Hyperimmune Plasma in Patients With COVID-19 Severe Infection (COV2-CP)

Efficacy and Safety of Hyperimmune Plasma Treatment in Patients With COVID-19 Severe Infection

Passive immunotherapy through plasma infusion of convalescent subjects - convalescent plasma - or "hyperimmune" plasma was one of the most widespread and effective anti-infective treatments in the pre-antibiotic era and one of the founding pillars of immunology, and has also been used during the SARS (2002-2003) and Ebola (2014-2016) viral epidemy for which there were no alternative immunoprophylactic or therapeutic interventions.

To date, there are not proven etiological therapies for SARS-CoV-2 infection, the agent responsible for the disease called Covid-19. Among those subjected to clinical studies during the current epidemic in China, hyperimmune plasma appears to be one of the most rational and promising.

The objective of this study will be to evaluate the efficacy and safety of the hyperimmune plasma administered add-on to the anti-Covid-19 treatment (standard therapy) according to clinical practice in patients with severe Covid-19 infection, compared to patients with severe Covid-19 infection treated only with standard therapy.

Study Overview

• Status: Unknown
• Conditions: COVID-19
• Intervention / Treatment: Other: plasma hyperimmune; Drug: standard therapy

Detailed Description

Passive immunotherapy through plasma infusion of convalescent subjects - convalescent plasma - or "hyperimmune" plasma was one of the most widespread and effective anti-infective treatments in the pre-antibiotic era and one of the founding pillars of immunology. Immunoprophylaxis represents an irreplaceable protection for post-exposure prevention of several viral infections such as measles, hepatitis B and rabies. Recently, the use of convalescent plasma for therapeutic purposes has been re-evaluated during the SARS (2002-2003) and Ebola (2014-2016) epidemic caused by serious viral infections for which there were no immunoprophylactic or therapeutic interventions. alternative. The results of these experimental interventions, despite the limited number and the often anecdotal character, have shown promise even if not conclusive. In the case of SARS, the first human respiratory disease caused by a Coronavirus, treatment with convalescent plasma was associated with a 23% reduction in mortality and with the best results if administered at an early stage of the disease. In addition, all the evidence available in the literature has confirmed the safety of convalescent plasma treatments, in line with what has already been observed in the transfusion practice with Fresh Frozen Plasma.

As is known, there are currently no proven etiological therapies to combat SARS-CoV-2 infection, the agent responsible for the disease called Covid-19. Among those subjected to clinical studies during the current epidemic in China, hyperimmune plasma appears to be one of the most rational and promising.

Waiting for the numerous clinical trials underway especially in Asia and accessible on the website http://apps.who.int/trialsearch/default.aspx to define if and to what extent this therapeutic contribution improves the prognosis of patients suffering from serious forms of infections from SARS-Co-2, the clinical guidelines of the People's Republic of China, already provide for the use of hyperimmune plasma with the indication "in rapidly progressive disease, severe and very severe form" and by the FDA .

As regards the technical protocols for the preparation of hyperimmune plasma for clinical use in the literature, precise references are available in particular for the preparation, qualification, viral inactivation and dosage of hyperimmune plasma for the treatment of viral epidemic infections such as MERS and Ebola and which can also be validated and used for the preparation of plasma from convalescent patients for Covid-19.

From the above, the objective of this study will be to evaluate the efficacy and safety of the hyperimmune plasma administered add-on to the anti-Covid-19 treatment (standard therapy) according to clinical practice in patients with severe Covid-19 infection, compared to patients with severe Covid-19 infection treated only with standard therapy.

• Study Type: Interventional
• Enrollment (Anticipated): 400
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Italy
  • Catanzaro, Italy, 88100
    • Recruiting
    • Azienda Ospedaliera Policlinico Mater Domini
    • Contact: Federico Longhini, MD; Phone Number: 0961712111; Email: longhini@unicz.it
    • Sub-Investigator: Carlo Torti, MD
    • Sub-Investigator: Giovanni Matera, MD
  • Catanzaro, Italy, 88100
    • Recruiting
    • Azienda Ospedaliera Pugliese Ciaccio Catanzaro
    • Contact: Andrea Dominijanni, MD; Phone Number: 0961883111; Email: trasfusionale@aocz.it
    • Sub-Investigator: Pasquale Minchella, MD
    • Sub-Investigator: Lucio Cosco, MD
    • Sub-Investigator: Maria Laura Guzzo, MD
    • Sub-Investigator: Piero Gangemi, MD
  • Cosenza, Italy, 87100
    • Recruiting
    • Azienda Ospedaliera Annunziata
    • Contact: Francesco Zinno, MD; Phone Number: 0984 6811; Email: f.zinno@aocs.it
  • Crotone, Italy, 88900
    • Recruiting
    • Azienda Sanitaria Provinciale
    • Contact: Patrizia Leonardo, MD; Phone Number: 0962924471; Email: centro.trasfusionale@asp.crotone.it
  • Reggio Calabria, Italy, 89133
    • Recruiting
    • Azienda Ospedaliera Bianchi Melacrino Morelli
    • Contact: Alfonso Trimarchi, MD; Phone Number: 0965 730011; Email: atrimarchi@aorc.it
  • Vibo Valentia, Italy, 89900
    • Recruiting
    • Azienda Sanitaria Provinciale
    • Contact: Paola Grandini, MD; Phone Number: 0963-962111; Email: trasfusionale@aspvv.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• inclusion criteria for donors: null-gravid, with a negative history of transfusion of blood components; possibility to sign the informed consent
• inclusion criteria for Covid-19 infected patients: serious Covid-19 infection, possibility to sign the informed consent (also through the legal tutor)

Exclusion Criteria:

