Clinical trial NCT04479163: Prevention of Severe Covid-19 in Infected Elderly by Early Administration of Convalescent Plasma With High-titers of Antibody Against SARS-CoV2
Official title: Prevention of Severe Covid-19 in Infected Elderly by Early Administration of Convalescent Plasma With High-titers of Antibody Against SARS-CoV2.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: COVID
Lead sponsor: Fundacion Infant
Sponsor class: OTHER
First posted: 2020-07-21
Enrollment: 165
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Trial design. Randomized, double-blind, placebo-controlled trial in a catchment population of 2,020,860 age-appropriate subjects in the state of Buenos Aires and 235,000 in the city of Buenos Aires.

Institutions. Hospitals San Juan de Dios, Simplemente Evita, Dr. Carlos Bocalandro, Evita Pueblo, Sanatorio Antartida, Hospital Central de San Isidro, Clinica Olivos in the state of Buenos Aires with 38 regional and town hospitals acting as referral centers, and Hospital Militar Central, Sanatorio de Los Arcos, Hospital Universitario CEMIC, Sanatorio Sagrado Corazon, Sanatorio Finochietto, Sanatorio Anchorena, Centro Gallego, and in the city of Buenos Aires in Argentina.

Study population. Subjects \>= 75 years of age irrespective of presenting comorbidities or between 65-74 years of age with at least one comorbidity (hypertension, diabetes, obesity, chronic renal failure, and COPD) who experience the following signs and symptoms for less than 48 hours at the time of screening for SARS CoV2 by RT-PCR: (a) a temperature \>=37.5°C and/or unexplained sweating and/or chills and (b) at least one of the following: dry cough, dyspnea, fatigue, myalgia, anorexia, sore throat, loss of taste and/or smell, rhinorrhea. Subjects consenting to screening will be tested by reverse-transcriptase-polymerase-chain-reaction (RT-PCR) for SARS-CoV-2 in a nasopharyngeal and an oropharyngeal swab and invited to participate when RNA for the virus is detected.

Intervention. Eligible, consenting patients will be randomized using an electronic system to receive 250 ml of convalescent plasma with an IgG titer against SARS-CoV2 spike (S) protein \>1:1,000 (COVIDAR IgG, Insituto Leloir, Argentina) or placebo (normal saline 0.9%) administered in a 1:1 ratio. Both treatment and placebo will be concealed using dark bags and tape to cover the infusion line. Treatment will be administered \<72 hours from initiation of symptoms. Subjects will be monitored for 12 hours after treatment for adverse events.

Clinical and laboratory monitoring. All participating subjects will be admitted to the hospital upon enrollment. Twenty-four hours after completing the infusion, a sample of venous blood (5 ml) will be obtained from all participants to measure anti-S IgG SARS-CoV2 in serum (COVIDAR IgG, Leloir) and preserved at -20°C until completion of the study. Patient evolution will be assessed daily by study physicians during hospitalization until day 25 and/or at home until day 15, in the event of earlier discharge from the hospital. Study physicians will use predesigned questionnaires to collect clinical information. An Independent Data Safety Monitoring Board (DSMB) will supervise participating subjects during the study.

Endpoints. The primary endpoint of the trial is development of severe respiratory disease defined as a respiratory rate (RR)\>30 and/or an O2 sat\<93% when breathing room air determined using a predefined protocol. Three other clinical endpoints include (a) life threatening respiratory disease, defined as need for 100% oxygen supplementation and/or non-invasive or invasive ventilation and/or admission to intensive care; (b) critical systemic illness, defined as respiratory failure (PaO2/FiO2 ≤ 200 mm Hg) and/or shock and/or multiorganic distress syndrome; and (c) death.

Statistical analysis. The study is designed to have one interim analysis when the outcome results for 50% of the subjects is obtained. The minimally clinically important difference was set at a 40% relative reduction for an expected outcome rate of 50% in the control group reduced to 30% in the intervention group. A total sample size of 210 subjects (105 per trial arm) was estimated to have 80% power at a significance level (alpha) of 0.05 using a two-sided z-test with continuity correction.

Ethical considerations. The trial has been approved by the institutional review boards of participating institutions and the Central Ethics Committee of the state of Buenos Aires. The study will be conducted in accordance with the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Conference on Harmonization. Written informed consent will be obtained from all patients for screening and enrollment.


