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Combination of Recombinant Bacterial ACE2 Receptors -Like Enzyme of B38-CAP and Isotretinoin Could be Promising COVID-19 Infection- and Lung Injury Preventing Drug Better Than Recombinant Human ACE2

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ClinicalTrials.gov Identifier: NCT04382950
Recruitment Status : Not yet recruiting
First Posted : May 11, 2020
Last Update Posted : June 4, 2020
Sponsor:
Information provided by (Responsible Party):
Mahmoud Ramadan mohamed Elkazzaz, Kafrelsheikh University

Brief Summary:

Combination of Recombinant Bacterial ACE2 Receptors -Like Enzyme of B38-CAP and Isotretinoin 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.

_____________________________________________________________________________________________________________________________________________________________________

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. A study demonstrated 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. pretreatment of B38-CAP markedly down regulated a massive increase of plasma Ang II levels at 5 min after Ang II injection In addition to the currently used drugs to inhibit Ang II generation or signaling, such as ACE inhibitors or Angiotensin receptor blockers, direct down-modulation of Ang II levels by rhACE2 protein is one of the promising candidates for new therapeutic strategy in cardiovascular disease and other Ang II-related diseases, e.g. ARDS. On the other hand, although mass production of rhACE2 as a protein drug costs due to requirement of mammalian cell expression systems, B38-CAP is easily prepared with E. coli expression system and is cost effective. Therapeutic efficacy and less toxicity in mouse heart failure models would warrant further investigation of B38-CAP or other microbial carboxypeptidases in disease models. Finally the principal investigator expects that treatment with ACE2-like enzyme of bacteria B38-CAP expected to work efficiently Like human ACE2 and it will save the lung cells from COVID - 19 inhibitory effect and down regulation of ACE2 because COVID-19 binds to human ACE2 and down regulates it and this receptors is very important for lung cells survival and function So ,the principal investigator also expects that B38-CAP ACE2 like enzyme may be not recognized by COVID -19 spike protein because evolutionary it is too far away from human ace2 and human ACE2 is a real receptor of COVID -19 not ACE2 like enzyme but in the same time it will make the same function of human ACE2 In another study by Sinha et al who analyzed a publicly available Connectivity Map (CMAP) dataset of pre/post transcriptomic profiles for drug treatment in cell lines for over 20,000 small molecules, isotretinoin was the strongest down-regulator of ACE 2 receptors. On the other hand, they found 6 drugs in CMAP that are currently being investigated in clinical trials for treating COVID-19 (chloroquine, thalidomide, methylprednisolone, losartan, lopinavir and ritonavir, from clinicaltrials.gov), none of which was found to significantly alter ACE2 expression (P>0.1) Moreover, another study demonstrated that isotretinoin is a Potential papain like protease (PLpro) inhibitors which is a protein encoded by SARS-CoV-2 genes and considered one of the proteins that should be targeted in COVID-19 treatment by performing target-based virtual ligand screening . So, the principal investigator expects strong inhibition of COVID - 19 infection And rescuing the lung cells from its serious attack by treating with ACE2 like enzyme and Isotretinoin

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


Condition or disease Intervention/treatment Phase
COVID Combination Product: Recombinant Bacterial ACE2 receptors -like enzyme of B38-CAP (rbACE2) plus Aerosolized 13 cis retinoic acid 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: Combination of Recombinant Bacterial ACE2 Receptors -Like Enzyme of B38-CAP and Isotretinoin Could be Promising COVID-19 Infection- and Lung Injury Preventing Drug Better Than Recombinant Human ACE2
Estimated Study Start Date : July 2020
Estimated Primary Completion Date : November 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Experimental: rbACE2 group plus Aerosolized Isotretinoin
rbACE2 0.4 mg/kg IV BID for 7 days (unblinded) plus Aerosolized 13 cis retinoic acid in gradual in 2 divided doses increases froms 0.2 mg/kg/day to 4 mg/kg/day as inhaled 13 cis retinoic acid therapy for 14 days
Combination Product: Recombinant Bacterial ACE2 receptors -like enzyme of B38-CAP (rbACE2) plus Aerosolized 13 cis retinoic acid
In this study, the experimental group will receive 0.4 mg/kg rbACE2 IV plus Aerosolized 13 cis retinoic acid in gradual in 2 divided doses increases froms 0.2 mg/kg/day to 4 mg/kg/day as inhaled 13 cis retinoic acid therapy for 14 days

No Intervention: No Intervention: Control group
Standard of care; no placebo



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


Secondary Outcome Measures :
  1. Viral load over time [ Time Frame: 14 days ]
    Compare viral load between two groups over time.

  2. P/F ratio over time [ Time Frame: 14 days ]
    PaO2/FiO2 ratio

  3. 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.

  4. Pulmonary Severity Index (PSI) [ Time Frame: 14 days ]
  5. 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.

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


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 to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

1.Laboratory diagnosis:

Adult SARI patients with 2019-ncov infection confirmed by PCR; Absolute value of lymphocytes < 0. 6x 109/L; Severe respiratory failure within 48 hours and requires admission to ICU. (severe respiratory failure was defined as PaO2/FiO2 < 200 mmHg and was supported by positive pressure mechanical ventilation (including non-invasive and invasive mechanical ventilation, PEEP>=5cmH2O))

Exclusion Criteria:

  • Age <18 years; Age >80 years
  • Pregnant or breast feeding woman
  • 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
  • Hypercholesterolemia
  • Hypertriglyceridemia
  • Liver disease
  • Renal disease
  • Sjögren syndrome
  • Pregnancy
  • Lactation
  • Depressive disorder
  • Contraindications for hormonal contraception or intrauterine device.
  • Autoimmune diseases A history of organ, bone marrow or hematopoietic stem cell transplantation
  • Patients receiving anti-hcv treatment
  • Permanent blindness in one eye
  • History of iritis, endophthalmitis, scleral inflammation or retinitis 15-90 days of retinal detachment or eye surgery
  • The competent physician considered it inappropriate to participate in the study

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): NCT04382950


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, Sponser Investigator, Kafrelsheikh University
ClinicalTrials.gov Identifier: NCT04382950    
Other Study ID Numbers: COV-2019 Treatment This is
First Posted: May 11, 2020    Key Record Dates
Last Update Posted: June 4, 2020
Last Verified: June 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lung Injury
Lung Diseases
Respiratory Tract Diseases
Thoracic Injuries
Wounds and Injuries
Tretinoin
Isotretinoin
Antineoplastic Agents
Keratolytic Agents
Dermatologic Agents