Safety and Efficacy of Maraviroc and/or Favipiravir With Standard Therapy in Severe COVID-19 Adults

Study Overview
=================
Brief Summary
-----------------
Phase 2, randomized, open-label study to evaluate the safety and efficacy of maraviroc, favipiravir, and both drugs administered along with currently used therapy in hospitalized patients with pulmonary SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infection (COVID-19)

Detailed Description
-----------------
The COVID-19 pandemic (Coronavirus Disease-19) caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) has caused more that 10 million infections worldwide, with a general mortality of 6%. Multiple studies have found that the hyperinflammatory immune response induced by SARS-CoV-2 is one of the main causes of severity and death in infected patients. In severe COVID-19 patients, an association was found between pneumonitis and/or ARDS (Acute Severe Respiratory Syndrome), increased serum levels of cytokines and chemokines, extensive lung damage and microthrombosis. Studies of both gene expression in lungs and blood cytokines and chemokines have related chemokine signaling clusters with COVID-19 severity, being CCL3, CCL4 and CCL7 (CC chemokine ligands 3, 4 and 7) particularly interesting. All these are CCR5 (CC chemokine receptor 5) ligands. A strategy to modulate activation and trafficking of leukocytes to the lungs is by blocking CCR5 by using maraviroc (MVC), which has shown capable of modulating conditions of generalized inflammation. Along with a good regulation of the immune response, an antiviral that helps to reduce the viral load must be considered. Favipiravir (FPV) has shown to be capable to reduce the time of viral clearance by half. Hence, we propose that the conjoint use of MVC and FPV could help to reduce the progression of severe hospitalized COVID-19 patients to critical by decreasing the percentage of patients in need of mechanical respiratory support or death by at least 30%. This is a randomized, controlled clinical trial that besides evaluating the safety and efficacy of MVC+FPV to avoid progression in severe COVID-19 patients as a primary endpoint, is also aimed at other secondary endpoints: A) Evaluate the activation of CCR5 in peripheral blood lymphocytes, monocytes, and neutrophils. B) Find possible modifications in the ongoing chemokine and cytokine storm in serum, particularly IL-6, IL-1b, (interleukins 6 and 1 beta) TNF (tumor necrosis factor), IFNa, IFNg (interferons alpha and gamma), VEGF (vascular endothelial growth factor), CXCL10 (CXC chemokine ligand 10), CCL7, CCL3, and CCL5 (CC chemokine ligands 7, 3 and 5), C) Search for alterations in the patterns of activation, trafficking, and exhaustion of peripheral blood lymphocytes, monocytes and neutrophils, and D) Determine if it has an effect in viral loads in saliva. 100 severe patients tested positive for SARS-CoV-2 will be randomized in 4 treatment arms: Arm A: Currently used therapy (CT) only, Enoxaparin, dexamethasone, and antibiotics if associated bacteremia is present, as per currently used at Hospital General de México Dr. Eduardo Liceaga). Arm B: CT+MVC Arm C: CT+FPV Arm D: CT+MVC+FPV

Official Title
-----------------
Phase2, Randomized, Controlled Study to Evaluate the Efficacy and Safety of Maraviroc and/or Favipiravir Plus Standard Therapy in Adult Patients With Severe Non-critical COVID-19

Conditions
-----------------
COVID-19

Intervention / Treatment
-----------------
* Drug: Maraviroc + Currently used therapy
* Procedure: Curently used therapy for COVID-19 non-critical patients
* Drug: Favipiravir + Currently used therapy
* Drug: Maraviroc+Favipiravir+CT


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: With severe non-critical stage of COVID at the time of admission. Patients tested positive for SARS-CoV-2 confirmed by PCR (Polymerase Chain Reaction) or quick antigen test Within the first 12 days post appearance of symptoms With at least one of the following risk factors: Diabetes mellitus (DM), obesity (BMI>30, hypertension, age > 65 years. Respiratory rate 25-34/min and no signs of respiratory distress. With at least two of the following indicators of severity: SpO2 81-90%, PaFi 150-300 mmHg, FiO2>60% , lung damage in thorax radiographic image => 25% as determined by RALE score (an equivalent to 2-4). Normal liver function (Considered up to a fivefold increase above the normal limits of hepatic transaminases) Signed informed consent Exclusion Criteria: Pregnant or lactating women Patients already participating in another clinical study Oxygen saturation < 70% (ambient) Clinical evidence of an infectious disease different from COVID at the time of admission Chronic kidney failure Coronary disease Glomerular filtration rate < 30ml/min/1.73 m2 and known history of preexisting chronic renal failure (Chronic kidney disease stages 4-5) Known history of HCV, HBV and/or clinical signs of hepatic liver failure. Any type of cancer HIV and/or any anti retroviral treatment Inability to freely decide to participate Psychotropics treatment Erythromycin treatment Polydrug use (Defined as more than two addictions combined) With transplant background With any autoimmune disorder With known hypersensibility to maraviroc and/or favipiravir On invasive mechanical ventilation at the time of randomization

