0.0584%氢化可的松醋丙酯喷雾剂治疗犬特应性皮炎的疗效：一项随 ...

王帆

Efficacy of a 0.0584% hydrocortisone aceponate spray in the management of canine atopic dermatitis: a randomised, double blind, placebo-controlled trial

0.0584%氢化可的松醋丙酯喷雾剂治疗犬特应性皮炎的疗效：一项随机、双盲、安慰剂对照试验

 

Abstract

摘要

This study evaluated a 0.0584% hydrocortisone aceponate (HCA) spray (Cortavance®; Virbac SA, Carros, France) in canine atopic dermatitis (AD). Initially, dogs with a canine AD extent and severity index (CADESI-03) ≥50 were randomly allocated to receive HCA (n = 15) or placebo (n =13) (two sprays from 10 cm away to treat an area of 100 cm2 ) once daily for 28 days. Twenty-one of the dogs then received HCA spray once daily, reducing to every other day or twice weekly over 42 days if improvement was maintained. CADESI, pruritus (14 cm visual-analogue-scale) and owner satisfaction (5-point scale) were recorded every 14 days. Haematology, biochemistry and adrenocorticotrophic hormone stimulation were performed at baseline, d28 and d70 (HCA n = 9; placebon = 7). Intention-to-treat data were analysed. HCA spray significantly decreased CADESI (–61.4% versus –13.4%, P = 0.0069) and pruritus (–38.8% versus +57.6%, P = 0.0015) at d28 compared to placebo. Scores were significantly decreased at d14 (CADESI –50.5%, P < 0.0021) and d28 (CADESI P < 0.0001; pruritus P = 0.018) compared to baseline following HCA but not placebo. At d28 11 of 15 and 7 of 15 HCA dogs had ≥ 50% reductions in CADESI and pruritus compared to 3 of 13 (P = 0.02) and 1 of 13 (P = 0.04) placebo dogs. Owner satisfaction scores were significantly higher in the HCA group (d28 P = 0.0001). Daily 3 of the 21 dogs required daily maintenance therapy, 7 every other day, 6 twice weekly and 5 dogs required additional therapy. Coat length did not influence the results. No adverse effects or changes to blood parameters were noted. HCA spray proved safe and effective up to 70 days. It is not, however, licensed for long-term treatment.

本研究评价了0.0584%氢化可的松醋丙酯（HCA）喷雾剂（皮乐美）治疗犬特应性皮炎（AD）的疗效。最初，患有犬AD程度和严重程度指数（CADESI-03）≥50的犬被随机分配接受HCA（n=15）或安慰剂（n=13）（从距离皮肤区域10厘米外，喷两次，治疗100平方厘米的面积），每天一次，持续28天。其中21只犬随后每天接受一次HCA喷雾剂，如果保持改善，则在42天内减少到隔日一次或每周2次。每14天记录一次CADESI、瘙痒（14 cm视觉模拟评分）和宠主满意度（5分表）。在基线、第28天和第70天进行血液学、生化和促肾上腺皮质激素刺激（HCA组 n = 9；安慰剂组n = 7）。对患有治疗意向的数据进行了分析。与安慰剂组相比，HCA喷雾剂组显著降低了第28天的CADESI（-61.4%vs-13.4%，P = 0.0069）和瘙痒（-38.8%vs+57.6%，P = 0.0015）。与HCA治疗后的基线水平但没有接受安慰剂治疗的相比，第14天（CADESI-50.5%，P < 0.0021）和第28天（CADESI P < 0.0001；瘙痒症P = 0.018）的评分显著下降。在第28 天15只中11只 和15只中7只犬有的CADESI和瘙痒≥降低了50%，而13只安慰剂犬中的3只（P = 0.02）和13只（P = 0.04）中有1只的CADESI和瘙痒降低了50%。HCA组的宠主满意度得分显著较高（d28 P = 0.0001）。21只犬中3只需要每日一次维持治疗，7只需要隔日一次治疗，6只需要每周2次治疗，5只需要额外治疗。被毛长度没有影响结果。没有发现不良反应或血液参数的变化。HCA喷雾剂被证明是安全有效的，最长可达70天。然而，它并没有获准用于长期治疗。

Introduction

介绍

Canine atopic dermatitis (AD) is a common, chronic, inflammatory dermatosis.  It is defined as a genetically predisposed inflammatory and pruritic allergic skin disease with characteristic clinical features, and is most commonly associated with IgE antibodies to environmental allergens. It has become clear that canine AD is a complex, multifactorial disease involving interactions between skin structure, the immune system and environmental influences. The complex pathology makes AD a challenging disease to manage. Treatment options include managing flare factors, bathing and skin care, allergen avoidance, allergen-specific immunotherapy (ASIT) and essential fatty acids, but many atopic dogs require long-term anti-inflammatory medication.

犬特应性皮炎（AD）是一种常见的慢性炎症性皮肤病。它被定义为一种遗传易感的炎症性和瘙痒性过敏性皮肤病，具有典型的临床特征，最常与针对环境过敏原的IgE抗体相关。很明显，犬AD是一种复杂的、多因素的疾病，涉及皮肤结构、免疫系统和环境影响之间的相互作用。复杂的病理使AD成为一种具有挑战性的管理疾病。治疗方案包括管理急性发作因素、洗澡和皮肤护理、避免过敏原、过敏原特异性免疫治疗（ASIT）和必需脂肪酸，但许多特应性皮炎患犬需要长期的抗炎药物。

 

Glucocorticoids are inexpensive, easy to administer and highly effective, but systemic treatment frequently results in serious acute and chronic adverse effects. Topical application is an attractive option as this delivers the drug to the site of inflammation, avoiding systemic exposure. Topical preparations containing hydrocortisone, betamethasone, triamcinolone and prednisolone are effective in a variety of inflammatory dermatoses including canine AD. Long-term treatment has nevertheless been associated with cutaneous atrophy, ulceration, telangectasia, alopecia, comedones, calcinosis cutis and altered hypothalamic-pituitary-adrenal axis function.

糖皮质激素价格低廉，易于给药和高效，但全身治疗经常导致严重的急性和慢性不良反应。外用是一个有吸引力的选择，因为它可以将药物输送到炎症部位，避免全身暴露。含氢化可的松、倍他米松、曲安奈德和泼尼松龙的外用制剂对包括犬AD在内的多种炎症性皮肤病都有效。然而，长期治疗与皮肤萎缩、溃疡、毛细血管扩张、脱毛、粉刺、皮肤钙质沉着和下丘脑-垂体-肾上腺轴功能的改变有关。

 

Nonhalogenated, di-ester topical glucocorticoids avoid many of these problems by virtue of their metabolism into largely inactive moieties within the skin. The absence of fluorine or chlorine at C6, C9 or C21 is associated with better local and systemic tolerance compared to conventional topical glucocorticoids. Acetate esterification at C21 increases stability, whereas propionate esterification at C17 enhances affinity for the corticosteroid receptor and anti-inflammatory activity. Double esterification greatly enhances penetration of the stratum corneum, but also ensures specific metabolism in the deeper dermis. This minimizes effects on hair follicles, dermal fibroblasts and blood vessels, decreasing the likelihood of local cutaneous and systemic adverse effects.

非卤化的二酯外用糖皮质激素，通过在皮肤内代谢成大部分无活性部分，避免了许多上述问题。与传统的外用糖皮质激素相比，C6、C9或C21中缺乏氟或氯与更好的外用和全身耐受性相关。C21上的醋酸酯化增加了稳定性，而C17的丙酸酯化增强了对皮质类固醇受体的亲和力和抗炎活性。双酯化极大地增强了角质层的渗透，但也确保了真皮深层的特异性代谢。这对毛囊、真皮成纤维细胞和血管的影响最小，减少皮肤局部和全身不良反应的可能性。

 

A number of these products are widely used in human dermatology with much improved benefit–risk ratios compared to traditional topical glucocorticoids. Methylprednisolone aceponate (Advantan®; Intendis GmbH, Berlin, Germany) is a highly effective treatment for AD and other forms of eczema with minimal local and systemic adverse effects. It is now regarded as a first-line product with an excellent therapeutic index and benefit–risk ratio in medical dermatology.

与传统的外用糖皮质激素相比，许多这些产品被广泛应用于人类皮肤科，具有大大提高的效益-风险比。甲基泼尼松龙是一种治疗AD和其他形式的湿疹的高效方法，局部和全身副作用最小。目前被认为是具有良好治疗指标和效益-风险比的一线产品。

 

An almost identical topical glucocorticoid, hydrocortisone aceponate (HCA; Cortavance®, Virbac SA, Carros, France), has been licensed in a 0.0584% spray formulation for the short-term treatment of pyotraumatic dermatitis, flea allergic dermatitis and other inflammatory dermatoses in dogs. The purpose of this trial was to assess its efficacy and safety profile in the treatment of canine AD.

一种几乎相同的外用糖皮质激素，一种0.0584%的氢化可的松醋丙酯（HCA）喷雾剂已被批准使用，用于短期治疗犬的脓性创伤性皮炎、跳蚤过敏性皮炎和其他炎症性皮肤病。本试验的目的是评估其治疗犬AD的有效性和安全性。

 

 

 

Materials and methods

材料和方法

Study subjects

研究对象

The study was performed in accordance with ethical guidelines laid down by the University of Liverpool, the University of Saragosa, Ludwig-Maximilan-University and Virbac SA. Dogs with a clinical diagnosis of AD according to accepted criteria were recruited from five European dermatology referral centres. It was estimated that with a mean baseline CADESI-0315 score of 100, a mean 50% reduction in the treatment group and 10% in the placebo group with an SD of ±30%, 15 dogs in each group would detect a statistically significant difference in response to treatment with > 95% power.

该研究是根据利物浦大学、萨拉戈萨大学、路德维希-马克西米兰大学和维尔巴克大学制定的伦理准则进行的。根据公认的标准，临床诊断为AD的犬从5个欧洲皮肤科转诊中心招募。据估计，平均基线CADESI-0315得分100，治疗组平均减少50%，安慰剂组减少10%的SD±30%，每组15只犬将检测有统计学意义的差异对治疗> 95%的力量。

 

Trial protocol

试验方案 

In part one of the trial, 29 dogs with AD that fulfilled the entry criteria (Table 1) were randomly allocated to receive either 0.0584% HCA or placebo spray. Dogs were sequentially allocated to treatment groups A, B, C or D according to a computer-generated random sequence established before the trial. Two groups were active HCA spray and two were the placebo. Four treatment identifiers were used to minimize detection bias that could arise from perceived efficacy or lack of efficacy with only two treatment identifiers. The packaging and nature of the active treatment and placebo were identical. Owners were instructed to apply the spray once daily to affected skin from 10 cm away at a dose rate of two sprays per 100 cm2 of affected skin. Affected skin was treated as required with no restriction on the body area that could be treated or the number of sprays per animal. All sizes of dog, type of lesions and coat lengths were treated in the same way. Clinical assessments (Table 2) were performed at days 0, 14 and 28.

在试验的第一部分中，29只符合入组标准的AD犬（表1）被随机分配接受0.0584%的HCA或安慰剂喷雾剂。根据试验前建立的计算机生成的随机序列，犬被依次分配到A、B、C或D治疗组。两组为活性HCA喷雾剂，两组为安慰剂。使用了四种治疗标识符来减少可能由感知疗效或缺乏疗效引起的检测偏差，只有两个治疗标识符。积极治疗和安慰剂的包装和性质是相同的。宠主被要求每天对距离皮肤10厘米外的患病皮肤喷一次喷雾，剂量率为每100厘米2的患病皮肤喷洒2剂。患病的皮肤按要求进行治疗，没有限制可以治疗的机体区域或每只动物的喷剂数量。所有大小的犬、病变类型和被毛长都用相同的方法治疗。分别在第0、14和28天进行了临床评估（表2）。

 

In part two of the trial all dogs received the 0.0584% HCA spray. There was no wash-out period between parts one and two of the trial. Treatment was initially administered once daily as described. Clinical assessments were performed at days 28, 42, 56 and 70. If the CADESI-03 was ≤ 50 at day 42 (i.e. after 14 or 42 days of daily HCA for dogs on placebo or HCA in part one, respectively) the owners were instructed to administer treatment every other day; if not, once-daily treatment was maintained. At day 56 (i.e. after 28 or 56 days of HCA) treatment was adjusted as follows: CADESI-03 ≤ 25 – administered twice weekly; CADESI-03 26–50 – administered every other day; CADESI-03 > 50 – administered once daily. Additional therapy was given to dogs on daily therapy with a CADESI-03 > 50 at the investigators’ discretion.

在试验的第二部分中，所有的犬都接受了0.0584%的HCA喷雾剂。在试验的第一部分和第二部分之间没有停药期。最初每天进行一次。分别在第28、42、56和70天进行临床评估。如果CADESI-03在第42天为≤50（即分别服用安慰剂或第一部分HCA的犬在每日HCA 14或42天后），宠主被指示隔日一次进行一次治疗；如果没有，则维持每天一次的治疗。第56天（即HCA 28或56天后）治疗调整如下： CADESI-03≤25-每周给予2次；CADESI-03 26-50-隔日一次给予一次；CADESI-03>50-每日1次。由研究人员决定，每天使用CADESI-03 > 50的犬接受额外治疗。

 

Outcome measures

结果测量

The outcome measures were the CADESI-03, pruritus and owner global evaluation (Table 3) scores. The CADESI-03 is a validated assessment of clinical lesions (erythema, excoriation, lichenification and self-induced alopecia) at 62 anatomical sites from 0 (normal) to 5 (most severe) yielding a score of 0–1240. Pruritus was assessed using a horizontal 14 cm visual analogue scale (VAS) marked ‘not itchy’ at the left edge and ‘very itchy all the time’ at the right edge. Owners were asked to mark the scale with a short vertical line according to their perception of their dog’s pruritus over the preceding 24 h. The pruritus score was the distance in cm from the left edge of the scale to their mark.

结果测量指标为CADESI-03、瘙痒症和宠主整体评价（表3）评分。CADESI-03是对62个解剖部位从0（正常）到5（最严重）的临床病变（发红、抓痕、苔斑化和自损性脱毛）的有效评估，得分为0-1240分。使用水平14厘米视觉模拟评分（VAS）评估瘙痒，在左边缘标记“不痒”，在右边缘标记“一直非常痒”。宠主被要求根据他们对犬过去24小时瘙痒的感知，用一条短的垂直线标记。瘙痒评分为从量表左边缘到其标记的距离，单位为厘米。

 

Compliance measures

合规措施

The owners were instructed to document the number of sprays administered each day, concomitant treatments and other events in a diary. The spray bottles were weighed when dispensed and at each revisit to determine the amount of medication used and whether this

tallied with the diary.

这些宠主被要求在日记中记录每天喷洒喷雾剂的次数、联合治疗和其他事件。喷瓶在分配时和每次复查时被称重，以确定药物的使用量和是否这样做。

 

 

Clinical assessments

临床评估

Investigators performed a thorough clinical examination at each visit, recording and investigating any adverse events as appropriate. At days 0, 28 and 70 samples for haematology and biochemistry were taken and an ACTH stimulation test performed. Briefly, serum was collected for cortisol assay immediately before and 1 h after intravenous administration of 0.25 mg synthetic ACTH (Synacthen®; Alliance Pharmaceuticals, Chippenham, UK).

研究人员在每次就诊时都进行了彻底的临床检查，记录并适当地调查任何不良事件。在第0、28和70天采集血液学和生化样本，并进行ACTH刺激试验。简单地说，在静脉注射0.25 mg合成ACTH前和注射后1小时收集血清进行皮质醇测定。

 

Data analysis

数据分析

Dogs were withdrawn if they required treatment with a prohibited medication, experienced unacceptable discomfort or for poor compliance. Owners were free to withdraw their animals at any point. End of dosing assessments were recorded for intention-to-treat (ITT) analyses using the last treatment value carried forward.

如果犬治疗需要使用禁止的药物，出现不可接受的不适或依从性差，病例将被排除。宠主可以在任何时候自由地退出他们的动物。记录意向治疗（ITT）的给药结束评估 使用最后一个处理值进行分析。

 

Data were tested for normal distribution before analysis (KolmogorovSmirnov tests; Instat®, Graphpad Inc., San Diego, CA, USA). Unpaired t-tests, Mann-Whitney U-tests and Fisher’s exact tests (Instat®) were used to compare demographic data between the two groups. A general linear model repeated measures two-way ANOVA with Tukey’s posttests (Minitab® 15; Minitab Ltd, Coventry, UK) was used to compare the CADESI-03 and pruritus scores between the HCA and placebo groups at days 0, 14 and 28, and CADESI-03 and pruritus scores at days 14 and 28 to baseline within each group. Repeated-measure ANOVAs were also used to compare the scores at each time point for dogs with short and medium/long coats in both treatment groups. Fisher’s exact tests (Instat®) were used to compare the proportion of dogs that achieved ≥ 50% reductions in CADESI-03 and pruritus scores in each group. Repeated-measure two-way ANOVA was used to compare the owners’ global evaluation scores between the two groups at days 14 and 28. For part two of the trial, chi-square tests (Graphpad Inc.) were used to compare the proportions of dogs that received HCA or placebo in part one that could be subsequently maintained on twice weekly, every other day and daily HCA treatment or daily HCA plus additional therapy. Significance was set at P < 0.05.

