Coronavirus, Covid19, Inflammation
Conditions
Keywords
coronavirus, inflammation, nanoparticles, methotrexate, covid19
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.
Interventions
DRUGMethotrexate-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
DRUGMethotrexate-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
DRUGPlacebo-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
Sponsors
Hospital Santa Marcelina
University of Sao Paulo General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Intervention model description
This will be a randomized, double-blind, placebo-controlled, multi-center study.
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Duration of hospital stay | 30 days after randomization | Compare the duration of hospital stay between groups |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants requiring vasoactive drugs | 15 days after randomization | The secondary outcome is the need for vasoactive drugs between groups |
| Number of participants requiring renal replacement therapy | 15 days after randomization | The secondary outcome is the need for renal replacement therapy between groups |
| Incidence of secondary infection | 15 days after randomization | The secondary outcome is the incidence of secondary infection between groups |
| Sequential Organ Failure Assessment (SOFA) score | Baseline and change from baseline to 15 days after randomization | The secondary outcome is the comparison of Sequential Organ Failure Assessment (SOFA) score between groups |
| World Health Organization (WHO) COVID-19 score | Baseline and change from baseline to 15 days after randomization | The secondary outcome is the comparison of World Health Organization (WHO) COVID-19 clinical score between groups |
| Number of participants requiring mechanical ventilation | 15 days after randomization | The secondary outcome is the need for mechanical ventilation between groups |
| Dimer-D | Baseline and change from baseline to 15 days after randomization | The secondary outcome is the comparison of dimer-D levels between groups |
| Chest CT scan | Baseline and change from baseline to 15 days after randomization | The secondary outcome is the comparison of chest CT scan between groups |
| Incidence and severity of laboratory alterations | 30 days after randomization | The secondary outcome is the comparison of red blood cells; white blood cells;Platelets; Urea;Creatinine levels between groups |
| Clinical side effects | 30 days after randomization | Compare the incidence of clinical significant symptoms (new and persistent stomatitis, vomiting, diarrhea, alopecia, neurotoxicity, bradycardia, hypotension, local pain) reported between groups. |
| Other adverse events | 30 days after randomization | Compare the incidence of other adverse events (not expected) between groups |
| Interleukin 6 (IL-6) | Baseline and change from baseline to 15 days after randomization | The secondary outcome is the comparison of IL-6 levels between groups |
Countries
Brazil
Contacts
Primary ContactRaul Maranhão, MD;PhD
Outcome results
None listed