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Trial record 67 of 873 for:    Not yet recruiting, Available Studies | Covid19 | Adult

Recombinant Bacterial ACE2 Receptors -Like Enzyme of B38-CAP Could be Promising COVID-19 Infection- and Lung Injury Preventing Drug 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 : September 30, 2020
Sponsor:
Information provided by (Responsible Party):
Mahmoud Ramadan mohamed Elkazzaz, Kafrelsheikh University

Brief Summary:

Recombinant Bacterial ACE2 receptors -like enzyme of B38-CAP could be promising COVID-19 infection- and lung injury preventing drug better than recombinant human ACE2 Mahmoud ELkazzaz1 1Department of chemistry and biochemistry, Faculty of Science, Damietta University, GOEIC, Egypt.

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B38-CAP is a bacteria-derived ACE2-like enzyme that suppresses hypertension and cardiac dysfunction Angiotensin-converting enzyme 2 (ACE2) is critically involved in cardiovascular physiology and pathology, and is currently clinically evaluated to treat acute lung failure. Here we show that the B38-CAP, a carboxypeptidase derived from Paenibacillus sp. B38, is an ACE2-like enzyme to decrease angiotensin II levels in mice. In protein 3D structure analysis, B38-CAP homolog shares structural similarity to mammalian ACE2 with low sequence identity. In vitro, recombinant B38-CAP protein catalyzed the conversion of angiotensin II to angiotensin 1-7, as well as other known ACE2 target peptides. Treatment with B38-CAP suppressed angiotensin II-induced hypertension, cardiac hypertrophy, and fibrosis in mice. Moreover, B38-CAP inhibited pressure overload-induced pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction in mice. A study demonestrated that the bacterial B38-CAP as an ACE2-like carboxypeptidase, indicating that evolution has shaped a bacterial carboxypeptidase to a human ACE2-like enzyme. Bacterial engineering could be utilized to design improved protein drugs for hypertension and heart failure. On the other hand, Treatment with recombinant human ACE2 protein (rhACE2), which is devoid of its membrane-anchored domain thus soluble, has been demonstrated to exhibit beneficial effects in various animal models including heart failure, acute lung injury, and diabetic nephropathy, and so forth. rhACE2 is currently tested in the clinic to treat ARDS and COVID-19 infected patients . Using cell cultures and organoids, researchers from the Karolinska Institutet in Sweden and the University of British Columbia (UBC) in Canada, showed that by adding a genetically modified variant of ACE2, called human recombinant soluble angiotensin-converting enzyme 2 (hrsACE2), COVID-19 was prevented from entering cells.The paper, published in Cell, shows that hrsACE2 had a dose dependent effect of viral growth of SARS-CoV-2 and was able to reduce it by a factor of 1,000 to 5,000 in cell cultures. Despite its beneficial effects, rhACE2 is a glycosylated protein and thus its preparation requires time- and cost-consuming protein expression system with mammalian or insect cells, which may not be advantageous in drug development and medical economy Although it had been reported that an immune response is associated with the chronic infusion of rhACE2 resulting in the degradation of rhACE226, this was not observed for B38-CAP; there were no antibodies against B38-CAP detectable in the serum of mice infused with B38-CAP for 2 weeks.B38-CAP is easily prepared with E. coli expression system and is cost effective. with therapeutic efficacy and less toxicity in mouse heart failure model. Implantation of B38-CAP-filled osmotic mini-pumps significantly suppressed Ang II-induced hypertension in conscious mice .without affecting the heart rate. These results indicate that B38-CAP antagonizes the vasopressor effect of Ang II. So the principle investigator expects and suggests that treating with cloned Bacterial ACE2 receptors -like enzyme of B38-CAP could be promising COVID-19 infection- and lung injury preventing drug better than recombinant human ACE2 in addition to brsACE2, expected to lure the virus to attach itself to the copy instead of the actual cells… It distracts the virus from infecting the cells to the same degree and should lead to a reduction in the growth of the virus in the lungs and other organs. A study showed that recombinant B38-CAP protein downregulates Ang II levels in mice and antagonizes Ang II-induced hypertension, pathological cardiac hypertrophy, and myocardial fibrosis. We also show beneficial effects of B38-CAP on the pathology of pressure overload-induced heart failure in mice without overt toxicities.Finally the principal investigator expect that treatment with ACE2-like enzyme in bacteria B38-CAP may be do the same mechanism of rhACE2 in inhibiting COVID -19 and the other suggested mechanism is that injection of ACE2-like enzyme of bacteria B38-CAP in human body may down regulate human ACE2 which is the real receptor of COVID -19 and in the same time it will be resistant to COVID- spike protein because there seems a difference in substrate specificity between two enzymes.

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

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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 COVID-19 Infection- and Lung Injury Preventing Drug Better Than Recombinant Human ACE2
Estimated Study Start Date : September 2020
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : October 2020

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



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 ]


Information from the National Library of Medicine

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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

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
Investigators
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Principal Investigator: M.Sc. Mahmoud Elkazzaz, M.Sc.Biochemistry General Organization of Export and Import control system
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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: September 30, 2020
Last Verified: September 2020
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
Lung Injury
Lung Diseases
Respiratory Tract Diseases
Thoracic Injuries
Wounds and Injuries