Guy de Bruyn1, Jamshid Saleh2, David Workman3, Richard Pollak4, Victor Elinoff5, Neil J Fraser6, Gigi Lefebvre7, Mark Martens8, Richard E Mills9, Richard Nathan10, Miguel Trevino11, Martin van Cleeff12, Ginamarie Foglia13, Ayca Ozol-Godfrey14, Dhaval M Patel14, Patricia J Pietrobon14, Richard Gesser14. 1. Sanofi Pasteur, Swiftwater, PA, USA. Electronic address: guy.debruyn@sanofipasteur.com. 2. Northern California Research Center, Redding, CA, USA. 3. Jean Brown Research, Salt Lake City, UT, USA. 4. Endeavor Clinical Trials, San Antonio, TX, USA. 5. Regional Clinical Research Inc., Endwell, NY, USA. 6. Troy Internal Medicine P.C./Research, Troy, MI, USA. 7. Meridien Research, St Petersburg, FL, USA. 8. Meridian Health, Neptune, NJ, USA. 9. PMG Research of Charleston, Mt Pleasant, SC, USA. 10. Idaho Falls Infectious Diseases PLC, Idaho Falls, ID, USA. 11. Innovative Research of West Florida Inc., Clearwater, FL, USA. 12. PMG Research of Cary, Cary, NC, USA. 13. Sanofi, Bridgewater, NJ, USA. 14. Sanofi Pasteur, Swiftwater, PA, USA.
Abstract
BACKGROUND: Clostridium difficile, a major cause of nosocomial and antibiotic-associated diarrhea, carries a significant disease and cost burden. This study aimed to select an optimal formulation and schedule for a candidate toxoid vaccine against C. difficile toxins A and B. METHODS: Randomized, placebo-controlled, two-stage, Phase 2 study in a total of 661 adults aged 40-75 years. Stage I: low (50 μg antigen) or high (100 μg antigen) dose with or without aluminum hydroxide (AlOH) adjuvant, or placebo, administered on Days 0-7-30. Stage II: Days 0-7-30, 0-7-180, and 0-30-180, using the formulation selected in Stage I through a decision tree defined a priori and based principally on a bootstrap ranking approach. Administration was intramuscular. Blood samples were obtained on Days 0, 7, 14, 30, 60 (Stage I and II), 180, and 210 (Stage II); IgG to toxins A and B was measured by ELISA and in vitro functional activity was measured by toxin neutralizing assay (TNA). Safety data were collected using diary cards. RESULTS: In Stage I the composite immune response against toxins A and B (percentage of participants who seroconverted for both toxins) was highest in the high dose+adjuvant group (97% and 92% for Toxins A and B, respectively) and was chosen for Stage II. In Stage II the immune response profile for this formulation through Day 180 given on Days 0-7-30 ranked above the other two administration schedules. There were no safety issues. CONCLUSIONS: The high dose+adjuvant (100 μg antigen+AlOH) formulation administered at 0-7-30 days elicited the best immune response profile, including functional antibody responses, through Day 180 and was selected for use in subsequent clinical trials.
RCT Entities:
BACKGROUND:Clostridium difficile, a major cause of nosocomial and antibiotic-associated diarrhea, carries a significant disease and cost burden. This study aimed to select an optimal formulation and schedule for a candidate toxoid vaccine against C. difficile toxins A and B. METHODS: Randomized, placebo-controlled, two-stage, Phase 2 study in a total of 661 adults aged 40-75 years. Stage I: low (50 μg antigen) or high (100 μg antigen) dose with or without aluminum hydroxide (AlOH) adjuvant, or placebo, administered on Days 0-7-30. Stage II: Days 0-7-30, 0-7-180, and 0-30-180, using the formulation selected in Stage I through a decision tree defined a priori and based principally on a bootstrap ranking approach. Administration was intramuscular. Blood samples were obtained on Days 0, 7, 14, 30, 60 (Stage I and II), 180, and 210 (Stage II); IgG to toxins A and B was measured by ELISA and in vitro functional activity was measured by toxin neutralizing assay (TNA). Safety data were collected using diary cards. RESULTS: In Stage I the composite immune response against toxins A and B (percentage of participants who seroconverted for both toxins) was highest in the high dose+adjuvant group (97% and 92% for Toxins A and B, respectively) and was chosen for Stage II. In Stage II the immune response profile for this formulation through Day 180 given on Days 0-7-30 ranked above the other two administration schedules. There were no safety issues. CONCLUSIONS: The high dose+adjuvant (100 μg antigen+AlOH) formulation administered at 0-7-30 days elicited the best immune response profile, including functional antibody responses, through Day 180 and was selected for use in subsequent clinical trials.
Authors: Matthew M Guilleman; Brenna A Y Stevens; Laura P Van Lieshout; Amira D Rghei; Yanlong Pei; Lisa A Santry; Brad Thompson; Sarah K Wootton Journal: Gene Ther Date: 2021-02-19 Impact factor: 5.250