Convalescent Plasma vs Human Immunoglobulin to Treat COVID-19 Pneumonia
Condition: COVID-19 Pneumonia
MeSH terms: COVID-19; Pneumonia
Study type: Interventional
Phase: Phase 3

Summary: 
      Background: On December 2019, a new human coronavirus infection (COVID-19) was detected in
      China. Its infectivity and virulence characteristics caused a rapid spread, being declared
      pandemic on March 2020. The mortality attributed to the infection ranges between 3 and 10%.
      Main risk factors are age, male sex, and chronic degenerative comorbidities. Due to the
      absence of therapeutic options, potential alternatives such as human immunoglobulin or plasma
      from convalescent patients have been administered. Due to the severity of the disease and the
      associated mortality, it is urgent to find therapeutic alternatives.

      Objective: To assess the safety and efficacy of the administration of Convalescent plasma vs
      human immunoglobulin in critically ill patients with COVID-19 infection.

      Material and methods: Randomized Controlled trial of patients diagnosed with respiratory
      infection by COVID-19, with severe respiratory failure without indication of mechanical
      ventilation, or those who due to their severity are intubated upon admission. Randomization
      will be performed 2:1 to receive plasma from convalescent patients or human immunoglobulin.

      Outcomes: The primary outcome will be time to discharge from hospital for improvement. The
      safety outcomes will be: Kirby index (PaO2/FiO2) evolution and dead.
    

Detailed description: 
      I. Background:

      In late December 2019, the health authorities of the Popular Republic of China reported
      several cases of pneumonia of unknown origin in Wuhan City, Hubei Province, China. On
      December 31, 2019, the Chinese Center for Disease Control and Prevention began etiological
      and epidemiological research on this disease. Three samples of bronchoalveolar lavage were
      taken from patients from the Jinyintan hospital in Wuhan and through various processes they
      came to identify a new coronavirus that they initially called on January 7, 2020 as:
      2019-nCoV. On January 2020, the World Health Organization (WHO) made the first
      recommendations on the epidemiological surveillance of this new coronavirus.

      On January 22, 2020, the first session of the Emergencies Committee was convened by WHO in
      Geneva, Switzerland and on January 30 a Public Health Emergency of International Importance
      (ESPII) was declared.

      On February 11, the International Committee on Virus Taxonomy named this new coronavirus as
      SARS-CoV-2 and responds to "Severe Acute Respiratory Syndrome Coronavirus 2 "(Severe Acute
      Respiratory Syndrome CoronaVirus 2), the WHO proposes that same day to call the disease
      caused by SARS-CoV-2 as COVID-19.

      The first case reported in Latin America was in Brazil on February 26 and on the 28th of the
      same month, Mexico communicates its first confirmed case of the new coronavirus in a
      35-year-old patient from a trip to Italy.

      Given the alarming levels of spread and severity of COVID-19, on March 11, WHO
      Director-General Tedros Adhanom Ghebreyesus declares the SARS-CoV-2.5 outbreak as a pandemic.
      A high percentage of patients especially over 50 y with comorbidities require hospitalization
      and intensive care. Mortality of patients with invasive mechanical intubation has been
      reported up to 61% .

      At this time, there are no treatment that has shown clinical efficacy, so the plasma from
      convalescent patients and human immunoglobulin (IVIG) have been proposed as alternatives.

      Human immunoglobulin:

      There are no controlled studies with the use of IVIG for the treatment of COVID-19 infection.
      In observational reports it was found in three patients with early forms in patients
      hospitalized for pneumonia secondary to COVID-19, treated with IVIG at a dose of 0.3 - 0.5 gr
      / kg. All three patients showed clinical improvement, so this study justified the start of a
      clinical trial.

      An observational experience with important limitations in its report, describes the
      experience with 58 patients with severe pneumonia who found differences in mortality at 28
      days when they divided the groups according to the IVIG administration time (48 hours),
      emphasizing the importance of early application.

      In similar situations historically diverse scenarios have been found where IVIG has been
      administered with apparent success. However, there are no clinical trials supporting its use.

      Convalescent patient plasma:

      The use of plasma from convalescent patients for the treatment of severe infection by COVID19
      has been considered as a first-line therapeutic option since the start of the pandemic. The
      seroconversion of the patients during the first months of the outbreak was unknown, being an
      obstacle to recommend this type of treatment. Very recently, the serological behavior of 285
      patients was published; 100% of the patients have detected antibodies 19 days after detection
      of the virus.

      The experiences reported so far are only case series without simultaneous comparative groups.
      Viral clearance has been effective, in all included patients in a small series of 6 patients.
      This viral clearance was not accompanied by mortality benefits, the authors suggesting that
      it was probably due to the late administration of plasma.

      Data supporting the use of convalescent plasma for severe acute respiratory syndrome (SARS)
      are limited to case reports and case series. Use in case series for severe infections due to
      MERS, Ebola and influenza have reported clinical improvement, although none of the studies
      were conducted comparatively.

      Risks associated with plasma transfusion include TRALI, transfusion-associated circulatory
      overload, and allergic transfusion reactions. Rare complications include transmission of
      infectious diseases and alloimmunization of red blood cells.

      Clinical trials are underway to evaluate both convalescent plasma and IVIG from SARS-CoV-2
      for the treatment of COVID-19.

      The FDA has approved a national expanded access program for the use of convalescent plasma
      for the treatment of patients with COVID-19. Physicians can refer to the National
      Convalescent Plasma Project COVID-19 website for more information. People who have fully
      recovered from COVID-19 for at least two weeks and are interested in donating plasma can
      contact their local blood donor or plasma collection center or consult the American Red Cross
      website.

      The national transfusion center in Mexico has published guidelines for the use of serum from
      convalescent patients.

      II. Definition of the problem:

      COVID-19 infection has had a high rate of spread. In patients with comorbidities and over 50
      years, the infection has presented the highest rate of respiratory deterioration and the
      requirement for invasive mechanical ventilation. Due to the absence of specific treatment,
      various alternatives have been explored. In critically ill patients, the administration of
      human immunoglobulin and plasma from convalescent patients have emerged as potential rescue
      therapies. The proposed treatments have an adequate margin of safety due to routine clinical
      use in other settings. Due to this, in conjunction with the urgent need to seek therapeutic
      alternatives, controlled studies are required without assuming efficacy.

      III. Justification COVID-19 infection has collapsed health systems in almost all the
      countries due to the large number of patients requiring respiratory assistance.

      There is no standard treatment for the management of this infection and the focus has been on
      the already known life support and management of Adult Respiratory Distress Syndrome in
      critically ill patients.

      The treatments used empirically have an adequate safety profile due to the experience in
      other clinical settings.

      The use of these empirical alternatives should be based on clinical trials since efficacy and
      safety should not be assumed in the group of patients with COVID-19.

      The Miguel Hidalgo Centennial Hospital has been designated as a hospitalization center for
      COVID-19 patients who do not have Social Security in the state of Aguascalientes.

      IV. Hypothesis

      In patients with COVID19 infection with severe respiratory failure or requiring invasive
      mechanical ventilation, plasma treatment of convalescent patients will be superior to
      immunoglobulin, with a shorter hospital stay and a lower rate of complications: deterioration
      of the oxygenation index or death.

      V. General objectives.

      To assess the safety and efficacy of plasma administration of convalescent patients or
      immunoglobulin in patients with severe COVID-19 infection with severe respiratory failure or
      requiring mechanical ventilation.

      Assess viral clearance time using PCR

      VI. Methodology

      Randomized controlled trial, Included patients will be randomized (2:1) to receive one of two
      maneuvers:

      Group 1: Plasma donated from convalescent patients will be extracted in strict compliance
      with the following criteria:

        -  History of a clinical event with symptoms attributed to COVID-19 and a positive PCR test
           for COVID-19

        -  Further confirmation of a negative PCR test for COVID-19

        -  In order to be eligible plasma donors must complete at least 14 days after the last
           negative PCR in the absence of any symptom attributable to COVID-19 infection

        -  IgG antibodies for COVID-19 must be confirmed POSITIVE when a qualitative assay is being
           used

        -  When quantification of IgG antibodies for COVID-19 is available a title > 1: 640 will be
           required for inclusion.

        -  Apheresis will be used as the only method for plasma extraction. Infusion of 400 ml of
           Plasma will be infused

      Group 2: Human immunoglobulin 0.3 gr / kg (5 doses)

      VII. Definition of the variables:

      Days of hospitalization: Days from admission as a suspected case of COVID with
      hospitalization criteria until discharge.

      Hospital discharge criteria: negative PCR for COVID-19, oxygen saturation in ambient air >
      90%, absence of fever and dyspnea.

      Oxygen supplementation requirement: This is based on the modality and FiO2 necessary to
      maintain a saturation of 90% of ambient air without respiratory distress.

      Respiratory distress syndrome: Respiratory rate greater than 25 x minute and use of accessory
      muscles.

      Respiratory failure: Saturation to ambient air below 90% or PO2 below 60 mmHg. Septic Shock:
      Requirement of vasoactive amines to maintain mean arterial pressure above 65 mmHg, in a
      patient previously with adequate water resuscitation.

      SOFA: Organic failure scale that includes: PaO2 / FiO2 ratio, platelet count, bilirubin,
      blood pressure, Glasgow scale and kidney function.

      APACHE 2: Morbidity scale in intensive care. PaO2 / FiO2 Index: Ratio of oxygen pressure to
      inspired fraction of oxygen RT-qPCR SARS-CoV-2: Quantitative measurement by RT-PCR method
      usually performed on blood. It will be evaluated as a start for diagnosis and then a test
      will be repeated on days 5, 14 and 21 to assess viral clearance.

      Inflammatory markers: Laboratory studies used as markers of disease severity, consist of
      procalcitonin, C-reactive protein, lactate dehydrogenase, blood cytometry, dimer-D, ferritin.
    

Intervention name(s): Plasma from COVID-19 convalescent patient; Human immunoglobulin
Intervention type(s): Drug; Drug
Intervention description(s): Infusion of 400 ml (2 units) of plasma.
Plasma donated from convalescent patients will be extracted in strict compliance with the following criteria:
History of a clinical event with symptoms attributed to COVID-19 and a positive PCR test for COVID-19
Further confirmation of a negative PCR test for COVID-19
In order to be eligible plasma donors must complete at least 14 days after the last negative PCR in the absence of any symptom attributable to COVID-19 infection
IgG antibodies for COVID-19 must be confirmed POSITIVE when a qualitative assay is being used
When quantification of IgG antibodies for COVID-19 is available a title > 1: 640 will be required for inclusion.
Apheresis will be used as the only method for plasma extraction.; Human immunoglobulin 0.3 gr/kg/day (5 doses)
Intervention MeSH terms: Immunoglobulins; Immunoglobulins, Intravenous; Antibodies
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment