Convalescent Plasma and Placebo for the Treatment of COVID-19 Severe Pneumonia (PLASM-AR)

Randomized, Double-blind, Placebo-controlled Clinical Trial of Convalescent Plasma for the Treatment of COVID-19 Pneumonia With Severity Criteria

A multicenter randomized, double-blind, placebo-controlled clinical trial of Convalescent SARS COVID-19 plasma versus Placebo to evaluate the effect between arms on an ordinal score of six mutually exclusive categories of clinical status at day 30 after study initiation.

Study Overview

• Status: Completed
• Conditions: COVID-19; SARS-CoV-2; SARS Virus
• Intervention / Treatment: Other: Convalescent SARS COVID-19 plasma; Other: Placebo

Detailed Description

Introduction

The use of convalescent plasma in the treatment of infectious diseases has been empirically performed for more than a century. It is based upon the assumption that providing exogenous neutralizing antibodies may provide protection while affected patients mount their own immune response. This therapeutic approach appears of particular interest in the context of the current pandemic, in which there is no specific vaccine available nor adequately proven effective pharmacological treatments.

Study purpose, hypothesis and general design

Purpose of the study: evaluate the effectiveness and safety of convalescent plasma in the treatment of SARS-CoV-2 pneumonia (Covid-19) Hypothesis: Convalescent plasma significantly improves the clinical outcome in patients with Covid-19 pneumonia and severity criteria.

Multicenter randomized, double-blind, placebo.controlled clinical trial. Placebo will be a saline solution.

3. Methodological sustain for including a control arm with placebo Quality evidence about the effectiveness of convalescent plasma in the treatment of Covid-19 pneumonia is not yet available. Although case series and anecdotal reports appear encouraging, the implementation of its use in routine clinical practice requires the validation through controlled clinical trials. In addition the collection, administration and control of plasma is technically demanding and needs a clear support before broadly recommending it. Different scientific institutions and international organisms had clearly suggested to prioritize the application of novel therapeutic techniques with yet unproven efficacy within the context of clinical studies over its empirical use.

On the other hand, for the present study, intervention strategy is proposed in "add-on" modality over the antiviral treatment that each participant may be already receiving, since they represent completely different therapeutic approaches. As such, participation in the present study will not condition the possibility of the participants to receive other treatments, either in intervention or control arms.

4. Study objectives Primary objective Analyze the difference between arms on an ordinal score of six mutually exclusive categories at day 30 after study initiation. This score includes the following categories

• Study Type: Interventional
• Enrollment (Actual): 333
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Argentina
  • Ciudad Autonoma De Buenos Aires
    • Ciudad Autonoma de Buenos Aire, Ciudad Autonoma De Buenos Aires, Argentina, 1181
      • Hospital Italiano de Buenos Aires

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:

• Confirmed diagnosis of Covid-19 through qualitative polymerase-reverse transcriptase (qRT-PCR -GeneDX Co, Ltd o similar).
• Imagining-diagnosed pneumonia (Rx or CT scan).
• MSOFA score (Modified SOFA) of 2 or more (modified organic failure assessment)
• Informed consent.

Exclusion Criteria:

