Treatment of Patients With Mild Coronavirus-19 (COVID-19) Disease With Methotrexate Associated to LDL Like Nanoparticles (Nano-COVID19)

Covid19 Clinical Trial

— Nano-COVID19  

Official title:

Two Phases Clinical Trial to Evaluate Safety and Efficacy of Methotrexate Associated to LDL Like Nanoparticles (LDE-MTX) in the Treatment of Patients With Mild Coronavirus-19 (COVID-19) Disease.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04610567
• Other study ID #: 36746020.5.1001.0068
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: October 27, 2020
• Est. completion date: July 15, 2021

Study information

• Verified date: January 2021
• Source: University of Sao Paulo General Hospital
• Contact: Raul Maranhão, MD;PhD
• Phone: +551126615951
• Email: raul.maranhao[@]incor.usp.br
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The investigators propose a prospective, randomized, double-blind, placebo-controlled study, conducted in two phases. The purpose of the study is to evaluate the safety and efficacy of methotrexate in a cholesterol-rich non-protein nanoparticle (MTX -LDE) in adults diagnosed with mild Coronavirus-19(COVID-19) disease.

A total of 100 patients will be randomized to receive MTX-LDE or placebo each 7 days, up to 3 times, during in hospital treatment.

Description:

The objective of the study is to evaluate the safety and efficacy of (MTX -LDE) in patients with mild Coronavirus-19 (COVID-19) disease.

In phase 1, firstly 3 patients with moderate COVID-19 disease will receive MTX-LDE IV 15mg each 7 days, up to 3 times, during hospitalization. After that, 9 patients with moderate COVID-19 disease will receive MTX-LDE IV 30mg each 7 days, up to 3 times, during hospitalization. Follow-up assessments will occur daily following randomization during in hospital treatment and 2 weeks after discharge for evaluation of the occurrence of adverse events.The purpose of this phase will be evaluate safety and pharmacokinetics.

If no objection by data and safety monitoring board (DSMB), will be authorized to start the second phase.

In phase 2, 88 patients with moderate COVID-19 disease will be randomized to receive MTX-LDE IV 30mg or placebo-LDE IV each 7 days, up to 3 times, during hospitalization. Follow-up assessments will occur daily following randomization during in hospital treatment and 2 weeks after discharge for evaluation of the occurrence of any trial endpoints or other adverse events.The primary endpoint of this phase will be reduction in duration of hospitalization stay between groups.

Patients will undergo clinical and laboratory safety evaluations daily. An algorithm for drug suspension based on clinical and laboratory finding will be followed.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: July 15, 2021
• Est. primary completion date: March 15, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

Inclusion Criteria:

• Patients who were hospitalized with confirmed COVID-19

• Mild Coronavirus-19 disease (WHO Coronavirus-19 scale < 5)

• Fewer than 14 days since symptom onset.

• Female patient is not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile.

• Female patient is of childbearing potential must has a negative pregnancy test.

• Signing the study informed consent.

Exclusion Criteria:

• Need for oxygen supplementation >4 L/min via nasal cannula or =40% via Venturi mask.

• Need for oxygen supplementation via high-flow nasal cannula.

• Need for invasive mechanical ventilation.

• Extent of pulmonary involvement > 50% by CT scan.

• Chronic renal failure (estimated glomerular filtration rate <30 mL/min/1.73 m2)

• History of liver cirrhosis (Bilirubins levels > 3mg/dl)

• History of heart failure ( Ejection fraction <40%)

• History of Steven-Johnson disease

• History of stroke in the last 6 months

• History of sickle cell disease

• Chronic use of oral steroid therapy or other immunosuppressive or biologic response modifiers.

• Prior history of chronic hepatitis B or C infection and known HIV positive.

• Patient undergoing chemotherapy for cancer

• Sepsis caused by fungal or multidrug resistant gram-negative bacteria

• Known allergy to methotrexate.

• Body mass index(BMI) > 40 or <18.5

• Pregnancy or breastfeeding.

