PMID- 32287316 OWN - NLM STAT- MEDLINE DCOM- 20200714 LR - 20231113 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 15 IP - 4 DP - 2020 TI - Ototopical drops containing a novel antibacterial synthetic peptide: Safety and efficacy in adults with chronic suppurative otitis media. PG - e0231573 LID - 10.1371/journal.pone.0231573 [doi] LID - e0231573 AB - OBJECTIVE: Chronic suppurative otitis media (CSOM) is a chronic infectious disease with worldwide prevalence that causes hearing loss and decreased quality of life. As current (antibiotic) treatments often unsuccessful and antibiotic resistance is emerging, alternative agents and/or strategies are urgently needed. We considered the synthetic antimicrobial and anti-biofilm peptide P60.4Ac to be an interesting candidate because it also displays anti-inflammatory activities including lipopolysaccharide-neutralizing activity. The aim of the present study was to investigate the safety and efficacy of ototopical drops containing P60.4Ac in adults with CSOM without cholesteatoma. METHODS: We conducted a range-finding study in 16 subjects followed by a randomized, double blinded, placebo-controlled, multicentre phase IIa study in 34 subjects. P60.4Ac-containing ototopical drops or placebo drops were applied twice a day for 2 weeks and adverse events (AEs) and medication use were recorded. Laboratory tests, swabs from the middle ear and throat for bacterial cultures, and audiometry were performed at intervals up to 10 weeks after therapy. Response to treatment was assessed by blinded symptom scoring on otoscopy. RESULTS: Application of P60.4Ac-containing ototopical drops (0.25-2.0 mg of peptide/ml) in the ear canal of patients suffering from CSOM was found to be safe and well-tolerated. The optimal dose (0.5 mg of peptide/ml) was selected for the subsequent phase IIa study. Safety evaluation revealed only a few AEs that were unlikely related to study treatment and all, except one, were of mild to moderate intensity. In addition to this excellent safety profile, P60.4Ac ototopical drops resulted in a treatment success in 47% of cases versus 6% in the placebo group. CONCLUSION: The efficacy/safety balance assessed in the present study provides a compelling justification for continued clinical development of P60.4Ac in therapy-resistant CSOM. FAU - Peek, Nanno F A W AU - Peek NFAW AD - Department of Ear Nose and Throat, Leiden University Medical Centre (LUMC), Leiden, The Netherlands. FAU - Nell, Marja J AU - Nell MJ AD - Octoplus Technologies BV/Dr Reddy's research and development BV, Leiden, The Netherlands. FAU - Brand, Ronald AU - Brand R AD - Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, The Netherlands. FAU - Jansen-Werkhoven, Thekla AU - Jansen-Werkhoven T AUID- ORCID: 0000-0002-1500-5424 AD - Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, The Netherlands. FAU - van Hoogdalem, Ewoud J AU - van Hoogdalem EJ AD - Octoplus Technologies BV/Dr Reddy's research and development BV, Leiden, The Netherlands. FAU - Verrijk, Ruud AU - Verrijk R AD - Octoplus Technologies BV/Dr Reddy's research and development BV, Leiden, The Netherlands. FAU - Vonk, Marcel J AU - Vonk MJ AD - Department of Pulmonology, Leiden University Medical Centre, Leiden, The Netherlands. FAU - Wafelman, Amon R AU - Wafelman AR AD - Clinical Pharmacology and Toxicology, Leiden University Medical Centre, Leiden, The Netherlands. FAU - Valentijn, A Rob P M AU - Valentijn ARPM AD - Clinical Pharmacology and Toxicology, Leiden University Medical Centre, Leiden, The Netherlands. FAU - Frijns, Johan H M AU - Frijns JHM AUID- ORCID: 0000-0002-1180-3314 AD - Department of Ear Nose and Throat, Leiden University Medical Centre (LUMC), Leiden, The Netherlands. FAU - Hiemstra, Pieter S AU - Hiemstra PS AD - Department of Pulmonology, Leiden University Medical Centre, Leiden, The Netherlands. FAU - Drijfhout, Jan W AU - Drijfhout JW AD - Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, The Netherlands. FAU - Nibbering, Peter H AU - Nibbering PH AUID- ORCID: 0000-0002-0432-8340 AD - Department of Infectious Diseases, Leiden University Medical Centre, Leiden, The Netherlands. FAU - Grote, Jan J AU - Grote JJ AD - Department of Ear Nose and Throat, Leiden University Medical Centre (LUMC), Leiden, The Netherlands. LA - eng PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20200414 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Anti-Bacterial Agents) RN - 0 (Antimicrobial Cationic Peptides) RN - 0 (OP-145 peptide) SB - IM MH - Adult MH - Anti-Bacterial Agents/administration & dosage/adverse effects/*therapeutic use MH - Antimicrobial Cationic Peptides/administration & dosage/adverse effects/*therapeutic use MH - Drug Tolerance MH - Female MH - Humans MH - Male MH - Middle Aged MH - Otitis Media, Suppurative/*drug therapy PMC - PMC7156094 COIS- RV is employed by OctoPlus Technologies BV (now Dr Reddy's). The patents WO2004/067563 and WO2006/011792 belong to the LUMC/OctoPlus Technologies BV. There are no further patents, products in development or marketed involving P60.4Ac to declare. This does not alter the authors' adherence to all PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors. EDAT- 2020/04/15 06:00 MHDA- 2020/07/15 06:00 PMCR- 2020/04/14 CRDT- 2020/04/15 06:00 PHST- 2018/08/13 00:00 [received] PHST- 2020/03/25 00:00 [accepted] PHST- 2020/04/15 06:00 [entrez] PHST- 2020/04/15 06:00 [pubmed] PHST- 2020/07/15 06:00 [medline] PHST- 2020/04/14 00:00 [pmc-release] AID - PONE-D-18-23641 [pii] AID - 10.1371/journal.pone.0231573 [doi] PST - epublish SO - PLoS One. 2020 Apr 14;15(4):e0231573. doi: 10.1371/journal.pone.0231573. eCollection 2020.