Safety and microbiological activity of phage therapy in persons with cystic fibrosis colonized with Pseudomonas aeruginosa: study protocol for a phase 1b/2, multicenter, randomized, double-blind, placebo-controlled trial
Pranita D. Tamma,
Maria Souli,
Michael Billard,
Joseph Campbell,
Douglas Conrad,
Damon W. Ellison,
Beth Evans,
Scott R. Evans,
Kerryl E. Greenwood-Quaintance,
Andrey A. Filippov,
Holly S. Geres,
Toshimitsu Hamasaki,
Lauren Komarow,
Mikeljon P. Nikolich,
Thomas P. Lodise,
Seema U. Nayak,
Carmelle Norice-Tra,
Robin Patel,
David Pride,
Janie Russell,
Daria Van Tyne,
Henry F. Chambers,
Vance G. FowlerJr,
Robert T. Schooley,
for the Antibacterial Resistance Leadership Group
Affiliations
Pranita D. Tamma
Department of Pediatrics, Johns Hopkins University School of Medicine
Maria Souli
Duke Clinical Research Institute, Duke University Medical Center
Michael Billard
Adaptive Phage Therapeutics, Inc.
Joseph Campbell
National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases
Douglas Conrad
Department of Medicine, University of California San Diego
Damon W. Ellison
Wound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research
Beth Evans
Duke Clinical Research Institute, Duke University Medical Center
Scott R. Evans
The Biostatistics Center, The George Washington University
Kerryl E. Greenwood-Quaintance
Department of Laboratory Medicine and Pathology, Mayo Clinic
Andrey A. Filippov
Wound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research
Holly S. Geres
Duke Clinical Research Institute, Duke University Medical Center
Toshimitsu Hamasaki
The Biostatistics Center, The George Washington University
Lauren Komarow
The Biostatistics Center, The George Washington University
Mikeljon P. Nikolich
Wound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research
Thomas P. Lodise
Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences
Seema U. Nayak
National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases
Carmelle Norice-Tra
National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases
Robin Patel
Department of Laboratory Medicine and Pathology, Mayo Clinic
David Pride
Departments of Medicine and Pathology, University of California San Diego
Janie Russell
National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases
Daria Van Tyne
Department of Medicine, University of Pittsburgh
Henry F. Chambers
Department of Medicine, University of California San Francisco
Vance G. FowlerJr
Duke Clinical Research Institute, Duke University Medical Center
Robert T. Schooley
Departments of Medicine and Pathology, University of California San Diego
Abstract Background Bacteriophages (phages) are a promising anti-infective option for human disease. Major gaps remain in understanding their potential utility. Methods This is a randomized, placebo-controlled, double-blind study of a single dose of intravenous phage in approximately 72 clinically stable adult cystic fibrosis volunteers recruited from up to 20 US sites with Pseudomonas aeruginosa airway colonization. The single dose of phage consists of a mixture of four anti-pseudomonal phages. Six sentinel participants will be sequentially enrolled with dose escalation of the phage mixture by one log10 beginning with 4 × 107 plaque-forming units in an unblinded stage 1. If no serious adverse events related to the study product are identified, the trial will proceed to a double-blinded stage 2. In stage 2a, 32 participants will be randomly assigned to one of three phage dosages or placebo in a 1:1:1:1 allocation. An interim analysis will be performed to determine the phage dosage with the most favorable safety and microbiological activity profile to inform phage dosing in stage 2b. During stage 2b, up to 32 additional volunteers will be randomized 1:1 to the phage or placebo arm. Primary outcomes include (1) the number of grade 2 or higher treatment-emergent adverse events, (2) change in log10 P. aeruginosa total colony counts in sputum, and (3) the probability of a randomly selected subject having a more favorable outcome ranking if assigned to receive phage therapy versus placebo. Exploratory outcomes include (1) sputum and serum phage pharmacokinetics, (2) the impact of phage on lung function, (3) the proportion of P. aeruginosa isolates susceptible to the phage mixture before and after study product administration, and (4) changes in quality of life. Discussion This trial will investigate the activity of phages in reducing P. aeruginosa colony counts and provide insights into the safety profile of phage therapy. Trial registration ClinicalTrials.gov NCT05453578. Registered on 12 July 2022.