• Pregnant women
• Women at reproductive age not willing to avoid unprotected sexual intercourse up to Day 30 after study initiation.
• Women in the breastfeeding period
• Patients receiving experimental treatments under development within 30 days prior to study initiation.
• Patients with a previous history of allergic reactions to blood or blood-components transfusion.
• Diagnosis or clinical suspicion of an alternative microbiological cause for pneumonia besides COVID-19
• Use of systemic corticosteroids within 15 days prior to entering the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Convalescent SARS COVID-19 plasma; Convalescent SARS COVID-19 plasma from a pool of 10 donor plasma, in addition to standard care.	Other: Convalescent SARS COVID-19 plasma; Convalescent SARS COVID-19 plasma from a pool of 10 donor plasma. The calculation of the volume to be transfused will be from 10 to 15 ml / kg adjusting the volume to the body weight of each patient, at a suggested infusion rate of 5 to 10 ml / kg / h with an intravenous infusion pump. The infusion rate will be adjusted according to the clinical stability of the patient according to the treating physician.
PLACEBO_COMPARATOR: Placebo; Single infusion of saline solution, in addition to standard care.	Other: Placebo; Single infusion of saline solution, in addition to standard care. The calculation of the volume to be transfused will be from 10 to 15 ml / kg adjusting the volume to the body weight of each patient, at a suggested infusion rate of 5 to 10 ml / kg / h with an intravenous infusion pump. The infusion rate will be adjusted according to the clinical stability of the patient according to the treating physician.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical status during follow-up at 30th day	Ordinal outcome with six mutually exclusive categories to describe the patient's clinical status during follow-up. The six categories are: (1) death; (2) in intensive care; (3) hospitalised but requiring supplemental oxygen; (4) hospitalised and not requiring supplemental oxygen; (5) discharged but unable to resume normal activities; or (6) discharged with full resumption of normal activities.	30th Day since study preparation infusion (Placebo or Convalescent SARS COVID-19 plasma)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical status during follow-up at 7th day	Ordinal outcome with six mutually exclusive categories to describe the patient's clinical status during follow-up. The six categories are: (1) death; (2) in intensive care; (3) hospitalised but requiring supplemental oxygen; (4) hospitalised and not requiring supplemental oxygen; (5) discharged but unable to resume normal activities; or (6) discharged with full resumption of normal activities.	7th Day since study preparation infusion (Placebo or Convalescent SARS COVID-19 plasma)
Clinical status during follow-up at 14th day	Ordinal outcome with six mutually exclusive categories to describe the patient's clinical status during follow-up. The six categories are: (1) death; (2) in intensive care; (3) hospitalised but requiring supplemental oxygen; (4) hospitalised and not requiring supplemental oxygen; (5) discharged but unable to resume normal activities; or (6) discharged with full resumption of normal activities.	14th Day since study preparation infusion (Placebo or Convalescent SARS COVID-19 plasma)
Time until hospital discharge (days).	Hospital discharge or intrahospital death	Whenever the patient is discharge from the hospital or die without discharge, through study completion, an average of 14 days from admission
Time until discharge from ICU (days)	ICU discharge or ICU death	Whenever the patient is discharge from ICU or die in ICU, through study completion, an average of 10 days from admission
Time to death	Death and time to death	In a 30 days follow up period
Time until complete functional recovery	Time until complete functional recovery (according to basal status).	Whenever the patient returns to basal functional status until 1 month from discharge
Percentage of participants with adverse events / serious adverse events	Percentage of participants with adverse events / serious adverse events	In a 30 days follow up period
Percentage of patients with negative SARS-CoV-3 PCR at Day 14th	Percentage of patients with negative SARS-CoV-3 PCR	14th Day since study preparation infusion (Placebo or Convalescent SARS COVID-19 plasma)
D Dimer plasma concentration at Day 14th	D Dimer plasma concentration	14th Day since study preparation infusion (Placebo or Convalescent SARS COVID-19 plasma)
Ferritin plasma concentration at Day 13th	Ferritin plasma concentration	13th Day since study preparation infusion (Placebo or Convalescent SARS COVID-19 plasma)
Plasma concentration of neutralizing antibodies at Day 2nd	Plasma concentration of neutralizing antibodies	2nd Day since study preparation infusion (Placebo or Convalescent SARS COVID-19 plasma)
Plasma concentration of neutralizing antibodies at Day 7th	Plasma concentration of neutralizing antibodies	7th Day since study preparation infusion (Placebo or Convalescent SARS COVID-19 plasma)
Post-transfusion adverse reactions	Post-transfusion adverse reactions between study groups	In a 30 days follow up period

Collaborators and Investigators

• Sponsor: Hospital Italiano de Buenos Aires
• Investigators: Principal Investigator: Nora A Fuentes, MD, Hospital Privado de la Comunidad de Mar del Plata; Principal Investigator: Florencia Otermin, MD, Hospital Italiano de La Plata; Principal Investigator: Esteban Nannini, MD, Sanatorio Britanico Rosario, pcia Santa Fe; Principal Investigator: Karina Rainiero, MD, Suiza Argentina; Principal Investigator: Erica Miyazaki, MD, Clínica Zabala; Principal Investigator: Gabriela Vidiella, MD, Sanatorio Agote; Principal Investigator: Wanda Cornistein, MD, Austral University, Argentina; Principal Investigator: Leandro Burgos, MD, Hospital Italiano de Buenos Aires

