Clinical trial NCT04610567: Treatment of Patients With Mild Coronavirus-19 (COVID-19) Disease With Methotrexate Associated to LDL Like Nanoparticles (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.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Coronavirus
Inflammation
Covid19
Keywords: coronavirus
inflammation
nanoparticles
methotrexate
covid19
Lead sponsor: University of Sao Paulo General Hospital
Sponsor class: OTHER
Collaborators: name: Hospital Santa Marcelina
First posted: 2020-10-30
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This will be a randomized, double-blind, placebo-controlled, multi-center study.
Primary purpose: TREATMENT

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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Duration of hospital stay
timeFrame: 30 days after randomization
Secondary outcomes:
measure: Number of participants requiring mechanical ventilation
timeFrame: 15 days after randomization
measure: Number of participants requiring vasoactive drugs
timeFrame: 15 days after randomization
measure: Number of participants requiring renal replacement therapy
timeFrame: 15 days after randomization
measure: Incidence of secondary infection
timeFrame: 15 days after randomization
measure: Sequential Organ Failure Assessment (SOFA) score
timeFrame: Baseline and change from baseline to 15 days after randomization
measure: World Health Organization (WHO) COVID-19 score
timeFrame: Baseline and change from baseline to 15 days after randomization
measure: Interleukin 6 (IL-6)
timeFrame: Baseline and change from baseline to 15 days after randomization
measure: Dimer-D
timeFrame: Baseline and change from baseline to 15 days after randomization
measure: Chest CT scan
timeFrame: Baseline and change from baseline to 15 days after randomization
measure: Incidence and severity of laboratory alterations
timeFrame: 30 days after randomization
measure: Clinical side effects
timeFrame: 30 days after randomization
measure: Other adverse events
timeFrame: 30 days after randomization
Other outcomes:
Locations:
city: São Paulo
country: Brazil
facility: Heart Institute (InCor) - University of São Paulo Medical School, São Paulo, Brazil
state: SP
city: São Paulo
country: Brazil
facility: Hospital Santa Marcelina
state: SP
city: São Paulo
country: Brazil
facility: Institute Prevent Senior
state: SP
Study officials:
References:
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.
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.
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):2095. doi: 10.3390/jcm9072095.
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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
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. No abstract available.
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.
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.
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.
citation: 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.