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

Study Overview
=================
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.

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.

Conditions
-----------------
Coronavirus, Inflammation, Covid19

Intervention / Treatment
-----------------
* Drug: Methotrexate-LDE phase 1
* Drug: Methotrexate-LDE phase 2
* Drug: Placebo-LDE phase 2


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This will be a randomized, double-blind, placebo-controlled, multi-center study.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MTX-LDE phase 1<br>Methotrexate carried by a lipid nanoparticle (MTX-LDE) | Drug: Methotrexate-LDE phase 1<br>* 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<br>* Other names: MTX-LDE phase 1;|
| Experimental: MTX-LDE phase 2<br>Methotrexate carried by a lipid nanoparticle (MTX-LDE) | Drug: Methotrexate-LDE phase 2<br>* 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<br>* Other names: MTX-LDE phase 2;|
| Placebo Comparator: Placebo-LDE phase 2<br>Lipid nanoparticle (LDE) | Drug: Placebo-LDE phase 2<br>* 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<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of hospital stay | Compare the duration of hospital stay between groups | 30 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants requiring mechanical ventilation | The secondary outcome is the need for mechanical ventilation between groups | 15 days after randomization | 
| Number of participants requiring vasoactive drugs | The secondary outcome is the need for vasoactive drugs between groups | 15 days after randomization | 
| Number of participants requiring renal replacement therapy | The secondary outcome is the need for renal replacement therapy between groups | 15 days after randomization | 
| Incidence of secondary infection | The secondary outcome is the incidence of secondary infection between groups | 15 days after randomization | 
| 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 | 
| 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 | 
| 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 | 
| Dimer-D | The secondary outcome is the comparison of dimer-D levels between groups | Baseline and change from baseline to 15 days after randomization | 
| 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 | 
| 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 | 
| 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 | 
| Other adverse events | Compare the incidence of other adverse events (not expected) between groups | 30 days after randomization | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
coronavirus, inflammation, nanoparticles, methotrexate, covid19