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; Antibacterial Resistance Leadership Group

doi:10.1186/s13063-022-07047-5

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

Trials. 2022 Dec 28;23(1):1057. doi: 10.1186/s13063-022-07047-5.

Authors

Pranita D Tamma¹, Maria Souli², Michael Billard³, Joseph Campbell⁴, Douglas Conrad⁵, Damon W Ellison⁶, Beth Evans², Scott R Evans⁷, Kerryl E Greenwood-Quaintance⁸, Andrey A Filippov⁶, Holly S Geres², Toshimitsu Hamasaki⁷, Lauren Komarow⁷, Mikeljon P Nikolich⁶, Thomas P Lodise⁹, Seema U Nayak⁴, Carmelle Norice-Tra⁴, Robin Patel^{8

10}, David Pride¹¹, Janie Russell⁴, Daria Van Tyne¹², Henry F Chambers¹³, Vance G FowlerJr^{2

14}, Robert T Schooley¹¹; Antibacterial Resistance Leadership Group

Affiliations

¹ Department of Pediatrics, Johns Hopkins University School of Medicine, 200 North Wolfe Street, Room 3149, Baltimore, MD, 21287, USA. ptamma1@jhmi.edu.
² Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA.
³ Adaptive Phage Therapeutics, Inc., Gaithersburg, MD, USA.
⁴ National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases, Bethesda, MD, USA.
⁵ Department of Medicine, University of California San Diego, San Diego, CA, USA.
⁶ Wound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
⁷ The Biostatistics Center, The George Washington University, Rockville, MD, USA.
⁸ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, USA.
⁹ Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, NY, USA.
¹⁰ Infectious Diseases and Occupational Medicine, Mayo Clinic, Rochester, MN, USA.
¹¹ Departments of Medicine and Pathology, University of California San Diego, San Diego, CA, USA.
¹² Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
¹³ Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
¹⁴ Department of Medicine, Duke University Medical Center, Durham, NC, USA.

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.

Keywords: Cystic fibrosis; Multidrug-resistant; Phage; Pseudomonas aeruginosa.

Publication types

Clinical Trial Protocol

MeSH terms

Adult
Anti-Bacterial Agents
Clinical Trials, Phase I as Topic
Clinical Trials, Phase II as Topic
Cystic Fibrosis* / therapy
Double-Blind Method
Humans
Multicenter Studies as Topic
Phage Therapy*
Pseudomonas aeruginosa
Quality of Life
Randomized Controlled Trials as Topic

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

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