Evaluation of Efficacy of Levamisole and Formoterol+Budesonide in Treatment of COVID-19

COVID-19 Clinical Trial

Official title:

Evaluation of Efficacy of Pharmacotherapy Treatment of COVID- 19 Infection Using Oral Levamisole and Formoterol+Budesonide Inhaler and Comparison of This Treatment Protocol With Standard National Treatment of the Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04331470
• Other study ID #: 97548
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: April 4, 2020
• Est. completion date: May 20, 2020

Study information

• Verified date: April 2020
• Source: Fasa University of Medical Sciences
• Contact: Siamack Afazeli, Pharm.D
• Phone: +989121392982
• Email: Dr.afazeli[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

New Corona virus (COVID-19) has made a horrible situation for all of the countries. This disease is not only a health problem but also economy, culture and the whole entity of the countries is under attack by the virus. This disease seems to affect the body in two different pathology pathways. From one side virus can decrease activity of immune system in the blood stream and whole body and from other side it can attack the respiratory cells. Tissue biopsy shows that immune cells penetrate into the Lung tissue and we have accumulation and over activity of Immune cells in the lung. This inflammation in respiratory tract probably is the major cause of Cytokine storm and release of TNF-α and IL-6 into the blood.

It seems that by three strategy disease can be treated. 1- By using systemic immune simulators. 2- By using topical anti-inflammatory drug in the respiratory system (Steroids or NSAIDs) 3- By inhibition of replication of the virus in the attacked cells.

Description:

Looking at the pathology of this disease shows that COVID-19 virus binds to the Angiotensin converting enzyme II (ACE II) which is located on the surface of different cells in the body and specially on the cells of respiratory system. This enzyme is responsible to turn angiotensin II into angiotensin1-7. It is also turns angiotensin I into angiotensin 1-9.

When ACEII would be blocked by virus level of angiotensin II will be increased and this enzyme along with vasoconstriction, makes cells to manufacture TNF α and IL-6 which are responsible for cytokine storm and Lymphopenia. Also presence of virus and virus shell on the surface of the infected cells make immune system to attack to the respiratory system hence effect of angiotensin II inside the cell causes fibrosis of the respiratory cells. This inflammation and tissue damage make Acute Respiratory Distress syndrome (ARDS) which is lethal for patients. There is a dilemma in treatment of this infection. From one side it doesn't make sense to decrease the immune response hence it will make the infection worse. And from other side stimulation of the immune response because of respiratory inflammation can expedite process of lethal ARDS. A new strategy for treatment of this disease which consists of local anti- inflammatory and systemic immune stimulant drugs can be considered as a reasonable strategy.As immunostimulator, Levamisole can increase Lymphocytes and empower the immunity of the body. This drug can also bind to Papaine Like Protease(PL-pro) of the shell of the virus which is necessary for virulence of COVID-19. It also can decrease level of TNF α and IL-6, and as a chemical adjutant can introduce the virus to the immune system. In addition to Levamisole, Formoterol+Budesonide inhaler can be used in this protocol. Budesonide is a steroid and can suppress the immune reaction locally in the respiratory system. Formoterol is β2 agonist and can open airways. It also can bind to PL-pro and can neutralize the virus according to the published articles.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: May 20, 2020
• Est. primary completion date: April 20, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 15 Years to 100 Years

Eligibility

Inclusion Criteria:

Definitely positive COVID-19 patients

Exclusion Criteria:

Patients with acute respiratory problems including patients with:

1. Spo2<60%

2. Severe respiratory distress

3. Heamodynamic instabilitty

4. Acid base disturbance

5. Severe Anemia Patients with severe hepatic diseases Patients with Nurvous system diseases

Related Conditions & MeSH terms

• COVID-19

Intervention

Drug:
• Levamisole Pill + Budesonide+Formoterol inhaler
Levamisole 50 mg tablet has to be taken 1-2 tablets every 8 hours Budesonide+Formoterol has to be inhaled 1-2 puff every 12 hours
• Lopinavir/Ritonavir + hydoxychloroquine
Hydroxy Chloroquine 200mg single dise Lopinavir/Ritonavir 2 tablets every 12 hours

Locations

Country	Name	City	State
Iran, Islamic Republic of	Vali-Asr Hospital	Fasa	Fars

Sponsors (1)

Lead Sponsor	Collaborator
Fasa University of Medical Sciences

Country where clinical trial is conducted

Iran, Islamic Republic of, 

References & Publications (18)

Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods

Chen J. [How to understand the histopathology of SARS and COVID-19 associated with acute respiratory distress syndrome]. Zhonghua Bing Li Xue Za Zhi. 2020 Mar 11;49(0):E007. doi: 10.3760/cma.j.cn112151-20200309-00185. [Epub ahead of print] Chinese. — View Citation

Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 Feb 15;395(10223):507-513. doi: 10.1016/S0140-6736(20)30211-7. Epub 2020 Jan 30. — View Citation

