary Completion Date : August 2021
Estimated Study Completion Date : October 2021
Arms and Interventions
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Arm Intervention/treatment
Experimental: Experimental: rbACE2 group
0.4 mg/kg IV BID for 7 days (unblinded) + standard of care
 Drug: Recombinant Bacterial ACE2 receptors -like enzyme of B38-CAP (rbACE2)
In this study, the experimental group will receive 0.4 mg/kg rbACE2 IV
No Intervention: No Intervention: Control group
Standard of care; no placebo


Outcome Measures
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Primary Outcome Measures :
  1. Time course of body temperature (fever) [ Time Frame: 14 days ]
    Compare the time course of body temperature (fever) between two groups over time.

  2. Viral load over time [ Time Frame: 14 days ]
    Compare viral load between two groups over time.


Secondary Outcome Measures :
  1. P/F ratio over time [ Time Frame: 14 days ]
    PaO2/FiO2 ratio

  2. Sequential organ failure assessment score(SOFA score) over time [ Time Frame: 14 days ]
    SOFA, including assessment of respiratory, blood, liver, circulatory, nerve, kidney, from 0 to 4 scores in each systems, the higher scores mean a worse outcome.

  3. Pulmonary Severity Index (PSI) [ Time Frame: 14 days ]
  4. Image examination of chest over time [ Time Frame: 14 days ]
    Based on radiologist's assessment of inflammatory exudative disease, category as follows: significant improvement, partial improvement, no improvement, increase of partial exudation, significant increase in exudation, unable to judge.

  5. Proportion of subjects who progressed to critical illness or death [ Time Frame: 14 days ]
  6. Time from first dose to conversion to normal or mild pneumonia [ Time Frame: 14 days ]
  7. T-lymphocyte counts over time [ Time Frame: 14 days ]
  8. C-reactive protein levels over time [ Time Frame: 14 days ]
  9. Angiotensin II (Ang II) changes over time [ Time Frame: 14 days ]
  10. Angiotensin 1-7 (Ang 1-7) changes over time [ Time Frame: 14 days ]
  11. Angiotensin 1-5 (Ang 1-5) changes over time [ Time Frame: 14 days ]
  12. Renin changes over time [ Time Frame: 14 days ]
  13. Aldosterone changes over time [ Time Frame: 14 days ]
  14. Angiotensin-converting enzyme (ACE) changes over time [ Time Frame: 14 days ]
  15. Angiotensin-converting enzyme 2 (ACE2) changes over time [ Time Frame: 14 days ]
  16. Interleukin 6 (IL-6) changes over time [ Time Frame: 14 days ]
  17. Interleukin 8 (IL-8) changes over time [ Time Frame: 14 days ]
  18. Soluble tumor necrosis factor receptor type II (sTNFrII) changes over time [ Time Frame: 14 days ]
  19. Plasminogen activator inhibitor type-1 (PAI-1) changes over time [ Time Frame: 14 days ]
  20. Von willebrand factor (vWF) changes over time [ Time Frame: 14 days ]
  21. Tumor necrosis factor-α (TNF-α) changes over time [ Time Frame: 14 days ]
  22. Soluble receptor for advanced glycation end products (sRAGE) changes over time [ Time Frame: 14 days ]
  23. Surfactant protein-D (SP-D) changes over time [ Time Frame: 14 days ]
  24. Angiopoietin-2 changes over time [ Time Frame: 14 days ]
  25. Frequency of adverse events and severe adverse events [ Time Frame: 14 days ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Laboratory diagnosis:

    Respiratory specimen is positive for SARS-CoV-2 nucleic acid by RT-PCR; OR, The viral gene sequencing of the respiratory specimen is highly homologous to known novel coronavirus.

  2. Fever:

    Axillary temperature >37.3℃

  3. Respiratory variables (meets one of the following criteria):

    • Respiratory rate: RR ≥25 breaths/min
    • Oxygen saturation ≤93% at rest on room air
    • PaO2/FiO2 ≤300 mmHg（1 mmHg=0.133 KPa）
    • Pulmonary imaging showed that the lesions progressed more than 50% within 24-48 hours, and the patients were managed as severe
  4. HBsAg negative, or HBV DNA ≤10^4 copy/ml if HBsAg positive; anti-HCV negative; HIV negative two weeks prior to signed Informed Consent Form (ICF)
  5. Appropriate ethics approval and
  6. ICF -

Exclusion Criteria:

  • Age <18 years; Age >80 years
  • Pregnant or breast feeding woman or with positive pregnancy test result P/F <100 mmHg
  • Moribund condition (death likely in days) or not expected to survive for >7 days Refusal by attending MD
  • Not hemodynamically stable in the preceding 4 hours (MAP ≤65 mmHg, or SAP <90 mmHg, DAP <60 mmHg, vasoactive agents are required)
  • Patient on invasive mechanical ventilation or ECMO
  • Patient in other therapeutic clinical trial within 30 days before ICF
  • Receive any other ACE inhibitors (ACEI), angiotensin-receptor blockers (ARB) treatment within 7 days before ICF
  • Chronic immunosuppression: current autoimmune diseases or patients who received immunotherapy within 30 days before ICF
  • Hematologic malignancy (lymphoma, leukemia, multiple myeloma)
  • Other patient characteristics (not thought to be related to underlying COVID-19) that portend a very poor prognosis (e.g, severe liver failure, and ect)
  • Known allergy to study drug or its ingredients related to renin-angiotensin system (RAS), or frequent and/or severe allergic reactions with multiple medications
  • Other uncontrolled diseases, as judged by investigators
  • Body weight ≥85 kg
Contacts and Locations
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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): NCT04375046


Contacts
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Contact: M.Sc.Mahmoud Elkazzaz, M.Sc.Biochemistry 00201090302015 mahmoudramadan2051@yahoo.com

Sponsors and Collaborators
Kafrelsheikh University
Foshan University Laboratory of Emerging Infectious Disease Institute of Translational Medicine The First Hospital of Jilin University China
Investigators
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Principal Investigator: M.Sc. Mahmoud Elkazzaz, M.Sc.Biochemistry General Organization of Export and Import control system
More Information
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Responsible Party: Mahmoud Ramadan mohamed Elkazzaz, Principal Investigator, Kafrelsheikh University
ClinicalTrials.gov Identifier: NCT04375046    
Other Study ID Numbers: proposed by Mahmoud kazazzaz
First Posted: May 5, 2020    Key Record Dates
Last Update Posted: June 9, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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 Mahmoud Ramadan mohamed Elkazzaz, Kafrelsheikh University:
COVID 2019 ,Infection, B38-CAP , Bacterial ACE2 receptors -like enzyme , rhACE226
Additional relevant MeSH terms:
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Infection