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How to Achieve a Good Phage Therapy Clinical Trial?

  • Jérôme Gabard
  • Patrick Jault
Chapter

Abstract

Modern and well-conducted clinical trials in phage therapy are counted on the fingers of a single hand. Needless to say, individual case treatments are numerous, especially in Eastern European countries like Russia, Georgia, or Poland. But most of the scientific evidence trials are missing or considered useless because of the current, pragmatic, and daily medicinal practice of phage therapy in these countries. However, in Western countries, phage therapy disappeared from pharmacopoeias for most than three decades and bacteriophages are unknown to the young generations of clinicians. The clinical knowledge data base needs to be rebuilt according to the most recent evaluation criteria.

This book chapter aims at providing supportive clinical and patient case data, but especially to provide practical recommendations for performing a phage therapy trial in line with Good Clinical Practices (GCP). A special focus is given on one-size-fits-all clinical trials in comparison to the recent regulatory evolution leading to personalized phage therapy treatments after preliminary diagnostic (phagogram). In addition, the authors are trying to open perspectives to speed up the recruitment process and reduce the length of phage therapy trials, by taking an example on the evaluation of personalized treatments in immuno-oncology.

The choice of primary endpoint tailored to the self-propagation properties of bacteriophages is also studied, in the context of Minimum Inhibition Concentration (MIC) standard used for antibiotic evaluation and often recommended for other anti-infective products, even if inappropriate.