Gruppen MP, Bouts AH, Jansen-van der Weide MC, Merkus MP, Zurowska A, Maternik M, Massella L, Emma F, Niaudet P, Cornelissen EAM, Schurmans T, Raes A, van de Walle J, van Dyck M, Gulati A, Bagga A, Davin JC; all members of the Levamisole Study Group. A randomized clinical trial indicates that levamisole increases the time to relapse in children with steroid-sensitive idiopathic nephrotic syndrome. Kidney Int. 2018 Feb;93(2):510-518. doi: 10.1016/j.kint.2017.08.011. Epub 2017 Oct 18. — View Citation

Guignabert C, de Man F, Lombès M. ACE2 as therapy for pulmonary arterial hypertension: the good outweighs the bad. Eur Respir J. 2018 Jun 21;51(6). pii: 1800848. doi: 10.1183/13993003.00848-2018. Print 2018 Jun. — View Citation

Gullestad L, Aukrust P, Ueland T, Espevik T, Yee G, Vagelos R, Frøland SS, Fowler M. Effect of high- versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure. J Am Coll Cardiol. 1999 Dec;34(7):2061-7. — View Citation

Jiang F, Yang J, Zhang Y, Dong M, Wang S, Zhang Q, Liu FF, Zhang K, Zhang C. Angiotensin-converting enzyme 2 and angiotensin 1-7: novel therapeutic targets. Nat Rev Cardiol. 2014 Jul;11(7):413-26. doi: 10.1038/nrcardio.2014.59. Epub 2014 Apr 29. Review. — View Citation

Jin HY, Chen LJ, Zhang ZZ, Xu YL, Song B, Xu R, Oudit GY, Gao PJ, Zhu DL, Zhong JC. Deletion of angiotensin-converting enzyme 2 exacerbates renal inflammation and injury in apolipoprotein E-deficient mice through modulation of the nephrin and TNF-alpha-TNFRSF1A signaling. J Transl Med. 2015 Aug 6;13:255. doi: 10.1186/s12967-015-0616-8. — View Citation

Lee KY. Pneumonia, Acute Respiratory Distress Syndrome, and Early Immune-Modulator Therapy. Int J Mol Sci. 2017 Feb 11;18(2). pii: E388. doi: 10.3390/ijms18020388. Review. — View Citation

Meng Y, Li T, Zhou GS, Chen Y, Yu CH, Pang MX, Li W, Li Y, Zhang WY, Li X. The angiotensin-converting enzyme 2/angiotensin (1-7)/Mas axis protects against lung fibroblast migration and lung fibrosis by inhibiting the NOX4-derived ROS-mediated RhoA/Rho kinase pathway. Antioxid Redox Signal. 2015 Jan 20;22(3):241-58. doi: 10.1089/ars.2013.5818. Epub 2014 Oct 2. — View Citation

Potential inhibitors against papain-like protease of novel coronavirus (COVID-19) from FDA approved drugs ,Rimanshee Arya1, Amit Das1, Vishal Prashar1,*, Mukesh Kumar1, 2,* 1Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai-400085, India 2Homi Bhabha National Institute, Mumbai-400094, India

Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun. 2020 May;109:102433. doi: 10.1016/j.jaut.2020.102433. Epub 2020 Feb 26. Review. — View Citation

Ruiz-Ortega M, Ruperez M, Lorenzo O, Esteban V, Blanco J, Mezzano S, Egido J. Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney. Kidney Int Suppl. 2002 Dec;(82):S12-22. — View Citation

Santos RA, Ferreira AJ, Verano-Braga T, Bader M. Angiotensin-converting enzyme 2, angiotensin-(1-7) and Mas: new players of the renin-angiotensin system. J Endocrinol. 2013 Jan 18;216(2):R1-R17. doi: 10.1530/JOE-12-0341. Print 2013 Feb. Review. — View Citation

Szefler SJ. Pharmacodynamics and pharmacokinetics of budesonide: a new nebulized corticosteroid. J Allergy Clin Immunol. 1999 Oct;104(4 Pt 2):175-83. Review. — View Citation

Tikellis C, Thomas MC. Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease. Int J Pept. 2012;2012:256294. doi: 10.1155/2012/256294. Epub 2012 Mar 20. — View Citation

Xu H, Zhong L, Deng J, Peng J, Dan H, Zeng X, Li T, Chen Q. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci. 2020 Feb 24;12(1):8. doi: 10.1038/s41368-020-0074-x. — View Citation

Zhang BN, Xu H, Gao XM, Zhang GZ, Zhang X, Yang F. Protective Effect of Angiotensin (1-7) on Silicotic Fibrosis in Rats. Biomed Environ Sci. 2019 Jun;32(6):419-426. doi: 10.3967/bes2019.057. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clear chest CT-scan	Chest Ct scan should be negative	between 3-7 days
Primary	PCR test	PCR test should be negative	between 3-7 days
Secondary	Physical statues of patient	Patient should relief from signs of disease	Between 3-7 days

External Links

•   Potential inhibitors against papain-like protease of novel coronavirus (COVID-19) from FDA approved drugs