Efficacy and safety of trimodulin in patients with severe COVID-19: results from a randomised, placebo-controlled, double-blind, multicentre, phase II trial (ESsCOVID)
Alina Agafina, Valeria Cristina Aguiar, Maria Rossovskaya, Muriel Sarah Fartoukh, Ludhmila Abrahao Hajjar, Guillaume Thiéry, Jean-François Timsit, Ivan Gordeev, Denis Protsenko, Javier Carbone, Rita Pellegrini, Claudio Marcel Berdun Stadnik, Sergey Avdeev, Miquel Ferrer, Corina C Heinz, Thomas Häder, Patrick Langohr, Iris Bobenhausen, Jörg Schüttrumpf, Alexander Staus, Markus Ruehle, Sabrina Weissmüller, Andrea Wartenburg-Demand, Antoni Torres
European Journal of Medical Research, doi:10.1186/s40001-024-02008-x
Background Trimodulin (human polyvalent immunoglobulin [Ig] M ~ 23%, IgA ~ 21%, IgG ~ 56% preparation) has previously been associated with a lower mortality rate in a subpopulation of patients with severe communityacquired pneumonia on invasive mechanical ventilation (IMV) and with clear signs of inflammation. The hypothesis for the ESsCOVID trial was that trimodulin may prevent inflammation-driven progression of severe coronavirus disease 2019 (COVID-19) to critical disease or even death. Methods Adults with severe COVID-19 were randomised to receive intravenous infusions of trimodulin or placebo for 5 consecutive days in addition to standard of care. The primary efficacy endpoint was a composite of clinical deterioration (Days 6-29) and 28-day all-cause mortality (Days 1-29).
Results One-hundred-and-sixty-six patients received trimodulin (n = 84) or placebo (n = 82). Thirty-three patients died, nine during the treatment phase. Overall, 84.9% and 76.5% of patients completed treatment and follow-up, respectively. The primary efficacy endpoint was reported in 33.3% of patients on trimodulin and 34.1% of patients on placebo (P = 0.912). No differences were observed in the proportion of patients recovered on Day 29, days of invasive mechanical ventilation, or intensive care unit-free days. Rates of treatment-emergent adverse events were comparable. A post hoc analysis was conducted in patients with early systemic inflammation by excluding those with high CRP (> 150 mg/L) and/or D-dimer (≥ 3 mg/L) and/or low platelet counts (< 130 × 10 9 /L) at baseline. Forty-seven patients in the trimodulin group and 49 in the placebo group met these criteria. A difference of 15.5 percentage points
SoC Standard of care SpO 2 Blood oxygen saturation TEEs Thromboembolic events TEAEs Treatment-emergent adverse events TNF Tumour necrosis factor ULN Upper limit of the normal WHO World Health Organization
Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s40001-024-02008-x. Additional file 1. Supplementary methods
Additional file 2. Supplementary results
Author contributions
Declarations Ethics approval and consent to participate The trial was conducted according to the International Council for Harmonisation, Good Clinical Practice standards and the Declaration of Helsinki, and with independent ethics committee approval. Written informed consent from the patient, or legally authorised representative, was obtained in compliance with all local legal requirements.
Consent for publication Not applicable.
Competing interests
Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2024, 8, 13]],
'date-time': '2024-08-13T16:07:33Z',
'timestamp': 1723565253000},
'score': 1,
'resource': { 'primary': { 'URL': 'https://eurjmedres.biomedcentral.com/articles/10.1186/s40001-024-02008-x'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2024, 8, 13]]},
'references-count': 63,
'journal-issue': {'issue': '1', 'published-online': {'date-parts': [[2024, 12]]}},
'alternative-id': ['2008'],
'URL': 'http://dx.doi.org/10.1186/s40001-024-02008-x',
'relation': {},
'ISSN': ['2047-783X'],
'subject': [],
'container-title-short': 'Eur J Med Res',
'published': {'date-parts': [[2024, 8, 13]]},
'assertion': [ { 'value': '15 April 2024',
'order': 1,
'name': 'received',
'label': 'Received',
'group': {'name': 'ArticleHistory', 'label': 'Article History'}},
{ 'value': '1 August 2024',
'order': 2,
'name': 'accepted',
'label': 'Accepted',
'group': {'name': 'ArticleHistory', 'label': 'Article History'}},
{ 'value': '13 August 2024',
'order': 3,
'name': 'first_online',
'label': 'First Online',
'group': {'name': 'ArticleHistory', 'label': 'Article History'}},
{'order': 1, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Declarations'}},
{ 'value': 'The trial was conducted according to the International Council for '
'Harmonisation, Good Clinical Practice standards and the Declaration of '
'Helsinki, and with independent ethics committee approval. Written informed '
'consent from the patient, or legally authorised representative, was obtained in '
'compliance with all local legal requirements.',
'order': 2,
'name': 'Ethics',
'group': {'name': 'EthicsHeading', 'label': 'Ethics approval and consent to participate'}},
{ 'value': 'Not applicable.',
'order': 3,
'name': 'Ethics',
'group': {'name': 'EthicsHeading', 'label': 'Consent for publication'}},
{ 'value': 'MSF reports grant support from BioMérieux, speaker fees from BioMérieux and '
'Fisher & Paykel, and consultancy fees from Pfizer (all outside the submitted '
'work); J-FT reports grant support from MSD, Pfizer and Thermo Fisher, '
'consultancy fees from Becton Dickinson, Gilead Sciences, MSD, and Pfizer, '
'speaker fees from MSD, Pfizer and Shionogi, and Chairmanship of the Critical '
'Care section of the European Congress of Clinical Microbiology and Infectious '
'Diseases; JC reports grant support from Biotest and Grifols, and consultancy '
'fees and speaker fees from LFB; SA reports consultancy fees from AstraZeneca '
'and Boehringer Ingelheim, speaker fees from AstraZeneca, Boehringer Ingelheim, '
'Chiesi, Novartis and Sandoz, and support for meeting attendance from '
'AstraZeneca and Boehringer Ingelheim (all outside the submitted work); AT '
'reports consultancy fees and speaker fees from Biotest AG, Janssen, MSD and '
'Pfizer. CCH, TH, PL, IB, AS, MR, and SW are employees of Biotest AG. AW-D was '
'an employee of Biotest AG during trial conduct and the writing of this '
'manuscript. JS is an employee of Grifols SA, as well as an executive board '
'member of Biotest AG, which has received a German Government Grant '
'(Bundesministerium für Bildung und Forschung [BMBF]). AA, VCA, MR, LAH, GT, MF, '
'IG, DP, and RP have no competing interests to declare.',
'order': 4,
'name': 'Ethics',
'group': {'name': 'EthicsHeading', 'label': 'Competing interests'}}],
'article-number': '418'}
