Clinical trial NCT04475991: Safety and Efficacy of Maraviroc and/or Favipiravir With Standard Therapy in Severe COVID-19 Adults
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"
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: COVID-19
Keywords: COVID-19
CCR5
Cytokine storm
Maraviroc
Favipiravir
RdRP inhibitors
Lead sponsor: Hospital General de México Dr. Eduardo Liceaga
Sponsor class: OTHER_GOV
Collaborators: name: CCINSHAE. Secretaría de Salud. México
name: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
name: Centro de Investigación en. Enfermedades Infecciosas, Mexico
First posted: 2020-07-17
Enrollment: 19
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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
Primary purpose: TREATMENT

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

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

Primary outcomes:
measure: Patients free of mechanical ventilation or death
timeFrame: 28 days post start
Secondary outcomes:
measure: Patients free of mechanical ventilation or death
timeFrame: 5 days post start
measure: Time of clinical improvement
timeFrame: 15 days post start
measure: Rate of change in phosphorylated CCR5
timeFrame: Day 10-1
measure: Rate of change in peripheral blood levels of proinflammatory cytokines and chemokines
timeFrame: Day 10-1
measure: Change in the trafficking and activation pattern of peripheral leukocytes
timeFrame: Day 10-1
Other outcomes:
Locations:
city: Mexico City
country: Mexico
facility: Hospital General de México "Dr. Eduardo Liceaga"
state: Cdmx
Study officials:
affiliation: Hospital General de México Dr. Eduardo Liceaga
name: María Luisa Hernández-Medel, MD
role: STUDY_CHAIR
References: