Department of Ear Nose and Throat, Leiden University Medical Centre (LUMC), Leiden, The Netherlands.
Octoplus Technologies BV/Dr Reddy's research and development BV, Leiden, The Netherlands.
PLoS One. 2020 Apr 14;15(4):e0231573. doi: 10.1371/journal.pone.0231573. eCollection 2020.
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.
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.
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.
The efficacy/safety balance assessed in the present study provides a compelling justification for continued clinical development of P60.4Ac in therapy-resistant CSOM.
慢性化脓性中耳炎（CSOM）是一种具有全球流行率的慢性感染性疾病，可导致听力损失和生活质量下降。由于目前（抗生素）治疗往往不成功，并且抗生素耐药性正在出现，因此迫切需要替代药物和/或策略。我们认为合成抗菌肽 P60.4Ac 是一种很有前途的候选药物，因为它还具有抗炎活性，包括中和脂多糖的活性。本研究旨在研究含有 P60.4Ac 的耳用滴剂在无胆脂瘤的 CSOM 成人患者中的安全性和疗效。
我们对 16 名受试者进行了范围发现研究，随后对 34 名受试者进行了随机、双盲、安慰剂对照、多中心 IIa 期研究。将含有 P60.4Ac 的耳用滴剂或安慰剂滴剂每天两次滴耳，持续 2 周，并记录不良反应（AE）和药物使用情况。在治疗后 10 周内，进行实验室检查、中耳和喉咙拭子细菌培养和听力测试。通过耳镜下的盲法症状评分评估治疗反应。
将含有 P60.4Ac 的耳用滴剂（肽浓度为 0.25-2.0 mg/ml）滴入耳道治疗 CSOM 患者，结果安全且耐受良好。选择最佳剂量（0.5 mg/ml 肽）进行随后的 IIa 期研究。安全性评估仅发现少数不太可能与研究治疗相关的 AE，除 1 例外，其余均为轻度至中度。除了这种出色的安全性外，P60.4Ac 耳用滴剂在 47%的病例中取得了治疗成功，而安慰剂组为 6%。
本研究中评估的疗效/安全性平衡为继续开发 P60.4Ac 治疗耐药性 CSOM 提供了有力的依据。
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