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

• ClinicalTrials.gov Identifier: NCT04475991
• Recruitment Status: Not yet recruiting
• First Posted: July 17, 2020
• Last Update Posted: April 9, 2021
• Sponsor: Hospital General de México Dr. Eduardo Liceaga
• Collaborators: CCINSHAE. Secretaría de Salud. México; Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran; Centro de Investigación en. Enfermedades Infecciosas, Mexico
• Information provided by (Responsible Party): María Luisa Hernández-Medel, Hospital General de México Dr. Eduardo Liceaga

Tracking Information

• First Submitted Date: July 15, 2020
• First Posted Date: July 17, 2020
• Last Update Posted Date: April 9, 2021
• Estimated Study Start Date: May 2021
• Estimated Primary Completion Date: July 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 15, 2020)

Patients free of mechanical ventilation or death [ Time Frame: 28 days post start ]

Percentage of patients free of mechanical ventilation or death

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 15, 2020)

• Patients free of mechanical ventilation or death [ Time Frame: 5 days post start ]
  Percentage of patients free of mechanical ventilation or death
• Time of clinical improvement [ Time Frame: 15 days post start ]
  Time of improvement in at least 2 items of the 7-item World Health Organization (WHO) ordinal scale for COVID-19 in days.
• Rate of change in phosphorylated CCR5 [ Time Frame: Day 10-1 ]
  Rate of change (Delta) in lymphocytes, monocytes and neutrophils with phosphorylated CCR5 as per measured by parameters of flow cytometry.
• Rate of change in peripheral blood levels of proinflammatory cytokines and chemokines [ Time Frame: Day 10-1 ]
  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
• Change in the trafficking and activation pattern of peripheral leukocytes [ Time Frame: Day 10-1 ]
  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.

Original Secondary Outcome Measures (submitted: July 15, 2020)

• Patients free of mechanical ventilation or death [ Time Frame: 5 days post start ]
  Percentage of patients free of mechanical ventilation or death
• Time of clinical improvement [ Time Frame: 15 days post start ]
  Time of improvement in at least 2 items of the 7-item WHO ordinal scale for COVID-19
• Rate of change in phosphorilated CCR5 [ Time Frame: Day 10-1 ]
  Rate of change (Delta) in lymphocytes, monocytes and neutrophils with phosphorilated CCR5
• Rate of change in peripheral blood levels of proinflammatory cytokines and chemokynes [ Time Frame: Day 10-1 ]
  Rate of change (Delta) in peripheral blood levels of proinflammatory cytokines and chemokynes (IL-6, IL-1b, TNF, IFNa, IFNg, VEGF, GM-CSF, CCL2, CCL3, CCL4, CCL5, CXCL10 and CCL7)
• Change in the trafficking and activation pattern of peripheral leukocytes [ Time Frame: Day 10-1 ]
  Statistically significant change in the expression of activation (phosphorilated CCR5,CD38, CD126, CD127, CD25, CD86, CD83, CD40, HLA-DR, Granzyme B, Perforin, CD107A, CD123, gp130, CD95), trafficking (CCR5, CCR2, CCR6, CCR7, CXCR1, CXCR3, CXCR5, CX3CR1) and exhausting (PD1) markers in peripheral blood lymphocytes, neutrophils and monocytes.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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"
• 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

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
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

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: COVID-19

Intervention

• 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

Study Arms

• Active Comparator: Currently used therapy (CT) only
  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.
  Intervention: Procedure: Curently used therapy for COVID-19 non-critical patients
• Experimental: Maraviroc+CT
  Maraviroc AND treatment currently used at Hospital General de México "Dr. Eduardo Liceaga" for non-critical COVID patients.
  Intervention: Drug: Maraviroc + Currently used therapy
• Experimental: Favipiravir+CT
  Favipiravir AND treatment currently used at Hospital General de México "Dr. Eduardo Liceaga" for non-critical COVID patients.
  Intervention: Drug: Favipiravir + Currently used therapy
• Experimental: Maraviroc+Favipiravir+CT
  Maraviroc AND Favipiravir AND treatment currently used at Hospital General de México "Dr. Eduardo Liceaga" for non-critical COVID patients
  Intervention: Drug: Maraviroc+Favipiravir+CT

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: July 15, 2020): 100
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: September 2021
• Estimated Primary Completion Date: July 2021 (Final data collection date for primary outcome measure)

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)
• 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.
• Thorax USG with LUS (Lung Ultrasonographic Score)>23
• With at least two of the following indicators of severity: SpO2 81-90%, PaFi 250-100 mmHg, FiO2>60% , LHD (Lactic Acid Dehydrogenase) >350 U/L, lung infiltration >50% determined by thorax radiography.
• 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
• Clinical evidence of an infectious disease different from COVID at the time of admission
• Signs of respiratory distress
• Chronic kidney failure
• Coronary disease
• Glasgow score < 13
• Glomerular filtration rate < 60ml/min/1.73 m2 and known history of preexisting chronic renal failure (Chronic kidney disease stages 3,4,5)
• Known history of HCV, HBV and/or clinical signs of hepatic liver failure.
• Any type of cancer
• HIV and/or any anti retroviral treatment
• Psychotropics treatment
• With transplant background
• With any autoimmune disorder
• With known hypersensibility to maraviroc and/or favipiravir

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Adolfo Pérez-García, PhD; +52(55)27892000 ext 1151; aperezg@hotmail.com

Contact: Joselin Hernández-Ruiz, PhD; +52(55)27892000 ext 1385; hernandezjoselin@hotmail.com

• Listed Location Countries: Mexico

Administrative Information

• NCT Number: NCT04475991
• Other Study ID Numbers: DI/20/407/04/38
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Inter-institutional exchange of data
• Supporting Materials: Study Protocol
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Information will be shared upon completion of the study for collaborative purposes
• Access Criteria: Upon request

• Responsible Party: María Luisa Hernández-Medel, Hospital General de México Dr. Eduardo Liceaga
• Study Sponsor: Hospital General de México Dr. Eduardo Liceaga

Collaborators

• CCINSHAE. Secretaría de Salud. México
• Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
• Centro de Investigación en. Enfermedades Infecciosas, Mexico

Investigators

• Study Chair: María Luisa Hernández-Medel, MD; Hospital General de México Dr. Eduardo Liceaga

• PRS Account: Hospital General de México Dr. Eduardo Liceaga
• Verification Date: April 2021