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 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: 100 participants will be included and allocated in 4 groups of 25 each [Currently used therapy (CT), Maraviroc+CT, Favipiravir+CT and Maraviroc+Favipiravir+CT]. Subjects will be randomized using EPIDAT 4.2
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Currently used therapy (CT) only<br>Treatment currently used at Hospital General de México Dr. Eduardo Liceaga for non-critical COVID patients: Enoxaparin, dexamethasone, and antibiotics if associated bacteremia is present. | Procedure: Curently used therapy for COVID-19 non-critical patients<br>* Enoxaparin, dexamethasone, and antibiotics if associated bacteremia is present, as per currently used at Hospital General de México Dr. Eduardo Liceaga<br>* Other names: CT only;|
| Experimental: Maraviroc+CT<br>Maraviroc AND treatment currently used at Hospital General de México Dr. Eduardo Liceaga for non-critical COVID patients. | Drug: Maraviroc + Currently used therapy<br>* Maraviroc tablets. 300 mg bid, given orally for a 10 day period AND CT (Enoxaparin, dexamethasone, and antibiotics if associated bacteremia is present, as per currently used at Hospital General de México Dr. Eduardo Liceaga)<br>* Other names: MVC+CT;|
| Experimental: Favipiravir+CT<br>Favipiravir AND treatment currently used at Hospital General de México Dr. Eduardo Liceaga for non-critical COVID patients. | Drug: Favipiravir + Currently used therapy<br>* Favipiravir tablets 200 mg. given orally for a 7 day period. 1600 mg bid on day 1 and 600 mg tid days 2-7 AND CT (Enoxaparin, dexamethasone, and antibiotics if associated bacteremia is present, as per currently used at Hospital General de México Dr. Eduardo Liceaga).<br>* Other names: FPV+CT;|
| Experimental: Maraviroc+Favipiravir+CT<br>Maraviroc AND Favipiravir AND treatment currently used at Hospital General de México Dr. Eduardo Liceaga for non-critical COVID patients | Drug: Maraviroc+Favipiravir+CT<br>* Maraviroc tablets. 300 mg bid, given orally for a 10 day period AND Favipiravir tablets 200 mg. given orally for the first 7 days. 1600 mg bid on day 1 and 600 mg tid days 2-7 AND CT (Enoxaparin, dexamethasone, and antibiotics if associated bacteremia is present, as per currently used at Hospital General de México Dr. Eduardo Liceaga)<br>* Other names: MVC+FPV+CT;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients free of mechanical ventilation or death | Percentage of patients free of mechanical ventilation or death | 28 days post start | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients free of mechanical ventilation or death | Percentage of patients free of mechanical ventilation or death | 5 days post start | 
| Time of clinical improvement | Time of improvement in at least 2 items of the 8-item World Health Organization (WHO) ordinal scale for COVID-19 in days. | 15 days post start | 
| Rate of change in phosphorylated CCR5 | Rate of change (Delta) in lymphocytes, monocytes and neutrophils with phosphorylated CCR5 as per measured by parameters of flow cytometry. | Day 10-1 | 
| Rate of change in peripheral blood levels of proinflammatory cytokines and chemokines | Rate of change (Delta) in peripheral blood levels of proinflammatory cytokines and chemokines [IL-6, IL-1b, TNF, IFNa, IFNg, VEGF, GM-CSF (granulocyte-macrophage colony stimulating factor), CCL2, CCL3, CCL4, CCL5, CXCL10 and CCL7], as per measured by parameters of flow cytometry | Day 10-1 | 
| Change in the trafficking and activation pattern of peripheral leukocytes | Statistically significant change in the expression of activation [phosphorylated CCR5,CD38, CD126, CD127, CD25, CD86, CD83, CD40 (clusters of differentiation 38, 126, 127, 25, 86 and 40), HLA-DR (Human Leukocyte Antigen-DR isotype), Granzyme B, Perforin, CD107A, CD123, gp130, CD95], trafficking [CCR5, CCR2, CCR6, CCR7, CXCR1, CXCR3 , CXCR5, (CXC chemokine receptors 1, 3 and 5), CX3CR1 (CX3C chemokine receptor] and exhaustion (PD1, programmed death-1 receptor) markers in peripheral blood lymphocytes, neutrophils and monocytes, as per measured by parameters of flow cytometry. | Day 10-1 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
COVID-19, CCR5, Cytokine storm, Maraviroc, Favipiravir, RdRP inhibitors