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Major gaps remain in understanding their potential utility.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>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 <jats:italic>Pseudomonas aeruginosa<\/jats:italic> 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<jats:sub>10<\/jats:sub> beginning with 4 \u00d7 10<jats:sup>7<\/jats:sup> 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<jats:sub>10<\/jats:sub><jats:italic>P. aeruginosa<\/jats:italic> 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 <jats:italic>P. aeruginosa<\/jats:italic> isolates susceptible to the phage mixture before and after study product administration, and (4) changes in quality of life.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Discussion<\/jats:title>\n                <jats:p>This trial will investigate the activity of phages in reducing <jats:italic>P. aeruginosa<\/jats:italic> colony counts and provide insights into the safety profile of phage therapy.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p>ClinicalTrials.gov NCT05453578. Registered on 12 July 2022.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13063-022-07047-5","type":"journal-article","created":{"date-parts":[[2022,12,28]],"date-time":"2022-12-28T11:05:51Z","timestamp":1672225551000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":69,"title":["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"],"prefix":"10.1186","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4143-6324","authenticated-orcid":false,"given":"Pranita D.","family":"Tamma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Souli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Billard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Campbell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Conrad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damon W.","family":"Ellison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beth","family":"Evans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott R.","family":"Evans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerryl E.","family":"Greenwood-Quaintance","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrey A.","family":"Filippov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly S.","family":"Geres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshimitsu","family":"Hamasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Komarow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikeljon P.","family":"Nikolich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas P.","family":"Lodise","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seema U.","family":"Nayak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmelle","family":"Norice-Tra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Pride","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janie","family":"Russell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria","family":"Van Tyne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry F.","family":"Chambers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vance G.","family":"FowlerJr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert T.","family":"Schooley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the Antibacterial Resistance Leadership Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,12,28]]},"reference":[{"issue":"10325","key":"7047_CR1","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1016\/S0140-6736(21)02724-0","volume":"399","author":"Antimicrobial resistance C.","year":"2022","unstructured":"Antimicrobial resistance C. 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The study protocol and centralized IRB conclusion will be reviewed and adopted by each site\u2019s relevant local IRB prior to participation. All volunteers require written informed consent to participate.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate\u00a0{24}"}},{"value":"Consent for publication was sought and approved by all listed authors. Material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and\/or publication. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting true views of the Department of the Army or the Department of Defense. The investigators have adhered to the policies for the protection of human subjects as prescribed in AR 70\u201325.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication\u00a0{32}"}},{"value":"The authors report the following outside financial activities: TPL: AbbVie (consultant), BioFire Diagnostics (grant\/research support), Cidara (advisor\/consultant), Entasis (grant\/research support), Ferring (advisor\/consultant\/speaker), Genentech (consultant), ICPD (consultant), Johnson and Johnson (consultant), Melinta (advisor\/consultant), Merck (advisor\/consultant, grant\/research support), Paratek (advisor\/consultant), Roche (consultant), Shionogi (advisor\/consultant\/speaker), Spero (advisor\/consultant), Wockhardt (grant\/research support), and Venatrox (advisor\/consultant). RP reports grants from ContraFect, TenNor Therapeutics Limited, and BioFire; is a consultant to Curetis, PathoQuest, Selux Diagnostics, 1928 Diagnostics, PhAST, Torus Biosystems, Day Zero Diagnostics, Mammoth Biosciences, Qvella, Netflix, Abbott Laboratories, and CARB-X; has research supported by Adaptive Phage Therapeutics; has a relationship with Pathogenomix; and has a patent for Bordetella pertussis\/parapertussis PCR, for a device\/method for sonication with royalties paid by Samsung, and for an antibiofilm substance. Adaptive Phage Therapeutics has a nonexclusive Biological Material License agreement with WRAIR for its therapeutic phages. VGF reports personal fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, and Roche; grants from MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, Deep Blue, Basilea, and Janssen; stock options from Valanbio and ArcBio; and a patent in sepsis diagnostics pending. RTS serves as a consultant or a member of Data Monitoring Committees for LyseNtech, Glaxo SmithKline, Pfizer, Merck, VIR, Sempra Energy, and SNIPR Biome. All other authors have nothing to disclose.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests\u00a0{28}"}}],"article-number":"1057"}}