Christopher Adlbrecht1, Raphael Wurm2, Pieter Depuydt3, Herbert Spapen4, Jose A Lorente5, Thomas Staudinger2, Jacques Creteur6, Christian Zauner2, Andreas Meier-Hellmann7, Philipp Eller8, Margot Vander Laenen9, Zsolt Molnár10, István Várkonyi11, Bernhard Schaaf12, Mária Héjja13, Vladimír Šrámek14, Hauke Schneider15,16, Niranjan Kanesa-Thasan17, Susanne Eder-Lingelbach18, Anton Klingler19, Katrin Dubischar18, Nina Wressnigg20, Jordi Rello21. 1. Department of Cardiology, Vienna North Hospital-Clinic Floridsdorf and the Karl Landsteiner Institute for Cardiovascular and Critical Care Research, Vienna, Austria. 2. Medical University of Vienna, Vienna, Austria. 3. Universitair Ziekenhuis Gent, Ghent, Belgium. 4. Universitair Ziekenhuis Brussel, Brussels, Belgium. 5. Hospital Universitario de Getafe, CIBER de Enfermedades Respiratorias, Universidad Europea, Madrid, Spain. 6. Erasme University Hospital, Brussels, Belgium. 7. HELIOS Klinikum Erfurt GmbH, Erfurt, Germany. 8. Medical University of Graz, Graz, Austria. 9. Ziekenhuis Oost-Limburg, Campus St. Jan, Genk, Belgium. 10. Szegedi Tudományegyetem, Szeged, Hungary. 11. Kenézy Kórház Debrecen, Debrecen, Hungary. 12. Klinikum Dortmund GmbH, Dortmund, Germany. 13. Országos Korányi TBC és Pulmonológiai Intézet, Budapest, Hungary. 14. Fakultní nemocnice U Svaté Anny v Brně, Brno, Czech Republic. 15. Technische Universität Dresden, Dresden, Germany. 16. University Hospital Augsburg, Augsburg, Germany. 17. GSK Vaccines, Rockville, MD, USA. 18. Valneva Austria GmbH, Campus Vienna Biocenter 3, 1030, Vienna, Austria. 19. Assign Data Management and Biostatistics GmbH, Innsbruck, Austria. 20. Valneva Austria GmbH, Campus Vienna Biocenter 3, 1030, Vienna, Austria. Nina.WRESSNIGG@valneva.com. 21. Centro de Investigacion Biomedica en Red (CIBERES), Hospital Universitari Vall d'Hebron, Barcelona, Spain.
Abstract
BACKGROUND: Pseudomonas aeruginosa infections are a serious threat in intensive care units (ICUs). The aim of this confirmatory, randomized, multicenter, placebo-controlled, double-blind, phase 2/3 study was to assess the efficacy, immunogenicity, and safety of IC43 recombinant Pseudomonas aeruginosa vaccine in non-surgical ICU patients. METHODS:Eight hundred patients aged 18 to 80 years admitted to the ICU with expected need for mechanical ventilation for ≥ 48 h were randomized 1:1 to either IC43 100 μg or saline placebo, given in two vaccinations 7 days apart. The primary efficacy endpoint was all-cause mortality in patients 28 days after the first vaccination. Immunogenicity and safety were also evaluated. FINDINGS: All-cause mortality rates at day 28 were 29.2% vs 27.7% in the IC43 and placebo groups, respectively (P = .67). Overall survival (Kaplan-Meier survival estimates, P = .46) and proportion of patients with ≥ one confirmed P. aeruginosa invasive infection or respiratory tract infection also did not differ significantly between both groups. The geometric mean fold increase in OprF/I titers was 1.5 after the first vaccination, 20 at day 28, after the second vaccination, and 2.9 at day 180. Significantly more patients in the placebo group (96.5%) had ≥ one adverse event (AE) versus the IC43 100 μg group (93.1%) (P = .04). The most frequently reported severe AEs in the IC43 and placebo groups were respiratory failure (6.9% vs 5.7%, respectively), septic shock (4.1% vs 6.5%), cardiac arrest (4.3% vs 5.7%), multiorgan failure (4.6% vs 5.5%), and sepsis (4.6% vs 4.2%). No related serious AEs were reported in the IC43 group. INTERPRETATION: The IC43 100 μg vaccine was well tolerated in this large population of medically ill, mechanically ventilated patients. The vaccine achieved high immunogenicity but provided no clinical benefit over placebo in terms of overall mortality. TRIAL REGISTRATION: https://clinicaltrials.gov (NCT01563263). Registration was sent to ClinicalTrials.gov on March 14, 2012, but posted by ClinicalTrials.gov on March 26, 2012. The first subject was included in the trial on March 22, 2012.