Publications and helpful links

General Publications

• Cheng Y, Wong R, Soo YO, Wong WS, Lee CK, Ng MH, Chan P, Wong KC, Leung CB, Cheng G. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis. 2005 Jan;24(1):44-6. doi: 10.1007/s10096-004-1271-9.
• Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, Wang F, Li D, Yang M, Xing L, Wei J, Xiao H, Yang Y, Qu J, Qing L, Chen L, Xu Z, Peng L, Li Y, Zheng H, Chen F, Huang K, Jiang Y, Liu D, Zhang Z, Liu Y, Liu L. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. 2020 Apr 28;323(16):1582-1589. doi: 10.1001/jama.2020.4783.
• 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.
• Roback JD, Guarner J. Convalescent Plasma to Treat COVID-19: Possibilities and Challenges. JAMA. 2020 Apr 28;323(16):1561-1562. doi: 10.1001/jama.2020.4940. No abstract available.
• Tanne JH. Covid-19: FDA approves use of convalescent plasma to treat critically ill patients. BMJ. 2020 Mar 26;368:m1256. doi: 10.1136/bmj.m1256. No abstract available.
• Maiztegui JI, Fernandez NJ, de Damilano AJ. Efficacy of immune plasma in treatment of Argentine haemorrhagic fever and association between treatment and a late neurological syndrome. Lancet. 1979 Dec 8;2(8154):1216-7. doi: 10.1016/s0140-6736(79)92335-3.
• Kalil AC. Treating COVID-19-Off-Label Drug Use, Compassionate Use, and Randomized Clinical Trials During Pandemics. JAMA. 2020 May 19;323(19):1897-1898. doi: 10.1001/jama.2020.4742. No abstract available.
• Angus DC. Optimizing the Trade-off Between Learning and Doing in a Pandemic. JAMA. 2020 May 19;323(19):1895-1896. doi: 10.1001/jama.2020.4984. No abstract available.
• Luke TC, Kilbane EM, Jackson JL, Hoffman SL. Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment? Ann Intern Med. 2006 Oct 17;145(8):599-609. doi: 10.7326/0003-4819-145-8-200610170-00139. Epub 2006 Aug 29.
• Simonovich VA, Burgos Pratx LD, Scibona P, Beruto MV, Vallone MG, Vazquez C, Savoy N, Giunta DH, Perez LG, Sanchez MDL, Gamarnik AV, Ojeda DS, Santoro DM, Camino PJ, Antelo S, Rainero K, Vidiella GP, Miyazaki EA, Cornistein W, Trabadelo OA, Ross FM, Spotti M, Funtowicz G, Scordo WE, Losso MH, Ferniot I, Pardo PE, Rodriguez E, Rucci P, Pasquali J, Fuentes NA, Esperatti M, Speroni GA, Nannini EC, Matteaccio A, Michelangelo HG, Follmann D, Lane HC, Belloso WH; PlasmAr Study Group. A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia. N Engl J Med. 2021 Feb 18;384(7):619-629. doi: 10.1056/NEJMoa2031304. Epub 2020 Nov 24.

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 15, 2020
• Primary Completion (ACTUAL): September 27, 2020
• Study Completion (ACTUAL): September 27, 2020

Study Registration Dates

• First Submitted: May 6, 2020
• First Submitted That Met QC Criteria: May 8, 2020
• First Posted (ACTUAL): May 12, 2020

Study Record Updates

• Last Update Posted (ACTUAL): September 30, 2020
• Last Update Submitted That Met QC Criteria: September 29, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: SARS-CoV-2; COVID-19; SARS Virus; Blood Plasma
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Lung Diseases; COVID-19; Pneumonia
• Other Study ID Numbers: 5565

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