Phase I and Preliminary Results of a Phase II Study (TERAPLASCoV2) of Convalescent Plasma in Patients with Severe and Life-Threatening Pneumonia Caused By Sars-Cov-2
Authors: Pérez-Jacobo Fernando , Villela Luis Villela , Velásquez-Vega Edgar , Hernández Jesús , Otañez Melani , Arellano-Mendoza Mónica , Sosa-Camas Rosa , Manríquez-Bonillas Víctor , Bejar-Cornejo Rubén , Pérez Fausto , Chávez-Ochoa Joanna , Ramos-Vadillo Bernardo , Limón-Palafox Mabel , Jacobo-López Karen , Vázquez Hernández Alondra , Rosales Del Real Ofelia , Mondragón-Posadas Lidia , Pérez De la O Alma , Rodríguez-Morales Pablo , Millán Cureño Ma. Luisa , Gómez Meza Martha , Padilla-Ibarra Cecilia , Soto-Gaxiola Alan , Melgoza-Gonzáles Edgar , Hinojosa-Trujillo Diana , Reyes-Jiménez Emilio , Serrato-Félix Marcos , Martínez Arredondo Hilario , Lehmann Mendoza Rodolfo 
Published: November 2020

Introduction: The current coronavirus disease- 2019 (COVID-19) pandemic has caused a sudden increase in pneumonia cases, with a case-fatality rate of 10.9% in Mexico. Two inpatient groups have been defined, with different clinical evolution: cases of severe pneumonia and those with life-threatening disease (Acute respiratory distress syndrome [ARDS], invasive mechanical ventilation [IMV] requirement, and multiorgan involvement).
Currently, there is no effective treatment. Convalescent plasma (CP) has been used to treat another viral infections and outbreaks since the last century. The rationale is that neutralizing antibodies contained in CP suppress viremia and produce immunoregulation. However, an established therapeutic dose during this pandemic is lacking.
Aim: To evaluate in a phase I trial the minimum effective dose of CP in severe and life-threatening disease patients and then carry out a phase II study to establish the effectiveness (overall survival at 30 days) comparing it with a non-randomized control group.
Methods and design. Our study is an open-label, multicenter, non-randomized and started in May, 2020 and was approved by the ethics committee at HGE & HCN Pemex; respectively. CP donor selection: pre-donors who were infected by SARS-CoV-2 were evaluated on +30 day by serum titration (≥1:320 IgG antibody); then connected to apheresis machine to obtain 600 ml of CP that were fractionated in 200 ml bags and stored. Patients: Two groups were formed: severe and life-threating disease. CP was offered to patients who were admitted on two hospitals. Patients should meet the following criteria: SARS-CoV-2 positive for qRT- PCR, respiratory rate&gt; 30 per minute or Kirby index &lt;300 or IMV requirement; be older than 18 years; and sign the informed consent. Statistics: For demographic variables, the differences were evaluated with parametric or non-parametric analysis. For survival, Kaplan Meier curves were assessed for each group. A p value &lt;0.05 was considered significant.
Outcomes: A total of 110 CP bags have been transfused. The median serum IgG antibody titers were 1: 960. Dosing, phase 1. Severe group (n=14): 71% received two CP bags (400 ml) and 29% three CP bags (600 mL). Life-threatening disease group (n=10): 60% received 4 CP bags (800 ml) and 40% 3 CP bags (600 ml). Dose was established at 400 ml for the severe group and 800 ml for the life-threatening group. Security: CP infusions were well tolerated, with only 3 adverse events (2.72%) reported: one case of transfusion associated circulatory overload (TACO) that resolved with the use of loop diuretics as a serious adverse event; one fever episode (grade 1) and one case of rash (grade 1) after CP infusion.
Phase II: The calculated n to be included in each arm (severe vs. life-threatening disease) is 68 and 52 patients, respectively. So far, we have included a total of 42 patients treated with CP. This entire cohort was compared with a historic group of COVID-19 patients who received other treatment strategies. Clinical characteristics on both plasma (PG) and control group (CG) are presented in table 1. We observed statistically significant differences on smoking habit, D-Dimer levels and ARDS severity between groups. The median overall follow- up was 24 days [PG 28 days vs. CG 21.5 days]. Overall Survival (OS) between PG and CG was 74% vs. 54% at 30-days respectively [HR=0.43 (C.I.95%=0.23 to 0.91, p=0.021); figure 1].
We analyzed OS by group stratification: COVID-19 severity (severe disease vs. life-threatening disease) and ARDS severity. We found no difference in OS between severe disease-PG and severe disease-CG; but we observed an OS difference between life-threatening-PG and life-threatening-CG [32% vs. 5.8% at 30-days; p=0.003].
ARDS-PG vs. ARDS-CG showed OS differences in moderate [59% vs. 25% at 30 days; p=0.01, respectively] and severe ARDS [63% vs. 0%; p=0.001, respectively]; however, there was not statistically significant difference between mild ARDS-PG and CG groups [89% vs. 86%; p=0.85, respectively].
Conclusion: This is the first phase I trial aiming to establish an effective CP dose for COVID-19 patients, at least in México. For severe and life-threatening disease, 2 and 4 CP bags were suggested. This treatment was secure, with &lt;3% of adverse events reported. OS could be modified using certain doses based on disease severity and pa02/Fi02 index. We will continue to include patients until the calculated n is reached.

Disclosures
Villela: Roche: Other: advisory board, Speakers Bureau; amgen: Speakers Bureau.