Convalescent Plasma Therapy vs. SOC for the Treatment of COVID-19 in Hospitalized Patients (ConPlas-19)

Multi-center, Randomized Clinical Trial of Convalescent Plasma Therapy Versus Standard of Care for the Treatment of COVID-19 in Hospitalized Patients

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.

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Other: Blood and derivatives.; Drug: Standard of Care

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.

• Study Type: Interventional
• Enrollment (Actual): 350
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Albacete, Spain, 02006
    • Hospital General de Albacete
  • Barcelona, Spain, 08003
    • Hospital del Mar
  • Ciudad Real, Spain, 13005
    • Hospital General Universitario De Ciudad Real
  • Donostia, Spain, 20014
    • Hospital Universitario Donostia
  • Girona, Spain, 17007
    • Hospital Doctor Josep Trueta
  • Las Palmas, Spain, 35010
    • Hospital Doctor Negrin
  • León, Spain, 24071
    • Complejo Asistencial Universitario de León
  • Lleida, Spain, 25198
    • Hospital Universitario Arnau de Vilanova
  • Logroño, Spain, 26006
    • Hospital San Pedro
  • Madrid, Spain, 28006
    • Hospital Universitario La Princesa
  • Madrid, Spain, 28034
    • Hospital Universitario Ramón y Cajal
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28009
    • Hospital General Universitario Gregorio Marañón
  • Madrid, Spain, 28050
    • Hospital Universitario HM Sanchinarro
  • Manresa, Spain, 08243
    • Hospital Sant Joan de Deu de Manresa. Fundación Althaia
  • Oviedo, Spain, 33011
    • Hospital Universitario de Asturias
  • Palma De Mallorca, Spain, 07120
    • Hospital Universitario Son Espases
  • Pamplona, Spain, 31008
    • Complejo Hospitalario de Navarra
  • Pamplona, Spain, 31008
    • Clínica Universidad de Navarra (CUN). Sedes Pamplona y Madrid
  • Salamanca, Spain
    • Hospital Universitario de Salamanca
  • Santander, Spain, 39008
    • Hospital Universitario Marques de Valdecilla
  • Toledo, Spain, 45007
    • Complejo Hospitalario de Toledo
  • Valencia, Spain, 46014
    • Hospital General Universitario de Valencia
  • Valladolid, Spain, 47003
    • Hospital Clínico Universitario de Valladolid
  • Zaragoza, Spain, 50009
    • Hospital Universitario Miguel Servet
  • Aragón
    • Zaragoza, Aragón, Spain, 50009
      • Hospital Clínico Universitario Lozano Blesa
  • Barcelona
    • Terrassa, Barcelona, Spain, 08221
      • Hospital Universitario Mútua Terrassa
  • Madrid
    • Majadahonda, Madrid, Spain, 28222
      • Hospital Universitario Puerta de Hierro Majadahonda

