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, Department of Pediatrics, Johns Hopkins University School of Medicine, 200 North Wolfe Street, Room 3149, Baltimore, MD, 21287, USA. ptamma1@jhmi.edu.
Maria Souli, Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA.
Michael Billard, Adaptive Phage Therapeutics, Inc., Gaithersburg, MD, USA.
Joseph Campbell, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases, Bethesda, MD, USA.
Douglas Conrad, Department of Medicine, University of California San Diego, San Diego, CA, USA.
Damon W. Ellison, Wound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Beth Evans, Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA.
Scott R. Evans, The Biostatistics Center, The George Washington University, Rockville, MD, USA.
Kerryl E. Greenwood-Quaintance, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, USA.
Andrey A. Filippov, Wound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Holly S. Geres, Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA.
Toshimitsu Hamasaki, The Biostatistics Center, The George Washington University, Rockville, MD, USA.
Lauren Komarow, The Biostatistics Center, The George Washington University, Rockville, MD, USA.
Mikeljon P. Nikolich, Wound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Thomas P. Lodise, Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, NY, USA.
Seema U. Nayak, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases, Bethesda, MD, USA.
Carmelle Norice-Tra, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases, Bethesda, MD, USA.
Robin Patel, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, USA.
David Pride, Departments of Medicine and Pathology, University of California San Diego, San Diego, CA, USA.
Janie Russell, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases, Bethesda, MD, USA.
Daria Van Tyne, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Henry F. Chambers, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
Vance G. FowlerJr, Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA.
Robert T. Schooley, Departments of Medicine and Pathology, University of California San Diego, San Diego, CA, USA.

Document Type

Journal Article

Publication Date

12-28-2022

Journal

Trials

Volume

23

Issue

1

DOI

10.1186/s13063-022-07047-5

Keywords

Cystic fibrosis; Multidrug-resistant; Phage; Pseudomonas aeruginosa

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 log beginning with 4 × 10 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 log 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.

Department

Biostatistics and Bioinformatics

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