Eligibility criteria: Inclusion Criteria:

- Age ≥ 75 or age 65-74 with at least 1 of the following comorbidities: arterial hypertension, diabetes, obesity, chronic obstructive pulmonary disease, heart disease, chronic kidney disease

* Last 48 hours: (A)Axillary temperature ≥ 37.5oC or febrile equivalent, combined with (a) dry cough and/or (b) breathing difficulty and/or (c) odinophagia and/or (d) anosmia/dysgeusia and/or (e) any of the following symptoms: fatigue, anorexia, myalgias or rhinorrhea.
* Confirmed diagnosis SARS-Cov2 by RT-PCR
* Give Informed consent

Exclusion Criteria:

* Severe respiratory disease
* Cardiac insufficiency,
* Chronic renal failure,
* Primary hypogammaglobulinemias,
* Myelodysplastic syndromes,
* Chronic linfoproliferative syndromes,
* Monoclonal gammapathies,
* Known hypersensitibility,
* Active cancer,
* HIV, HBV or HCV infection,
* Chronic administration of immunosuppressants,
* Body transplant history,
* Chronic liver disease, Chronic lung disease with oxygen requirement.

Primary outcomes:
measure: Development of severe respiratory disease defined as a respiratory rate (RR)>30 and/or an O2 sat<93%
timeFrame: From 12 hours post infusion to day 15 post infusion
Secondary outcomes:
measure: Life threatening respiratory disease
timeFrame: From 12 hours post infusion to day 25 post infusion
measure: Critical systemic illness, defined as respiratory failure
timeFrame: From 12 hours post infusion to day 25 post infusion
measure: Death
timeFrame: From 12 hours post infusion to day 25 post infusion
measure: Combination of secondary outcomes #2 (Life threatening respiratory disease) and/or #3 (Critical systemic illness, defined as respiratory failure) and//or #4 (death)
timeFrame: From 12 hours post infusion to day 25 post infusion
measure: Duration of oxygen support requirement in patients with covid-19 due to saturation in ambient air <93%.
timeFrame: From 12 hours post infusion to day 25 post infusion
Other outcomes:
Locations:
city: Caba
country: Argentina
facility: Hospital Militar Central
state: Buenos Aires
city: Caba
country: Argentina
facility: CEMIC
state: Buenos Aires
city: Caba
country: Argentina
facility: Centro de Investigacion Clinica OSECAC
state: Buenos Aires
city: Caba
country: Argentina
facility: Centro Gallego de Buenos Aires
state: Buenos Aires
city: Caba
country: Argentina
facility: Sanatorio Anchorena
state: Buenos Aires
city: Caba
country: Argentina
facility: Sanatorio de Los Arcos
state: Buenos Aires
city: González Catán
country: Argentina
facility: Hospital "Simplemente Evita"
state: Buenos Aires
city: La Plata
country: Argentina
facility: Hospital Especializado de Agudos y Crónicos "San Juan de Dios"
state: Buenos Aires
city: Buenos Aires
country: Argentina
facility: Clinica Olivos
city: Buenos Aires
country: Argentina
facility: Hospital Central de San Isidro
city: Buenos Aires
country: Argentina
facility: Hospital General de Agudos "Dr. Carlos Bocalandro"
Study officials:
affiliation: Fundacion Infant
name: Fernando P Polack, MD
role: STUDY_DIRECTOR
References:
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: Libster R, Perez Marc G, Wappner D, Coviello S, Bianchi A, Braem V, Esteban I, Caballero MT, Wood C, Berrueta M, Rondan A, Lescano G, Cruz P, Ritou Y, Fernandez Vina V, Alvarez Paggi D, Esperante S, Ferreti A, Ofman G, Ciganda A, Rodriguez R, Lantos J, Valentini R, Itcovici N, Hintze A, Oyarvide ML, Etchegaray C, Neira A, Name I, Alfonso J, Lopez Castelo R, Caruso G, Rapelius S, Alvez F, Etchenique F, Dimase F, Alvarez D, Aranda SS, Sanchez Yanotti C, De Luca J, Jares Baglivo S, Laudanno S, Nowogrodzki F, Larrea R, Silveyra M, Leberzstein G, Debonis A, Molinos J, Gonzalez M, Perez E, Kreplak N, Pastor Arguello S, Gibbons L, Althabe F, Bergel E, Polack FP; Fundacion INFANT-COVID-19 Group. Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults. N Engl J Med. 2021 Feb 18;384(7):610-618. doi: 10.1056/NEJMoa2033700. Epub 2021 Jan 6.