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Safety and tolerability of topical polyhexamethylene biguanide: a randomised clinical trial in healthy adult volunteers
  1. Vincenzo Papa1,
  2. Ivanka van der Meulen2,
  3. Sylvie Rottey3,
  4. Guy Sallet4,
  5. Jolanda Overweel5,
  6. Nino Asero6,
  7. Darwin C Minassian7,
  8. John K G Dart8,9
  1. 1 SIFI S.p.A., 36, via Ercole Patti, 95025 Lavinaio (Catania), Italy, Lavinaio, Italy
  2. 2 Amsterdam UMC Locatie AMC, Amsterdam, Netherlands
  3. 3 DRUG Research Unit, Ghent, Belgium
  4. 4 Ooginstituut, Aalst, Belgium
  5. 5 PSR Group BV, Hoofddorp, Netherlands
  6. 6 SIFI SpA, Catania, Italy
  7. 7 Epivision Ophthalmic Epidemiology Consultants, Penn, UK
  8. 8 Corneal & External Disease, Moorfields Eye Hospital NHS Foundation Trust, London, UK
  9. 9 Ocular Biology & Therapeutics, UCL Institute of Ophthalmology, London, UK
  1. Correspondence to John K G Dart, Corneal & External Disease, Moorfields Eye Hospital NHS Foundation Trust, 162 City Road, London EC1V 2PD, UK; j.dart{at}ucl.ac.uk

Abstract

Background and Aims Polyhexamethyl biguanide (PHMB), a widely used topical treatment for Acanthamoeba keratitis (AK), is unlicensed with no formal safety assessment. This study evaluated its safety and tolerability.

Methods A prospective, randomised, double-masked controlled trial in 90 healthy volunteers. Subjects were treated with topical 0.04%, 0.06%, 0.08% PHMB or placebo (vehicle) 12× daily for 7 days, then 6× daily for 7 days. The rates of dose-limiting adverse events (DLAEs) leading to interruption of dosing, mild adverse events (AEs) (not dose limiting) and incidental AEs (unrelated to treatment) were compared. The primary outcome was the difference between treatments for DLAE rates.

Results 5/90 subjects developed DLAE within <1–4 days of starting treatment; 2/5 using PHMB 0.06% and 3/5 PHMB 0.08%. These resolved within 1–15 days. There were no significant differences in DLAE between treatment groups. Mild AEs occurred in 48/90 subjects (including placebo). There was no trend for an increased incidence of any AE with increasing concentrations of PHMB, except for corneal punctate keratopathy with PHMB 0.08%, which fully resolved within 7–14 days.

Conclusion These findings are reassuring for PHMB 0.02% users. They also suggest that higher PHMB concentrations may show acceptable levels of tolerance and toxicity in AK subjects, whose susceptibility to AE may be greater than for the normal eyes in this study. Given the potential benefits of higher PHMB concentrations for treating deep stromal invasion in AK, we think that the use of PHMB 0.08% is justified in treatment trials.

Trial registration number NCT02506257.

  • Clinical Trial
  • Cornea
  • Drugs
  • Infection
  • Treatment Medical

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Footnotes

  • Contributors Protocol development: VP, NA, DCM, JKGD. Ethics submission and approval: NA, VP, JO, JKGD, IvdM, SR and GS. Study implementation (recruitment, assessment, data collection): JO, IvdM, SR and GS. Data analysis and preparation for publication, manuscript preparation: VP, DCM and JKGD.

  • Funding The study was funded by the European Union under the Seventh Framework Program (Grant no. 304661) and by SIFI SpA (Catania, Italy), no grant number. Part of John Dart’s salary was paid by the Moorfields Eye Hospital and UCL Institute of Ophthalmology National Institute of Research (NIHR) Biomedical Research Centre (BRC), no grant number.

  • Competing interests Vincenzo Papa and Antonino Asero are employees of SIFI S.p.A. who manufacture and supply PHMB eye drops in Italy, and who are carrying out studies to develop it as a licenced therapy for the treatment of Acanthamoeba keratitis in Europe. John Dart and Darwin Minassian are consultants to SIFI SpA. The remaining authors have no proprietary or commercial interest in any materials discussed in this article.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement The study report with tabulated study data is available on request to the first author (VP).

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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