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)
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
Drug: Maraviroc + Currently used therapy
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")
Other Name: MVC+CT
Procedure: Curently used therapy for COVID-19 non-critical patients
Enoxaparin, dexamethasone, and antibiotics if associated bacteremia is present, as per currently used at Hospital General de México "Dr. Eduardo Liceaga"
Other Name: CT only
Drug: Favipiravir + Currently used therapy
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").
Other Name: FPV+CT
Drug: Maraviroc+Favipiravir+CT
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"")
Other Name: MVC+FPV+CT
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
Hospital General de México "Dr. Eduardo Liceaga"
Mexico City, Cdmx, Mexico
María Luisa Hernández-Medel, MD, Study Chair
Hospital General de México Dr. Eduardo Liceaga