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Arm; Pathogen-reduced CP from patients recovered from COVID-19, whom, for the purpose of this trial, are herein designated as donors.	Other: Blood and derivatives.; Administration of fresh plasma from donor immunized against COVID-19; Other Names: Convalescent Plasma from patients recovered from COVID-19
Active Comparator: Control Arm; Standard of Care (SOC) for COVID-19	Drug: Standard of Care; Standard of care for the treatment of COVID-19 in hospitalized patients; Other Names: SOC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Category Changes in the "7-Ordinal Scale"	Proportion of patients in categories 5, 6 or 7 of the 7-point ordinal scale at day 15 7- Ordinal scale: Not hospitalized, no limitations on activities.; Not hospitalized, limitation on activities.; Hospitalized, not requiring supplemental oxygen.; Hospitalized, requiring supplemental oxygen.; Hospitalized, on non-invasive ventilation or high flow oxygen devices.; Hospitalized, on invasive mechanical ventilation or ECMO.; Death.	15 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to category 5, 6 or 7 of the " 7-Ordinal scale"	Time to change from baseline category to worsening into 5,6 or 7 categories of the "7-Ordinal scale"	29 days
Time to an improvement of one category from admission in the "7-Ordinal scale"	Time to an improvement of one category from admission in the "7-Ordinal scale"	29 days
Status at day 30 in the "11-Ordinal scale"	Status at day 30 in the "11-Ordinal scale" "11-Ordinal scale" : 0. Uninfected ; no viral RNA detected.; Asymptomatic; viral RNA detected, limitation on activities.; Symptomatic; independent; Symptomatic; assistance needed; Hospitalized, no oxygen therapy.; Hospitalized, oxygen by mask or nasal prongs; Oxygen by mask or nasal prongs; Intubation and mechanical ventilation, pO2/FiO2 ≥150 or SpO2/FiO2 ≥200; Mechanical ventilation pO2/FIO2 <150 (SpO2/FiO2 <200) or vasopressors; Mechanical ventilation pO2/FiO2 <150 and vasopressors, dialysis, or ECMO; Dead	30 days
Status at day 15 and 30 in the "11-Ordinal scale"	Status at day 15 and 30 in the "11-Ordinal scale" Status at day 15 and 30 in the "11-Ordinal scale"	30 days
Time to first deterioration	Time to first deterioration	60 days
Mean change in the ranking in the "7-Ordinal scale" from baseline to days 3,5,8,11,15,29 and 60	Mean change in the ranking in the "7-Ordinal Scale" from baseline to days 3,5,8,11,15,29 and 60	60 days
Mean change in the ranking in the "11-Ordinal scale from baseline to days 3,5,8,11,15,29 and 60.	Mean change in the ranking in the "11- Ordinal scale" from baseline to days 3,5,8,11,15,29 and 60.	60 days
Mortality of any cause at 15 days	Rate of mortality of any cause within first 15 days.	15 days
Mortality of any cause at 28 days (day 29)	Rate of mortality of any cause within first 28 days.	28 days (day 29)
Mortality of any cause at 60 days	Rate of mortality of any cause within first 60 days.	60 days
Oxygenation free days	days free from oxygen supplementation	29 days
Ventilator free days	days free from mechanical ventilation	29 days
Duration of hospitalization (days)	days of hospitalization	60 days
Infusion-related adverse events	Infusion-related adverse events Cumulative incidence of serious adverse events (SAEs) Cumulative incidence of Grade 3 and 4 adverse events (AEs).	60 days
Incidence of Treatment-Emergent Adverse Events	cumulative incidence of Grade 3 and 4 adverse events (AEs) Cumulative incidence of serious adverse events (SAEs) Cumulative incidence of Grade 3 and 4 adverse events (AEs).	60 days
Antibodies levels in CP donors recovered from COVID-19	Quantitative total antibodies and neutralizing antibody activity against SARSCoV-2 in the sera from donors and patients using viral pseudotypes	3 months
Viral load	Change in PCR for SARS-CoV-2 in naso/oropharyngeal swabs at baseline and at discharge	Days 1,3,5,8,11,15, 29 and 60
Viral load	Change in PCR for SARS-CoV-2 in blood on Days 3,5,8,11,15,29 and 60 (while hospitalized) until two of them are negative consecutively	Days 1,3,5,8,11,15,29 and 60
Incidence of thrombotic arterial events	incidence of thrombotic arterial events	60 days
Incidence of thrombotic venous events	incidence of thrombotic venous events	60 days
rate of rehospitalizations	rehospitalizations	60 days

Collaborators and Investigators

• Sponsor: Cristina Avendaño Solá
• Collaborators: Instituto de Salud Carlos III
• Investigators: Study Chair: Cristina Avendaño Solá, MD, PhD, Hospital Universitario Puerta de Hierro Majadahonda; Study Chair: Rafael Duarte Palomino, MD, PhD, Hospital Universitario Puerta de Hierro Majadahonda; Principal Investigator: Antonio Ramos, MD, PhD, Hospital Universitario Puerta de Hierro Majadahonda; Principal Investigator: José Luis Bueno, MD, Hospital Universitario Puerta de Hierro Majadahonda; Principal Investigator: Inmaculada Casas Flecha, PharmD, PhD, Centro Nacional de Microbiología, Instituto de Salud Carlos III

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 3, 2020
• Primary Completion (Actual): February 5, 2021
• Study Completion (Actual): April 5, 2021

Study Registration Dates

• First Submitted: April 2, 2020
• First Submitted That Met QC Criteria: April 10, 2020
• First Posted (Actual): April 14, 2020

Study Record Updates

• Last Update Posted (Actual): May 13, 2021
• Last Update Submitted That Met QC Criteria: May 12, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: SARS-CoV-2; CP; Coronavirus; COVID-19; Convalescent Plasma; SOC
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: ConPlas-19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: PD that underlie the results reported in this article, after deidenficiation (text, tables, figures, and appendices) will be shared. The data will be available after main report is published.
• IPD Sharing Time Frame: Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research
• IPD Sharing Access Criteria: The investigator who proposed to use the data will have access to the data upon reasonable request.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No