References

  1. Abedon ST (2009) Kinetics of phage-mediated biocontrol of bacteria. Foodborne Pathog Dis 6:807–815.  https://doi.org/10.1089/fpd.2008.0242 CrossRefPubMedGoogle Scholar
  2. Abedon S (2011) Phage therapy pharmacology: calculating phage dosing. Adv Appl Microbiol 77:1–40.  https://doi.org/10.1016/B978-0-12-387044-5.00001-7 CrossRefPubMedGoogle Scholar
  3. Abedon ST (2016) Phage therapy dosing: the problem(s) with multiplicity of infection (MOI). Bacteriophage 6:e1220348.  https://doi.org/10.1080/21597081.2016.1220348 CrossRefPubMedPubMedCentralGoogle Scholar
  4. Abedon ST (2018) Phage therapy: various perspectives on how to improve the art. Methods Mol Biol 1734:113–127.  https://doi.org/10.1007/978-1-4939-7604-1_11 CrossRefPubMedGoogle Scholar
  5. Abedon ST, Thomas-Abedon C (2010) Phage therapy pharmacology. Curr Pharm Biotechnol 11:28–47CrossRefGoogle Scholar
  6. Babalova EG, Katsitadze KT, Sakvarelidze LA, et al (1968) [Preventive value of dried dysentery bacteriophage]. Zh Mikrobiol Epidemiol Immunobiol 45:143–145Google Scholar
  7. Brussow H (2005) Phage therapy: the Escherichia coli experience. Microbiology 151:2133–2140.  https://doi.org/10.1099/mic.0.27849-0 CrossRefPubMedGoogle Scholar
  8. Bruttin A, Brussow H (2005) Human volunteers receiving Escherichia coli phage T4 Orally: a safety test of phage therapy. Antimicrob Agents Chemother 49:2874–2878.  https://doi.org/10.1128/AAC.49.7.2874-2878.2005 CrossRefPubMedPubMedCentralGoogle Scholar
  9. D’Herelle F (2007) On an invisible microbe antagonistic toward dysenteric bacilli: brief note by Mr. F. D’Herelle, presented by Mr. Roux. 1917. Res Microbiol 158:553–554.  https://doi.org/10.1016/j.resmic.2007.07.005 CrossRefPubMedGoogle Scholar
  10. Debarbieux L, Pirnay J-P, Verbeken G et al (2016) A bacteriophage journey at the European Medicines Agency. FEMS Microbiol Lett 363:fnv225.  https://doi.org/10.1093/femsle/fnv225 CrossRefPubMedGoogle Scholar
  11. Duerkop BA (2018) Bacteriophages shift the focus of the mammalian microbiota. PLoS Pathog 14:e1007310.  https://doi.org/10.1371/journal.ppat.1007310 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Ferry T, Boucher F, Fevre C et al (2018) Innovations for the treatment of a complex bone and joint infection due to XDR Pseudomonas aeruginosa including local application of a selected cocktail of bacteriophages. J Antimicrob Chemother 73:2901–2903.  https://doi.org/10.1093/jac/dky263 CrossRefPubMedGoogle Scholar
  13. Fish R, Kutter E, Wheat G et al (2016) Bacteriophage treatment of intransigent diabetic toe ulcers: a case series. J Wound Care 25(Suppl 7):S27–S33.  https://doi.org/10.12968/jowc.2016.25.7.S27 CrossRefGoogle Scholar
  14. Furfaro LL, Payne MS, Chang BJ (2018) Bacteriophage therapy: clinical trials and regulatory hurdles. Front Cell Infect Microbiol 8:376.  https://doi.org/10.3389/fcimb.2018.00376 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Garralda E, Dienstmann R, Piris-Giménez A et al (2019) New clinical trial designs in the era of precision medicine. Mol Oncol 13:549–557.  https://doi.org/10.1002/1878-0261.12465 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Golan T, Milella M, Ackerstein A, Berger R (2017) The changing face of clinical trials in the personalized medicine and immuno-oncology era: report from the international congress on clinical trials in Oncology & Hemato-Oncology (ICTO 2017). J Exp Clin Cancer Res 36:192.  https://doi.org/10.1186/s13046-017-0668-0 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Górski A, Dąbrowska K, Międzybrodzki R et al (2017) Phages and immunomodulation. Future Microbiol 12:905–914.  https://doi.org/10.2217/fmb-2017-0049 CrossRefGoogle Scholar
  18. Hirakawa A, Asano J, Sato H, Teramukai S (2018) Master protocol trials in oncology: review and new trial designs. Contemp Clin Trials Commun 12:1–8.  https://doi.org/10.1016/j.conctc.2018.08.009 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Huys I, Vaneechoutte M, Verbeken G, Debarbieux L (2013) Key issues in phage therapy: a report of a dedicated workshop at the viruses of microbes II meeting. Res Microbiol 164:806–810.  https://doi.org/10.1016/j.resmic.2013.03.020 CrossRefPubMedGoogle Scholar
  20. Jault P, Leclerc T, Jennes S et al (2019) Efficacy and tolerability of a cocktail of bacteriophages to treat burn wounds infected by Pseudomonas aeruginosa (PhagoBurn): a randomised, controlled, double-blind phase 1/2 trial. Lancet Infect Dis 19:35–45.  https://doi.org/10.1016/S1473-3099(18)30482-1 CrossRefGoogle Scholar
  21. Jennes S, Merabishvili M, Soentjens P et al (2017) Use of bacteriophages in the treatment of colistin-only-sensitive Pseudomonas aeruginosa septicaemia in a patient with acute kidney injury—a case report. Crit Care 21.  https://doi.org/10.1186/s13054-017-1709-y
  22. Khawaldeh A, Morales S, Dillon B et al (2011) Bacteriophage therapy for refractory Pseudomonas aeruginosa urinary tract infection. J Med Microbiol 60:1697–1700.  https://doi.org/10.1099/jmm.0.029744-0 CrossRefGoogle Scholar
  23. Krut O, Bekeredjian-Ding I (2018) Contribution of the immune response to phage therapy. J Immunol 200:3037–3044.  https://doi.org/10.4049/jimmunol.1701745 CrossRefGoogle Scholar
  24. Kutateladze M, Adamia R (2010) Bacteriophages as potential new therapeutics to replace or supplement antibiotics. Trends Biotechnol 28:591–595.  https://doi.org/10.1016/j.tibtech.2010.08.001 CrossRefPubMedGoogle Scholar
  25. Kutter E, De Vos D, Gvasalia G et al (2010) Phage therapy in clinical practice: treatment of human infections. Curr Pharm Biotechnol 11:69–86CrossRefGoogle Scholar
  26. Lehman SM, Mearns G, Rankin D et al (2019) Design and preclinical development of a phage product for the treatment of antibiotic-resistant Staphylococcus aureus infections. Viruses 11.  https://doi.org/10.3390/v11010088 CrossRefGoogle Scholar