RCT Entities:
BACKGROUND:Pseudomonas aeruginosa infections are a serious threat in intensive care units (ICUs). The aim of this confirmatory, randomized, multicenter, placebo-controlled, double-blind, phase 2/3 study was to assess the efficacy, immunogenicity, and safety of IC43 recombinant Pseudomonas aeruginosa vaccine in non-surgical ICU patients. METHODS: Eight hundred patients aged 18 to 80 years admitted to the ICU with expected need for mechanical ventilation for ≥ 48 h were randomized 1:1 to either IC43 100 μg or saline placebo, given in two vaccinations 7 days apart. The primary efficacy endpoint was all-cause mortality in patients 28 days after the first vaccination. Immunogenicity and safety were also evaluated. FINDINGS: All-cause mortality rates at day 28 were 29.2% vs 27.7% in the IC43 and placebo groups, respectively (P = .67). Overall survival (Kaplan-Meier survival estimates, P = .46) and proportion of patients with ≥ one confirmed P. aeruginosa invasive infection or respiratory tract infection also did not differ significantly between both groups. The geometric mean fold increase in OprF/I titers was 1.5 after the first vaccination, 20 at day 28, after the second vaccination, and 2.9 at day 180. Significantly more patients in the placebo group (96.5%) had ≥ one adverse event (AE) versus the IC43 100 μg group (93.1%) (P = .04). The most frequently reported severe AEs in the IC43 and placebo groups were respiratory failure (6.9% vs 5.7%, respectively), septic shock (4.1% vs 6.5%), cardiac arrest (4.3% vs 5.7%), multiorgan failure (4.6% vs 5.5%), and sepsis (4.6% vs 4.2%). No related serious AEs were reported in the IC43 group. INTERPRETATION: The IC43 100 μg vaccine was well tolerated in this large population of medically ill, mechanically ventilated patients. The vaccine achieved high immunogenicity but provided no clinical benefit over placebo in terms of overall mortality. TRIAL REGISTRATION: https://clinicaltrials.gov (NCT01563263). Registration was sent to ClinicalTrials.gov on March 14, 2012, but posted by ClinicalTrials.gov on March 26, 2012. The first subject was included in the trial on March 22, 2012.
Authors: Mohammad Omar Faruk Shaikh; Matthew M Schaefers; Christina Merakou; Marco DiBlasi; Sarah Bonney; Tiffany Liao; David Zurakowski; Margaret Kehl; David E Tabor; Antonio DiGiandomenico; Gregory P Priebe Journal: Infect Immun Date: 2022-09-07 Impact factor: 3.609
Authors: Wieslaw Swietnicki; Waldemar Goldeman; Mateusz Psurski; Anna Nasulewicz-Goldeman; Anna Boguszewska-Czubara; Marek Drab; Jordan Sycz; Tomasz M Goszczyński Journal: Int J Mol Sci Date: 2021-06-23 Impact factor: 5.923
Authors: Luke L Proctor; Whitney L Ward; Conner S Roggy; Alexandra G Koontz; Katie M Clark; Alyssa P Quinn; Meredith Schroeder; Amanda E Brooks; James M Small; Francina D Towne; Benjamin D Brooks Journal: Antibiotics (Basel) Date: 2021-12-14