• Patients enrolled in other clinical trials in the last 12 months

• Patient is considered by the investigator, for any reason, to be an unsuitable candidate for the study.

Related Conditions & MeSH terms

• Coronavirus
• Coronavirus Infections
• Covid19
• Inflammation

Intervention

Drug:
• Methotrexate-LDE phase 1
3 patients will receive MTX-LDE at the dose of 15mg IV each 7 days during hospitalization, up to 3 times . After that, 9 patients will receive MTX-LDE at the dose of 30mg IV each 7 days during hospitalization, up to 3 times . All patients will receive Leucovorin (calcium foliate) 25mg IV, 24hr after administration of MTX-LDE
• Methotrexate-LDE phase 2
44 patients will receive MTX-LDE at the dose of 30mg IV each 7 days during hospitalization, up to 3 times dose of 30mg IV each 7 days during hospitalization, up to 3 times . All patients will receive Leucovorin (calcium foliate) 25mg IV, 24hr after administration of MTX-LDE
• Placebo-LDE phase 2
44 patients will receive Placebo-LDE IV each 7 days during hospitalization, up to 3 times dose of 30mg IV each 7 days during hospitalization, up to 3 times . All patients will receive Leucovorin (calcium foliate) 25mg IV, 24hr after administration of Placebo-LDE

Locations

Country	Name	City	State
Brazil	Heart Institute (InCor) - University of São Paulo Medical School, São Paulo, Brazil	São Paulo	SP
Brazil	Hospital Santa Marcelina	São Paulo	SP
Brazil	Institute Prevent Senior	São Paulo	SP

Sponsors (2)

Lead Sponsor	Collaborator
University of Sao Paulo General Hospital	Hospital Santa Marcelina

Country where clinical trial is conducted

Brazil, 

References & Publications (14)

Barbieri LR, Lourenço-Filho DD, Tavares ER, Carvalho PO, Gutierrez PS, Maranhão RC, Stolf NAG. Influence of Drugs Carried in Lipid Nanoparticles in Coronary Disease of Rabbit Transplanted Heart. Ann Thorac Surg. 2017 Aug;104(2):577-583. doi: 10.1016/j.athoracsur.2016.12.044. Epub 2017 Mar 24. — View Citation

Bulgarelli A, Leite AC Jr, Dias AA, Maranhão RC. Anti-atherogenic effects of methotrexate carried by a lipid nanoemulsion that binds to LDL receptors in cholesterol-fed rabbits. Cardiovasc Drugs Ther. 2013 Dec;27(6):531-9. doi: 10.1007/s10557-013-6488-3. — View Citation

Bulgarelli A, Martins Dias AA, Caramelli B, Maranhão RC. Treatment with methotrexate inhibits atherogenesis in cholesterol-fed rabbits. J Cardiovasc Pharmacol. 2012 Apr;59(4):308-14. doi: 10.1097/FJC.0b013e318241c385. — 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 — View Citation

Cronstein BN. Molecular therapeutics. Methotrexate and its mechanism of action. Arthritis Rheum. 1996 Dec;39(12):1951-60. Review. — View Citation

Liu PP, Blet A, Smyth D, Li H. The Science Underlying COVID-19: Implications for the Cardiovascular System. Circulation. 2020 Jul 7;142(1):68-78. doi: 10.1161/CIRCULATIONAHA.120.047549. Epub 2020 Apr 15. — View Citation

Maranhão RC, Guido MC, de Lima AD, Tavares ER, Marques AF, Tavares de Melo MD, Nicolau JC, Salemi VM, Kalil-Filho R. Methotrexate carried in lipid core nanoparticles reduces myocardial infarction size and improves cardiac function in rats. Int J Nanomedicine. 2017 May 17;12:3767-3784. doi: 10.2147/IJN.S129324. eCollection 2017. — View Citation

Maranhão RC, Tavares ER. Advances in non-invasive drug delivery for atherosclerotic heart disease. Expert Opin Drug Deliv. 2015 Jul;12(7):1135-47. doi: 10.1517/17425247.2015.999663. Epub 2015 Jan 14. Review. — View Citation

