Evaluation of the safety and efficacy of XAV-19 in patients with COVID-19-induced moderate pneumonia: study protocol for a randomized, double-blinded, placebo-controlled phase 2 (2a and 2b) trial
Authors: Gaborit Benjamin , Vanhove Bernard , Vibet Marie-Anne , Le Thuaut Aurélie , Lacombe Karine , Dubee Vincent , Ader Florence , Ferre Virginie , Vicaut Eric , Orain Jéremie , Le Bras Morgane , Omnes Anne , Berly Laetitia , Jobert Alexandra , Morineau-Le Houssine Pascale , Botturi Karine , Josien Régis , Flet Laurent , Degauque Nicolas , Brouard Sophie , Duvaux Odile , Poinas Alexandra , Raffi François ,   POLYCOR study group, Dailly Eric , Guimard Thomas , Braudeau Cécile , Malvy Denis , Faucher Jean-François , Illes Hajnal Gabriela , Vareil Marc-Olivier , Roncato-Saberam Mariam , Vacher Laurent , Biron Charlotte , Lefebvre Maeva , Gallot Géraldine , Le Turnier Paul , Deschanvres Colin , Lecomte Raphael , Chauveau Marie , Lecompte Anne-sophie , Grégoire Matthieu , Bellouard Ronan , Deslandes Guillaume , Ouazene Zineb , Bollens Diane , Chiarabani Thibault , Krause-Le Garrec Jessica , Becker Agathe , Chauvelot Pierre , Conrad Anne , Ferry Tristan , Miailhes Patrick , Pouderoux Cécile , Roux Sandrine , Triffault-Fillit Claire 
Published: March 2021

Abstract
Background
Early inhibition of entry and replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a very promising therapeutic approach. Polyclonal neutralizing antibodies offers many advantages such as providing immediate immunity, consequently blunting an early pro-inflammatory pathogenic endogenous antibody response and lack of drug-drug interactions.
By providing immediate immunity and inhibiting entry into cells, neutralizing antibody treatment is of interest for patient with COVID-19-induced moderate pneumonia. Convalescent plasma to treat infected patients is therefore a relevant therapeutic option currently under assessment (CORIMUNO-PLASM NCT04324047). However, the difficulties of collecting plasma on the long term are not adapted to a broad use across all populations.
New polyclonal humanized anti-SARS-CoV2 antibodies (XAV-19) developed by Xenothera and administered intravenous. XAV-19 is a heterologous swine glyco-humanized polyclonal antibody (GH-pAb) raised against the spike protein of SARS-CoV-2, blocking infection of ACE-2-positive human cells with SARS-CoV-2.

Methods
Pharmacokinetic and pharmacodynamic studies have been performed in preclinical models including primates. A first human study with another fully representative GH-pAb from Xenothera is ongoing in recipients of a kidney graft. These studies indicated that 5 consecutive administrations of GH-pAbs can be safely performed in humans.
The objectives of this 2-step phase 2 randomized double-blinded, placebo-controlled study are to define the safety and the optimal XAV-19 dose to administrate to patients with SARS-CoV-2 induced moderate pneumonia, and to assess the clinical benefits of a selected dose of XAV-19 in this population.

Discussion
This study will determine the clinical benefits of XAV-19 when administered to patients with SARS-CoV-2-induced moderate pneumonia. As a prerequisite, a first step of the study will define the safety and the dose of XAV-19 to be used.
Such treatment might become a new therapeutic option to provide an effective treatment for COVID-19 patients (possibly in combination with anti-viral and immunotherapies). Further studies could later evaluate such passive immunotherapy as a potential post-exposure prophylaxis.

Trial registration
ClinicalTrials.gov NCT04453384, registered on 1 July 2020, and EUDRACT 2020-002574-27, registered 6 June 2020.