  27. Letkiewicz S, Miedzybrodzki R, Fortuna W et al (2009) Eradication of Enterococcus faecalis by phage therapy in chronic bacterial prostatitis—case report. Folia Microbiol (Praha) 54:457–461.  https://doi.org/10.1007/s12223-009-0064-z CrossRefGoogle Scholar
  28. Mattey M, Spencer J (2008) Bacteriophage therapy—cooked goose or phoenix rising? Curr Opin Biotechnol 19:608–612.  https://doi.org/10.1016/j.copbio.2008.09.001 CrossRefPubMedGoogle Scholar
  29. McCallin S, Alam Sarker S, Barretto C et al (2013) Safety analysis of a Russian phage cocktail: from metagenomic analysis to oral application in healthy human subjects. Virology 443:187–196.  https://doi.org/10.1016/j.virol.2013.05.022 CrossRefGoogle Scholar
  30. Merabishvili M, Pirnay J-P, Verbeken G et al (2009) Quality-controlled small-scale production of a well-defined bacteriophage cocktail for use in human clinical trials. PLoS One 4:e4944.  https://doi.org/10.1371/journal.pone.0004944 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Międzybrodzki R, Borysowski J, Weber-Dąbrowska B et al (2012) Clinical aspects of phage therapy. Adv Virus Res 83:73–121.  https://doi.org/10.1016/B978-0-12-394438-2.00003-7 CrossRefPubMedPubMedCentralGoogle Scholar
  32. Mirnezami R, Nicholson J, Darzi A (2012) Preparing for precision medicine. N Engl J Med 366:489–491.  https://doi.org/10.1056/NEJMp1114866 CrossRefPubMedGoogle Scholar
  33. Mirzaei MK, Maurice CF (2017) Ménage à trois in the human gut: interactions between host, bacteria and phages. Nat Rev Microbiol 15:397–408.  https://doi.org/10.1038/nrmicro.2017.30 CrossRefPubMedGoogle Scholar
  34. Moelling K, Broecker F, Willy C (2018) A wake-up call: we need phage therapy now. Viruses 10.  https://doi.org/10.3390/v10120688 CrossRefGoogle Scholar
  35. Morozova VV, Vlassov VV, Tikunova NV (2018) Applications of bacteriophages in the treatment of localized infections in humans. Front Microbiol 9.  https://doi.org/10.3389/fmicb.2018.01696
  36. Patey O, McCallin S, Mazure H et al (2018) Clinical indications and compassionate use of phage therapy: personal experience and literature review with a focus on osteoarticular infections. Viruses 11.  https://doi.org/10.3390/v11010018 CrossRefGoogle Scholar
  37. Pirnay J-P, De Vos D, Verbeken G et al (2011) The phage therapy paradigm: prêt-à-porter or sur-mesure? Pharm Res 28:934–937.  https://doi.org/10.1007/s11095-010-0313-5 CrossRefPubMedGoogle Scholar
  38. Pirnay J-P, Blasdel BG, Bretaudeau L et al (2015) Quality and safety requirements for sustainable phage therapy products. Pharm Res 32:2173–2179.  https://doi.org/10.1007/s11095-014-1617-7 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Pirnay J-P, Verbeken G, Ceyssens P-J et al (2018) The magistral phage. Viruses 10.  https://doi.org/10.3390/v10020064 CrossRefGoogle Scholar
  40. Renfro LA, Sargent DJ (2017) Statistical controversies in clinical research: basket trials, umbrella trials, and other master protocols: a review and examples. Ann Oncol Off J Eur Soc Med Oncol 28:34–43.  https://doi.org/10.1093/annonc/mdw413 CrossRefGoogle Scholar
  41. Sarker SA, Sultana S, Reuteler G et al (2016) Oral phage therapy of acute bacterial diarrhea with two coliphage preparations: a randomized trial in children from Bangladesh. EBioMedicine 4:124–137.  https://doi.org/10.1016/j.ebiom.2015.12.023 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Schooley RT, Biswas B, Gill JJ et al (2017) Development and use of personalized bacteriophage-based therapeutic cocktails to treat a patient with a disseminated resistant Acinetobacter baumannii infection. Antimicrob Agents Chemother 61:e00954–e00917.  https://doi.org/10.1128/AAC.00954-17 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Sulakvelidze A, Alavidze Z, Morris JG (2001) Bacteriophage therapy. Antimicrob Agents Chemother 45:649–659.  https://doi.org/10.1128/AAC.45.3.649-659.2001 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Summers WC (2016) Félix Hubert d’Herelle (1873-1949): history of a scientific mind. Bacteriophage 6:e1270090.  https://doi.org/10.1080/21597081.2016.1270090 CrossRefPubMedGoogle Scholar
  45. Twort FW (1915) An investigation on the nature of ultra-microscopic viruses. Lancet 186:1241–1243.  https://doi.org/10.1016/S0140-6736(01)20383-3 CrossRefGoogle Scholar
  46. van Zyl LJ, Abrahams Y, Stander EA et al (2018) Novel phages of healthy skin metaviromes from South Africa. Sci Rep 8:12265.  https://doi.org/10.1038/s41598-018-30705-1 CrossRefPubMedPubMedCentralGoogle Scholar
  47. Verbeken G, De Vos D, Vaneechoutte M et al (2007) European regulatory conundrum of phage therapy. Future Microbiol 2:485–491.  https://doi.org/10.2217/17460913.2.5.485 CrossRefPubMedGoogle Scholar
  48. Verbeken G, Huys I, Ceulemans C et al (2016a) Bacteriophage therapy: fast-forward to the past lessons identified from the advanced therapy regulation. Burns 42:11–12.  https://doi.org/10.1016/j.burns.2015.10.022 CrossRefPubMedGoogle Scholar
  49. Verbeken G, Huys I, De Vos D et al (2016b) Access to bacteriophage therapy: discouraging experiences from the human cell and tissue legal framework. FEMS Microbiol Lett 363.  https://doi.org/10.1093/femsle/fnv241 CrossRefGoogle Scholar
  50. Woodcock J, LaVange LM (2017) Master protocols to study multiple therapies, multiple diseases, or both. N Engl J Med 377:62–70.  https://doi.org/10.1056/NEJMra1510062 CrossRefPubMedGoogle Scholar
  51. Wright A, Hawkins CH, Änggård EE, Harper DR (2009) A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy. Clin Otolaryngol 34:349–357CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Jérôme Gabard
    • 1
  • Patrick Jault
    • 2
  1. 1.Saint Barthélemy d’AnjouFrance
  2. 2.Clinique de la MuetteParisFrance

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