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Combination of Chemopreventive Agents (All- Trans Retinoic Acid and Tamoxifen) as Potential Treatment for the Lung Complication of COVID-19

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ClinicalTrials.gov Identifier: NCT04568096
Recruitment Status : Unknown
Verified October 2020 by Mahmoud Ramadan mohamed Elkazzaz, Kafrelsheikh University.
Recruitment status was:  Not yet recruiting
First Posted : September 29, 2020
Last Update Posted : October 26, 2020
Sponsor:
Information provided by (Responsible Party):
Mahmoud Ramadan mohamed Elkazzaz, Kafrelsheikh University

Tracking Information
First Submitted Date  ICMJE September 26, 2020
First Posted Date  ICMJE September 29, 2020
Last Update Posted Date October 26, 2020
Estimated Study Start Date  ICMJE November 2020
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 26, 2020)
lung injury score [ Time Frame: at 7and 14 days ]
Proportion of lung injury score decreased or increased after treatment
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 26, 2020)
  • Angiotensin 1-7 (Ang 1-7) changes over time [ Time Frame: at day 7 and 14 ]
  • Angiotensin 1-5 (Ang 1-5) changes over time [ Time Frame: at day 7 and 14 ]
  • Renin changes over time [ Time Frame: at day 7 and 14] ]
  • Aldosterone changes over time [ Time Frame: at day 7 and 14 ]
  • Angiotensin-converting enzyme (ACE) changes over time [ Time Frame: at day 7 and 14 ]
  • Frequency of adverse events and severe adverse events [ Time Frame: 14 days ]
  • Angiotensin II (Ang II) changes over time [ Time Frame: at day 7 and 14 ]
  • Sequential organ failure assessment score(SOFA score) over time [ Time Frame: at day 7 and 14 ]
  • Transe membrane protease ,serine II (TMPRSS2) changes over time [ Time Frame: at day 7 and 14 ]
  • Testosterone levels changes over time [ Time Frame: day 7 and 14 ]
  • Dihydrotestosterone(DHT) levels changes over time [ Time Frame: day 7 and 14 ]
  • Thrombin time (TT) [ Time Frame: day 7 and 14 ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Combination of Chemopreventive Agents (All- Trans Retinoic Acid and Tamoxifen) as Potential Treatment for the Lung Complication of COVID-19
Official Title  ICMJE Combination of Chemopreventive Agents (All- Trans Retinoic Acid and Tamoxifen) as Potential Treatment for the Lung Complication of COVID-19
Brief Summary

Combination of Chemopreventive agents (All- Trans Retinoic Acid and Tamoxifen) as potential treatment for the Lung Complication of COVID-19

Abstract

Angiotensin-converting enzyme (ACE2) protein found on the cell membranes is the target of SARS-CoV-2 for entering into the host cells. Viral spike protein-binding with ACE2 down-regulates it. As ACE2 is known to protect the lung from injuries, SARS-CoV-2-induced ACE2 deficiency may expose patients to lung damage. In this Review, we use established and emerging evidence based on the findings of previous studies and researches to propose a testable hypothesis that Combination of chemopreventive agents (All Trans Retinoic acid and Tamoxifen) can be tested to prevent inflammatory complication in severe acute respiratory syndrome coronavirus 2 infection via two mechanisms by inhibiting bradykinin B1,B2 receptors expression and upregulating the depleted ACE2 in COVID-19 . Bradykinin B1 receptors are not expressed under physiological conditions but are induced under inflammatory conditions. Here we hypothesize that permanent attack and invasion of COVID-19 to lung epithelial cells via binding to ACE2 leads to tissue injury and inflammation and that increases BK levels and BK-B2-receptor (B2R) stimulation A study reported that tissue injury and inflammation increases BK levels and BK-B2-receptor (B2R) stimulation. We suggest that Bradykinin mediates and induces lung injury, proinflammatory cytokines and inflammation likely precipitates life threatening respiratory complications in COVID-19. Further experiments showed that BK treatment stimulated IL-6 production On the other hand a study reported that cells treated with Retinoic acid and Tamoxifen for 48 h significantly decreased the BK-B2 receptor protein levels (70.3 ± 0.6% vs. 100% of control, P < 0.05). Retinoids inhibit bradykinin B1 receptor-sensitized responses and this action could participate in their anti-inflammatory and immunomodulatory effects. In addition retinoic acid, is known to possess in vivo anti-inflammatory, anti-platelet and fibrinolytic activities. A study investigated the in vitro thrombin and platelet aggregation inhibitory activities of retinoic acid and retinaldehyde.Retinoic acid, retinaldehyde and retinol exhibited potent inhibition of thrombin, with IC50 values of 67μg/ml, 74μg/ml and 152μg/ml, respectively for the inhibition of thrombin (Sigma); and 49μg/ml, 74μg/ml and 178μg/ml, respectively for the inhibition of thrombin (plasma). Amongst vitamin A and its derivatives, retinoic acid showed the highest inhibition of both the forms of thrombin. Beside the effectiveness of TAM on cancer cells, it also has other effects on numerous microbes including parasite, fungi, bacteria, and some viruses such as Ebola virus and human immunodeficiency virus (HIV).Furthermore Tamoxifen can block the action of interleukin 6 and inhibit neutrophils. A study demonstrated that tamoxifen has side effects associated with neutropenia. Since tamoxifen can cause neutropenia and subsequently influence the neutrophil-to-lymphocyte ratio (NLR) value In addition it has anti malarial effect similar to chloroquine In conclusion