• exclusion criteria for donors: presence of pregnancy, recent history of transfusion of blood components, < 18 years.
• exclusion criteria for Covid-19 infected patients: non serious Covid-19 infection, impossibility to sign the informed consent (also through the legal tutor)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: plasma-hyperimmune; enrolled patients (n=200) with severe Covid-19 infection will receive a treatment with plasma hyperimmune add on to the standard therapy	Other: plasma hyperimmune; patients will receive this as add on therapy; Drug: standard therapy; patients will receive only standard therapy for Covid-19 infection
ACTIVE_COMPARATOR: standard therapy; enrolled patients (n=200) with severe Covid-19 infection will receive a treatment with the standard therapy	Drug: standard therapy; patients will receive only standard therapy for Covid-19 infection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
decrease in mortality	Statistically significant reduction (P <0.05) of mortality in the group of patients treated with hyperimmune plasma vs patients treated with standard therapy.	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
lymphocytes	Statistically significant increase (P <0.05) of lymphocyte levels after 7 and 14 days after the start of treatment with hyperimmune plasma (treated group), compared to the control group.	7 and 14 days
PCR levels vs control	Statistically significant reduction (P <0.05) of plasma levels of reactive protein C (expressed as mg/L), 7 and 14 days after the start of treatment with hyperimmune plasma vs standard therapy (group control)	7 and 14 days
PCR levels vs before treatment	Statistically significant reduction (P <0.05) of plasma levels of reactive protein C (expressed as mg/L), 7 and 14 days after the start of treatment with hyperimmune plasma vs the same patients before the beginning of the treatment	7 and 14 days
AB levels and clinical improvement	Significant Correlation (P<0.05) between hyperimmune plasma antibody levels and clinical improvement time (expressed in days)	30 days
Inflammatory cytokines vs controls	Statistically significant reduction (P <0.05) of plasma levels of IL-6 (expressed as pg/mL) and TNF-alpha (expressed as pg/mL), 7 and 14 days after the start of treatment with hyperimmune plasma vs standard therapy (group control)	7 and 14 days
Inflammatory cytokines vs before treatment	Statistically significant reduction (P <0.05) of plasma levels of IL-6 (expressed as pg/mL) and TNF-alpha (expressed as pg/mL), 7 and 14 days after the start of treatment with hyperimmune plasma vs the same patients before the beginning of the treatment	7 and 14 days

Collaborators and Investigators

• Sponsor: University of Catanzaro
• Collaborators: Azienda Sanitaria Provinciale Di Catanzaro; Azienda Ospedaliera Universitaria Mater Domini, Catanzaro; Azienda Ospedaliera Bianchi-Melacrino-Morelli; Annunziata Hospital, Cosenza, Italy

Publications and helpful links

General Publications

• Chen L, Xiong J, Bao L, Shi Y. Convalescent plasma as a potential therapy for COVID-19. Lancet Infect Dis. 2020 Apr;20(4):398-400. doi: 10.1016/S1473-3099(20)30141-9. Epub 2020 Feb 27. No abstract available.
• Casadevall A, Pirofski LA. The convalescent sera option for containing COVID-19. J Clin Invest. 2020 Apr 1;130(4):1545-1548. doi: 10.1172/JCI138003. No abstract available.
• Marano G, Vaglio S, Pupella S, Facco G, Catalano L, Liumbruno GM, Grazzini G. Convalescent plasma: new evidence for an old therapeutic tool? Blood Transfus. 2016 Mar;14(2):152-7. doi: 10.2450/2015.0131-15. Epub 2015 Nov 6.
• Mair-Jenkins J, Saavedra-Campos M, Baillie JK, Cleary P, Khaw FM, Lim WS, Makki S, Rooney KD, Nguyen-Van-Tam JS, Beck CR; Convalescent Plasma Study Group. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. J Infect Dis. 2015 Jan 1;211(1):80-90. doi: 10.1093/infdis/jiu396. Epub 2014 Jul 16.
• Linee Guida Cinesi sulla Gestione di COVID-19 Versione 7° Pubblicate in data 3/3/2020 dalla Commissione della Salute Nazionale della R.P.C..
• Arabi Y, Balkhy H, Hajeer AH, Bouchama A, Hayden FG, Al-Omari A, Al-Hameed FM, Taha Y, Shindo N, Whitehead J, Merson L, AlJohani S, Al-Khairy K, Carson G, Luke TC, Hensley L, Al-Dawood A, Al-Qahtani S, Modjarrad K, Sadat M, Rohde G, Leport C, Fowler R. Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study protocol. Springerplus. 2015 Nov 19;4:709. doi: 10.1186/s40064-015-1490-9. eCollection 2015.
• Dean CL, Hooper JW, Dye JM, Zak SE, Koepsell SA, Corash L, Benjamin RJ, Kwilas S, Bonds S, Winkler AM, Kraft CS. Characterization of Ebola convalescent plasma donor immune response and psoralen treated plasma in the United States. Transfusion. 2020 May;60(5):1024-1031. doi: 10.1111/trf.15739. Epub 2020 Mar 4.

Helpful Links

• reference 6
• reference 9

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 1, 2020
• Primary Completion (ANTICIPATED): October 15, 2020
• Study Completion (ANTICIPATED): May 15, 2021

Study Registration Dates

• First Submitted: May 4, 2020
• First Submitted That Met QC Criteria: May 11, 2020
• First Posted (ACTUAL): May 12, 2020

Study Record Updates

• Last Update Posted (ACTUAL): May 12, 2020
• Last Update Submitted That Met QC Criteria: May 11, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: convalescent plasma; severe Covid-19; severe coronavirus-2; plasma hyperimmune
• 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: COVID-19 convalescent plasma

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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