Clinical trial NCT04345523: Convalescent Plasma Therapy vs. SOC for the Treatment of COVID-19 in Hospitalized Patients
Official title: Multi-center, Randomized Clinical Trial of Convalescent Plasma Therapy Versus Standard of Care for the Treatment of COVID-19 in Hospitalized Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: COVID-19
Keywords: COVID-19
Coronavirus
SARS-CoV-2
Convalescent Plasma
SOC
CP
Lead sponsor: Puerta de Hierro University Hospital
Sponsor class: OTHER
Collaborators: name: Instituto de Salud Carlos III
First posted: 2020-04-14
Enrollment: 350
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 1:1 ratio for CP: Control arm. Also, approximately 140-200 CP donors.
Primary purpose: TREATMENT

Brief summary: A total of 278 patients are planned.

All patients will be in an early-stage of COVID-19. They must be adults and hospitalized.

In this study, all participating patients will receive the standard treatment provided according to the current treatment protocols for coronavirus disease. In addition to this treatment, each patient will be randomly assigned to receive additional treatment with convalescent plasma transfusion (CP; blood plasma from patients who have been cured of coronavirus), or continue with standard treatment but without adding transfusion.

50% of the chances of additional treatment with CP, and 50% of the chances of receiving only the standard treatment for coronavirus.

The duration of the study shall be one month from the assignment of the treatment.

The patient and the doctor will know the treatment assigned.

Detailed description: A multi-center, randomized, clinical trial with two arms to study the efficacy and safety of passive immunotherapy with CP compared to a control of standard of care (SOC).

All trial participants will receive SOC:

* Treatment arm: Pathogen-reduced CP from patients recovered from COVID-19, whom, for the purpose of this trial, are herein designated as donors.
* Control arm: SOC for COVID-19.

Randomization among the two arms will be 1:1 and will be stratified per center. Of note, in the current status of a worldwide pandemic for which we have no approved vaccines or drugs, for the purpose of this trial SOC would also accept any drugs that are being used in clinical practice (e.g. lopinavir/ritonavir; darunavir/cobicistat; hydroxy/chloroquine, tocilizumab, etc.), other than those used as part of another clinical trial.

The study is planned with a sequential design. Interim analyses: comprehensive safety data monitoring analyses will be conducted when 20%, 40%, 60% and 80% of patients, or at the discretionary DSMB criteria when needed. A DSMB charter will be set before the trial initiation where criteria for prematurely stopping the trial due to safety issues will be set. Interim analyses will be predefined upfront based on the DSMB recommendations.

Eligibility criteria: Inclusion Criteria:

1. Written informed consent prior to performing study procedures. Witnessed oral consent will be accepted in order to avoid paper handling. Written consent by patient or representatives will be obtained as soon as possible.
2. Male or female adult patient ≥18 years of age at time of enrolment.
3. Has laboratory-confirmed SARS-CoV-2 infection as determined by PCR in naso/oropharyngeal swabs or any other relevant specimen in the ongoing COVID-19 symptomatic period. Alternative test (i.e antigenic tests) are also acceptable as laboratory confirmation if their adequate specificity has been accepted by the sponsor.
4. Patients requiring hospitalization for COVID-19 without mechanical ventilation (invasive or non-invasive) or high flow oxygen devices and at least one of the following:

   * Radiographic evidence of pulmonary infiltrates by imaging (chest x-ray, CT scan, etc.), OR
   * Clinical assessment (evidence of rales/crackles on exam) AND SpO2 ≤ 94% on room air that requires supplemental oxygen.
5. No more than 7 days between the onset of symptoms (fever or cough) and treatment administration day.

Exclusion Criteria:

1. Requiring mechanical ventilation (invasive or non-invasive) or high flow oxygen devices.
2. More than 7 days since symptoms (fever or cough).
3. Participation in any other clinical trial of an experimental treatment for COVID-19.
4. In the opinion of the clinical team, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatments.
5. Any incompatibility or allergy to the administration of human plasma.
6. Stage 4 severe chronic kidney disease or requiring dialysis (i.e. eGFR \<30).

