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

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ClinicalTrials.gov Identifier: NCT04475991
Recruitment Status : Not yet recruiting
First Posted : July 17, 2020
Last Update Posted : April 9, 2021
Sponsor:
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  ICMJE July 15, 2020
First Posted Date  ICMJE July 17, 2020
Last Update Posted Date April 9, 2021
Estimated Study Start Date  ICMJE May 2021
Estimated Primary Completion Date July 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE
 (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  ICMJE Safety and Efficacy of Maraviroc and/or Favipiravir With Standard Therapy in Severe COVID-19 Adults
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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  ICMJE COVID-19
Intervention  ICMJE
  • 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  ICMJE
  • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: July 15, 2020)
100
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2021
Estimated Primary Completion Date July 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
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  ICMJE Mexico
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04475991
Other Study ID Numbers  ICMJE 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  ICMJE
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  ICMJE Hospital General de México Dr. Eduardo Liceaga
Collaborators  ICMJE
  • CCINSHAE. Secretaría de Salud. México
  • Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
  • Centro de Investigación en. Enfermedades Infecciosas, Mexico
Investigators  ICMJE
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

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP