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

NCT04610567 | Unknown Phase 1 DMC

• 1 other identifier: 36746020.5.1001.0068
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 3

Brief 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.

Conditions

Coronavirus; Inflammation; Covid19

Keywords

coronavirus; inflammation; nanoparticles; methotrexate; covid19

Outcome Measures

Primary Outcomes (1)

• Duration of hospital stay

  Compare the duration of hospital stay between groups

  30 days after randomization

Secondary Outcomes (12)

• Number of participants requiring mechanical ventilation

  15 days after randomization

• Number of participants requiring vasoactive drugs

  15 days after randomization

• Number of participants requiring renal replacement therapy

  15 days after randomization

• Incidence of secondary infection

  15 days after randomization

• Sequential Organ Failure Assessment (SOFA) score

  Baseline and change from baseline to 15 days after randomization

Study Arms (3)

MTX-LDE phase 1

EXPERIMENTAL

Methotrexate carried by a lipid nanoparticle (MTX-LDE)

Drug: Methotrexate-LDE phase 1

MTX-LDE phase 2

EXPERIMENTAL

Methotrexate carried by a lipid nanoparticle (MTX-LDE)

Drug: Methotrexate-LDE phase 2

Placebo-LDE phase 2

PLACEBO COMPARATOR

Lipid nanoparticle (LDE)

Drug: Placebo-LDE phase 2

Interventions

Methotrexate-LDE phase 1 DRUG

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

Also known as: MTX-LDE phase 1

MTX-LDE phase 1

Methotrexate-LDE phase 2 DRUG

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

Also known as: MTX-LDE phase 2

MTX-LDE phase 2

Placebo-LDE phase 2 DRUG

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

Placebo-LDE phase 2

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Sao Paulo General Hospital: lead
• Hospital Santa Marcelina: collaborator

Study Sites (3)

Heart Institute (InCor) - University of São Paulo Medical School, São Paulo, Brazil

São Paulo, São Paulo, 05403900, Brazil

RECRUITING

Hospital Santa Marcelina

São Paulo, São Paulo, Brazil

NOT YET RECRUITING

Institute Prevent Senior

São Paulo, São Paulo, Brazil

NOT YET RECRUITING

Related Publications (14)

• 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.

  PMID: 32293910 BACKGROUND

• 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.

  PMID: 32616381 BACKGROUND

• 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):2095. doi: 10.3390/jcm9072095.

  PMID: 32635302 BACKGROUND

• 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.

  PMID: 32337664 BACKGROUND

• Barbieri LR, Lourenco-Filho DD, Tavares ER, Carvalho PO, Gutierrez PS, Maranhao 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.

  PMID: 28347533 BACKGROUND

• Bulgarelli A, Leite AC Jr, Dias AA, Maranhao 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.

  PMID: 24065615 BACKGROUND

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

  PMID: 22113347 BACKGROUND

• Maranhao 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.

  PMID: 25585820 BACKGROUND

• Maranhao 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.

  PMID: 28553113 BACKGROUND

• 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. No abstract available.

  PMID: 32122636 RESULT

• 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.

  PMID: 32007143 RESULT

• 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.

  PMID: 32653469 RESULT

• 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.

  PMID: 32211963 RESULT

• Cronstein BN. Molecular therapeutics. Methotrexate and its mechanism of action. Arthritis Rheum. 1996 Dec;39(12):1951-60. doi: 10.1002/art.1780391203. No abstract available.

  PMID: 8961899 RESULT

Related Links

• WHO COVID-19 Therapeutic Trial Synopsis

MeSH Terms

Conditions

Coronavirus Infections; Inflammation; COVID-19

Condition Hierarchy (Ancestors)

Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Central Study Contacts

Raul Maranhão, MD;PhD

CONTACT

+551126615951; raul.maranhao@incor.usp.br

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD; PHD. Director Lipid Metabolism Laboratory, Heart Institute

Model Details: This will be a randomized, double-blind, placebo-controlled, multi-center study.

Study Record Dates

• First Submitted: October 24, 2020
• First Posted: October 30, 2020
• Study Start: October 27, 2020
• Primary Completion: March 15, 2021
• Study Completion: July 15, 2021
• Last Updated: January 14, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share

Locations

BR (3)