Primary outcomes:
measure: Category Changes in the "7-Ordinal Scale"
timeFrame: 15 days
Secondary outcomes:
measure: Status at day 30 in the "7-point ordinal scale"
timeFrame: 30 days
measure: Time to category 5, 6 or 7 of the " 7-Ordinal scale"
timeFrame: 29 days
measure: Time to an improvement of one category from admission in the "7-Ordinal scale"
timeFrame: 29 days
measure: Time to first deterioration
timeFrame: 60 days
measure: Mean change in the ranking in the "7-Ordinal scale" from baseline to days 3,5,8,11,15,29 and 60
timeFrame: 60 days
measure: Mean change in the ranking in the "11-Ordinal scale from baseline to days 3,5,8,11,15,29 and 60.
timeFrame: 60 days
measure: Status at day 15 and 30 in the "11-Ordinal scale"
timeFrame: 30 days
measure: Mortality of any cause at 15 days
timeFrame: 15 days
measure: Mortality of any cause at 28 days (day 29)
timeFrame: 28 days (day 29)
measure: Mortality of any cause at 60 days
timeFrame: 60 days
measure: Oxygenation free days
timeFrame: 29 days
measure: Ventilator free days
timeFrame: 29 days
measure: Duration of hospitalization (days)
timeFrame: 60 days
measure: Incidence of thrombotic arterial events
timeFrame: 60 days
measure: Incidence of thrombotic venous events
timeFrame: 60 days
measure: Status at day 30 in the "11-Ordinal scale"
timeFrame: 30 days
measure: Infusion-related adverse events
timeFrame: 60 days
measure: Incidence of Treatment-Emergent Adverse Events
timeFrame: 60 days
measure: rate of rehospitalizations
timeFrame: 60 days
measure: Antibodies levels in CP donors recovered from COVID-19
timeFrame: 3 months
measure: Viral load
timeFrame: Days 1,3,5,8,11,15, 29 and 60
measure: Viral load
timeFrame: Days 1,3,5,8,11,15,29 and 60
Other outcomes:
Locations:
city: Zaragoza
country: Spain
facility: Hospital Clínico Universitario Lozano Blesa
state: Aragón
city: Terrassa
country: Spain
facility: Hospital Universitario Mútua Terrassa
state: Barcelona
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro Majadahonda
state: Madrid
city: Albacete
country: Spain
facility: Hospital General de Albacete
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Ciudad Real
country: Spain
facility: Hospital General Universitario de Ciudad Real
city: Donostia
country: Spain
facility: Hospital Universitario Donostia
city: Girona
country: Spain
facility: Hospital Doctor Josep Trueta
city: Las Palmas
country: Spain
facility: Hospital Doctor Negrín
city: León
country: Spain
facility: Complejo Asistencial Universitario de León
city: Lleida
country: Spain
facility: Hospital Universitario Arnau de Vilanova
city: Logroño
country: Spain
facility: Hospital San Pedro
city: Madrid
country: Spain
facility: Hospital Universitario La Princesa
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario HM Sanchinarro
city: Manresa
country: Spain
facility: Hospital Sant Joan de Deu de Manresa. Fundación Althaia
city: Oviedo
country: Spain
facility: Hospital Universitario de Asturias
city: Palma De Mallorca
country: Spain
facility: Hospital Universitario Son Espases
city: Pamplona
country: Spain
facility: Clínica Universidad de Navarra (CUN). Sedes Pamplona y Madrid
city: Pamplona
country: Spain
facility: Complejo Hospitalario de Navarra
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla
city: Toledo
country: Spain
facility: Complejo Hospitalario de Toledo
city: Valencia
country: Spain
facility: Hospital General Universitario de Valencia
city: Valladolid
country: Spain
facility: Hospital Clínico Universitario de Valladolid
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
Study officials:
affiliation: Hospital Universitario Puerta de Hierro Majadahonda
name: Cristina Avendaño Solá, MD, PhD
role: STUDY_CHAIR
affiliation: Hospital Universitario Puerta de Hierro Majadahonda
name: Rafael Duarte Palomino, MD, PhD
role: STUDY_CHAIR
affiliation: Hospital Universitario Puerta de Hierro Majadahonda
name: Antonio Ramos, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario Puerta de Hierro Majadahonda
name: José Luis Bueno, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centro Nacional de Microbiología, Instituto de Salud Carlos III
name: Inmaculada Casas Flecha, PharmD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Avendano-Sola C, Ramos-Martinez A, Munez-Rubio E, Ruiz-Antoran B, Malo de Molina R, Torres F, Fernandez-Cruz A, Calderon-Parra J, Payares-Herrera C, Diaz de Santiago A, Romera-Martinez I, Pintos I, Lora-Tamayo J, Mancheno-Losa M, Paciello ML, Martinez-Gonzalez AL, Vidan-Estevez J, Nunez-Orantos MJ, Saez-Serrano MI, Porras-Leal ML, Jarilla-Fernandez MC, Villares P, de Oteyza JP, Ramos-Garrido A, Blanco L, Madrigal-Sanchez ME, Rubio-Batlles M, Velasco-Iglesias A, Pano-Pardo JR, Moreno-Chulilla JA, Muniz-Diaz E, Casas-Flecha I, Perez-Olmeda M, Garcia-Perez J, Alcami J, Bueno JL, Duarte RF; ConPlas-19 Study Group. A multicenter randomized open-label clinical trial for convalescent plasma in patients hospitalized with COVID-19 pneumonia. J Clin Invest. 2021 Oct 15;131(20):e152740. doi: 10.1172/JCI152740.
citation: Piechotta V, Iannizzi C, Chai KL, Valk SJ, Kimber C, Dorando E, Monsef I, Wood EM, Lamikanra AA, Roberts DJ, McQuilten Z, So-Osman C, Estcourt LJ, Skoetz N. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review. Cochrane Database Syst Rev. 2021 May 20;5(5):CD013600. doi: 10.1002/14651858.CD013600.pub4.
citation: Diago-Sempere E, Bueno JL, Sancho-Lopez A, Rubio EM, Torres F, de Molina RM, Fernandez-Cruz A, de Diego IS, Velasco-Iglesias A, Payares-Herrera C, Flecha IC, Avendano-Sola C, Palomino RD, Ramos-Martinez A, Ruiz-Antoran B. Evaluation of convalescent plasma versus standard of care for the treatment of COVID-19 in hospitalized patients: study protocol for a phase 2 randomized, open-label, controlled, multicenter trial. Trials. 2021 Jan 20;22(1):70. doi: 10.1186/s13063-020-05011-9.