Mitchell WB. Thromboinflammation in COVID-19 acute lung injury. Paediatr Respir Rev. 2020 Sep;35:20-24. doi: 10.1016/j.prrv.2020.06.004. Epub 2020 Jun 11. Review. — View Citation

Shah A, Kashyap R, Tosh P, Sampathkumar P, O'Horo JC. Guide to Understanding the 2019 Novel Coronavirus. Mayo Clin Proc. 2020 Apr;95(4):646-652. doi: 10.1016/j.mayocp.2020.02.003. Epub 2020 Feb 28. — View Citation

Solinas C, Perra L, Aiello M, Migliori E, Petrosillo N. A critical evaluation of glucocorticoids in the management of severe COVID-19. Cytokine Growth Factor Rev. 2020 Aug;54:8-23. doi: 10.1016/j.cytogfr.2020.06.012. Epub 2020 Jun 24. Review. — View Citation

Vinciguerra M, Romiti S, Fattouch K, De Bellis A, Greco E. Atherosclerosis as Pathogenetic Substrate for Sars-Cov2 Cytokine Storm. J Clin Med. 2020 Jul 3;9(7). pii: E2095. doi: 10.3390/jcm9072095. Review. — View Citation

Zhang S, Li L, Shen A, Chen Y, Qi Z. Rational Use of Tocilizumab in the Treatment of Novel Coronavirus Pneumonia. Clin Drug Investig. 2020 Jun;40(6):511-518. doi: 10.1007/s40261-020-00917-3. Review. — View Citation

Zhou Z, Guo D, Li C, Fang Z, Chen L, Yang R, Li X, Zeng W. Coronavirus disease 2019: initial chest CT findings. Eur Radiol. 2020 Aug;30(8):4398-4406. doi: 10.1007/s00330-020-06816-7. Epub 2020 Mar 24. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Duration of hospital stay	Compare the duration of hospital stay between groups	30 days after randomization
Secondary	Number of participants requiring mechanical ventilation	The secondary outcome is the need for mechanical ventilation between groups	15 days after randomization
Secondary	Number of participants requiring vasoactive drugs	The secondary outcome is the need for vasoactive drugs between groups	15 days after randomization
Secondary	Number of participants requiring renal replacement therapy	The secondary outcome is the need for renal replacement therapy between groups	15 days after randomization
Secondary	Incidence of secondary infection	The secondary outcome is the incidence of secondary infection between groups	15 days after randomization
Secondary	Sequential Organ Failure Assessment (SOFA) score	The secondary outcome is the comparison of Sequential Organ Failure Assessment (SOFA) score between groups	Baseline and change from baseline to 15 days after randomization
Secondary	World Health Organization (WHO) COVID-19 score	The secondary outcome is the comparison of World Health Organization (WHO) COVID-19 clinical score between groups	Baseline and change from baseline to 15 days after randomization
Secondary	Interleukin 6 (IL-6)	The secondary outcome is the comparison of IL-6 levels between groups	Baseline and change from baseline to 15 days after randomization
Secondary	Dimer-D	The secondary outcome is the comparison of dimer-D levels between groups	Baseline and change from baseline to 15 days after randomization
Secondary	Chest CT scan	The secondary outcome is the comparison of chest CT scan between groups	Baseline and change from baseline to 15 days after randomization
Secondary	Incidence and severity of laboratory alterations	The secondary outcome is the comparison of red blood cells; white blood cells;Platelets; Urea;Creatinine levels between groups	30 days after randomization
Secondary	Clinical side effects	Compare the incidence of clinical significant symptoms (new and persistent stomatitis, vomiting, diarrhea, alopecia, neurotoxicity, bradycardia, hypotension, local pain) reported between groups.	30 days after randomization
Secondary	Other adverse events	Compare the incidence of other adverse events (not expected) between groups	30 days after randomization

External Links

•   WHO COVID-19 Therapeutic Trial Synopsis