Keywords: COVID 2019 , Retinoic acid, Endosomal toll-like receptor 3,T Cells, IFN type1, AT1, ACE2,TMPRSS2

Detailed Description

This is a Phase 2, , randomized (1:1), placebo-controlled, 2-weeks, proof-of-concept study to evaluate the safety and tolerability as well as the mechanistic effect of Aerosol administration of Inhaled All trans retinoic acid and oral Tamoxifen in subjects infected with COVID -19

After randomization and standard treatment The infected patients will receive Aerosolized All-Trans Retinoic Acid in gradual in 2 divided doses increases from 0.2 mg/kg/day to 4 mg/kg/day as inhaled All-Trans Retinoic Acid therapy plus tamoxifen 20mg orally once daily. for 14 days

Inclusion Criteria:

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 Pregnant Allergic to experimental drugs and patients have the following conditions:

Hypercholesterolemia Hypertriglyceridemia Liver disease Renal disease Sjögren syndrome Pregnancy Lactation Depressive disorder Body mass index less than 18 points or higher than 25 points 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 Previous history of deep vein thrombosis or pulmonary embolism in the last 12 months.

Patients with postmenopausal vaginal bleeding with no defined etiology. Patients with breast cancer who need to use tamoxifen for this neoplasm Another synchronous neoplasm that requires systemic treatment Patients with aggressive disease requiring cytotoxic therapy or locoregional therapies (eg hepatic embolization) A history of serious clinical or psychiatric illness that, by clinical judgment, may involve participation risk in this study Patients participating in other protocols with experimental drugs. Patients with oral food difficulties. Patients who underwent major recent surgery less than 4 weeks previously. Patients receiving chemotherapy or other oncologic therapy for less than 3 weeks

Study Type: Interventional Primary Purpose: Treatment Study Phase: Phase 2 Interventional Study Model: Parallel Assignment Number of Arms: 2 Masking: None (Open Label) Allocation: Randomized Enrollment: 160 [Anticipated]

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE the Lung Complication of COVID-19
Intervention  ICMJE
  • Combination Product: Aerosolized All-Trans Retinoic acid plus oral Tamoxifen
    After randomization and standard treatment The infected patients will receive Aerosolized All-Trans Retinoic Acid in gradual in 2 divided doses increases from 0.2 mg/kg/day to 4 mg/kg/day as inhaled All-Trans Retinoic Acid therapy plus tamoxifen 20mg orally once daily. for 14 days
  • Other: Standard treatment
    Standard treatment is according to the protocol of treatment of 2019-nCoV infection
Study Arms  ICMJE
  • Active Comparator: Aerosolized All-Trans Retinoic acid plus oral Tamoxifen
    The infected patients will receive Aerosolized All-Trans Retinoic Acid in gradual in 2 divided doses increases from 0.2 mg/kg/day to 4 mg/kg/day as inhaled All-Trans Retinoic Acid therapy plus tamoxifen 20mg orally once daily. for 14 days
    Intervention: Combination Product: Aerosolized All-Trans Retinoic acid plus oral Tamoxifen
  • Placebo Comparator: The standard therapy
    The infected patients will receive the standard therapy for COVID-19 for 14 days
    Intervention: Other: Standard treatment
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: September 26, 2020)
160
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2020
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

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 Pregnant Allergic to experimental drugs and patients have the following conditions:

  • Hypercholesterolemia
  • Hypertriglyceridemia
  • Liver disease
  • Renal disease
  • Sjögren syndrome
  • Pregnancy
  • Lactation
  • Depressive disorder
  • Body mass index less than 18 points or higher than 25 points
  • 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 Previous history of deep vein thrombosis or pulmonary embolism in the last 12 months.
  • Patients with postmenopausal vaginal bleeding with no defined etiology.
  • Patients with breast cancer who need to use tamoxifen for this neoplasm
  • Another synchronous neoplasm that requires systemic treatment Patients with aggressive disease requiring cytotoxic therapy or locoregional therapies (eg hepatic embolization) A history of serious clinical or psychiatric illness that, by clinical judgment, may involve participation risk in this study
  • Patients participating in other protocols with experimental drugs.
  • Patients with oral food difficulties.
  • Patients who underwent major recent surgery less than 4 weeks previously.
  • Patients receiving chemotherapy or other oncologic therapy for less than 3 weeks
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04568096
Other Study ID Numbers  ICMJE COVID-2019
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Mahmoud Ramadan mohamed Elkazzaz, Kafrelsheikh University
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Kafrelsheikh University
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Mahmoud Elkazzaz, B.Sc in Biochemistry Facculty of Science, Damietta University
PRS Account Kafrelsheikh University
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP