Safety and Efficacy of Single-use Cliradex Pads for Ocular Mites

描述（由申请方提供）：蠕形螨是显微镜下的体外寄生虫，通常侵染皮肤的毛囊皮脂腺单位。螨的不受控制的过度生长与引起皮肤的丘疹脓疱性病变、面部的红斑痤疮和眼睛的睑缘炎有关。眼睑炎（眼睑边缘炎症）与睫毛中含有螨虫的圆柱形头皮屑相关，是最常见的眼部疾病之一。传统的治疗方法，用婴儿洗发水擦洗眼睑，在根除眼部蠕形螨感染（蠕形螨病）方面无效。然而，我们已经发现茶树油（TTO），一种从互叶白千层叶中蒸汽蒸馏的天然精油，对治疗眼部蠕形螨病有效。我们的初步临床研究表明，眼睑擦洗方案（基于每周使用50%TTO进行办公室擦洗，然后每天使用茶树洗发水进行家庭擦洗）可有效解决刺激性症状和眼表炎症，以及改善许多患者的视力。然而，这种治疗不便于患者自我给药，并导致一些患者的眼部刺激。我们已经完成了I期申请中描述的以下三个目标，以确定TTO中负责杀灭蠕形螨的最有效成分，并消除剩余成分，以开发一次性使用的Cliradex（R）垫，以便于患者自行给药（目标1），为了完成临床前安全性研究，以验证这种新的Cliradex（R）垫是无刺激性的，基于体外细胞毒性试验和人类受试者的9次重复损伤斑贴试验（目的2），并证明该新制剂具有有效的抗微生物作用，因此无需添加防腐剂，并且在玻璃罐和包装中均稳定（目标3）。在这 II期申请，我们建议进行随机，双盲，对照临床试验， 证明与安慰剂垫相比，一次性使用Cliradex（R）垫治疗眼部蠕形螨病的安全性和有效性。在目标1中，我们将在一个研究中心，通过比较三种不同的眼睑擦洗方案，确定应用Cliradex（R）垫的最佳方案，以最大限度地减少眼部蠕形螨计数，并在不引发不良事件的情况下改善患者的症状和体征。在目标2中，我们将在多个部位使用目标1中优化的眼睑擦洗方案，以确定最佳持续时间，从而实现眼部蠕形螨计数的最大减少和解决患者炎症症状和体征的最大疗效。这两个目标的实现将使我们能够为III期FDA关键研究收集数据，以便可以提交NDA，最终目标是开发首个FDA批准的处方眼科治疗药物，其中含有TTO的最有效成分，以根除眼部蠕形螨病。 公共卫生相关性：我们在本II期申请中描述的拟议随机、双盲、对照临床试验旨在证明一次性使用Cliradex（R）垫的临床安全性和有效性，该垫含有在I期批准期间从茶树油中确定的最有效成分，以根除眼部蠕形螨病。在第一阶段，我们收集了强有力的数据，支持新配方还发挥独特的广谱抗菌作用，从而消除了添加防腐剂的需要。此外，我们已根据体外细胞毒性试验和人类受试者的9次重复损伤斑贴试验验证了该新制剂无刺激性，并且该新制剂在玻璃瓶和起搏器中均稳定。因此，我们在I期期间的成就证明我们进一步追求本文所述的两个目标是合理的，以便我们最终可以开发一种新的安全、有效和方便的治疗方法来根除眼部蠕形螨病，这是困扰眼部刺激患者的睑缘炎的最常见原因之一，特别是在我们的老龄化人群中。

DESCRIPTION (provided by applicant): Demodex mites are microscopic ectoparasites that commonly infest the pilosebaceous unit of the skin. Uncontrolled overgrowth of mites has been implicated in causing papulopustular lesions in the skin, rosacea in the face, and blepharitis in the eye. Blepharitis (lid margin inflammation) associated with mite-harboring cylindrical dandruff in eyelashes is one of the most common eye diseases. The conventional treatment, using lid scrub with Baby Shampoo, is ineffective in eradicating ocular Demodex infestation (demodicosis). However, we have discovered that tea tree oil (TTO), a natural essential oil steam-distilled from the leaf of Melaleuca alternifolia, is effective in treating ocular demodicosi. Our preliminary clinical studies showed that the lid scrub regimen, based on a weekly office scrub with 50% TTO followed by daily home scrubs with tea tree shampoo, is effective in resolving irritating symptoms and ocular surface inflammation, as well as in improving vision in a number of patients. However, this treatment was not convenient for patient self-administration and resulted in ocular irritation in some patients. We have completed the following three Aims described in Phase I application to identify the most active ingredient in TTO responsible for killing Demodex mites and to eliminate the remaining ingredients in order to develop single-use Cliradex(R) Pads to facilitate the patient's ease of self- administration (Aim 1), to complete preclinical safety studies to verify that this new Cliradex(R) Pad was non- irritative based on an in vitro cytotoxic assay and 9 Repeated Insult Patch Test in human subjects (Aim 2), and to demonstrate that the new formulation exerts potent anti-microbial effects, thus eliminating the need to add preservatives, and is stable both in the glass jar and in the packette (Aim 3). In this Phase II application, we propose to conduct randomized, double-blind, controlled clinical trials to demonstrate the safety and efficacy of the single-use Cliradex(R) Pad compared to the Placebo Pad for treating ocular demodicosis. In Aim 1, at a single site, we will determine the optimal regimen for applying Cliradex(R) Pads to achieve maximal reduction in ocular Demodex counts and clinical improvement in patients' symptoms and signs without eliciting adverse events by comparing three different lid scrub regimens for a period of 1 month. In Aim 2, at multiple sites, we will use the lid scrub regimen optimized in Aim 1 to determine the optimal duration to achieve maximal reduction of ocular Demodex counts and maximal efficacy in resolving patient's inflammatory symptoms and signs. Accomplishment of these two Aims will allow us to gather data for Phase III FDA pivotal studies so that an NDA can be submitted to for the ultimate goal of developing the first FDA-approved prescription ophthalmic therapy containing the most active ingredient of TTO to eradicate ocular demodicosis. PUBLIC HEALTH RELEVANCE: Our proposed randomized, double-blind, controlled clinical trials described in this Phase II application aim to demonstrate the clinical safety and efficacy o single-use Cliradex(R) Pads that contain the most active ingredient identified during the Phase I grant from tea tree oil to eradicate ocular demodicosis. During Phase I, we have gathered strong data supporting that the new formulation also exerts unique broad-spectrum anti- microbial effects, thus eliminating the need for adding preservatives. Furthermore, we have verified that this new formulation is not irritative based on an in vitro cytotoxic assay and 9 Repeated Insult Patch Test in human subjects, and the new formulation is stable both in the glass jar and in the packette. Hence, our accomplishments during Phase I justifies our further pursuit of the two Aims described herein so that we may eventually develop a new safe, effective, and convenient treatment for eradicating ocular demodicosis, which is one of the most common causes of blepharitis that has plagued patients with ocular irritation, especially in our aging population.