数据在分析前对数据进行正态分布检验。采用非配对t检验、Mann-惠特尼u检验和Fisher精确检验来比较两组间的人口统计学数据。一般线性模型重复测量Tukey后测的双向方差分析比较HCA组和安慰剂组在第0、第14和第28天的CADESI-03和瘙痒评分，以及第14天的CADESI-03和第28天与各组的瘙痒评分。重复测量方差分析也用于比较两个治疗组中短、中/长被毛犬在每个时间点的得分。Fisher精确检验用于比较每组中达到≥的CADESI-03和瘙痒评分降低50%的犬的比例。采用重复测量双向方差分析方法比较两组宠主在第14天和第28天的整体评价得分。在试验的第二部分，使用卡方检验（图形板公司）比较第一部分中接受HCA或安慰剂的犬的比例，随后可以维持每周两次，隔日一次和每日HCA治疗或每日HCA加额外治疗的比例。显著性设为P < 0.05。

 

Results

结果

Demographic data

统计数据

Sixteen dogs from 14 breeds and crosses were enrolled in the HCA group, and 13 dogs from 11 breeds and crosses in the placebo group. The range of breeds did not appear to differ between the groups, but the low numbers of each breed prevented statistical analysis. Coat length was subjectively reported according to type and breed. Coat length was evenly distributed between the treatment groups (chi square test P = 0.96): short coat (e.g. boxer, Jack Russell terrier and English bulldog) HCA n = 7 and placebo n = 5; medium coat (e.g. golden retriever, cocker spaniel and poodle) HCA n = 8 and placebo n = 7; and long coat (chow and Yorkshire terrier) HCA n = 1 and placebo n = 1. There were no significant differences in age (HCA – mean 4.7 years, range 1.5–10; placebo – mean 3.7 years, range 1–8 [unpaired t-test P = 0.32]), sex (HCA – 9 female, 7 male; 7 female, 6 male [Fisher’s exact test P = 0.90]) or weight (HCA: median 25.6 kg, range 2.1–83; placebo: median 20.1 kg, range 2.7–35 [Mann-Whitney U-test P = 0.50]). Concomitant treatments included essential fatty acids (HCA n = 3; placebo n = 2), meloxicam (HCA n = 1), ear cleaner (HCA n = 2), shampoo (HCA n = 1; placebo n = 2), ASIT (HCA n = 2; placebo n = 1), ivermectin (HCA n = 1) and levothyroxine (placebo n = 1).

HCA组共16只犬来自14个品种犬和杂交犬，安慰剂组共13只犬来自11个品种犬和杂交犬被纳入安慰剂组。品种的范围在组之间没有差异，但每个品种的低数量妨碍了统计分析。根据类型和品种主观报道。毛发长度均匀分布在治疗组之间（卡方检验P = 0.96）：短被毛（如拳击犬、杰克罗素梗和英国斗牛犬）HCA=7和安慰剂n = 5；中被毛（如金毛猎犬、可卡犬和贵宾犬）HCA=8和安慰剂n = 7；长被毛（松狮犬和约克夏犬）HCA=1和安慰剂=1。在年龄（HCA-平均4.7岁，范围1.5-10；安慰剂-平均3.7岁，范围1-8[未配对t检验P = 0.32])、性别（HCA-9雌，7雄；安慰剂组7雄；7雌[费舍尔确切检验P = 0.90])或体重（HCA：中位数25.6公斤，范围2.1.-83；安慰剂：中位数20.1公斤，范围2.7-35[曼恩-惠特尼U检验P = 0.50]）方面无显著差异。伴随治疗包括必需脂肪酸（HCA=3；安慰剂= 2)、美洛昔康（HCA=1）、洗耳液（HCA=2）、香波（HCA=1；安慰剂= 2)、ASIT（HCA=2；安慰剂= 1)、伊维菌素（HCA=1）和左旋甲状腺素（安慰剂= 1)。

 

Intention-to-treat analyses

意向治疗分析

Five dogs were prematurely withdrawn: one dog in the HCA group that received prohibited medication after 3 days following a possible adverse reaction (see succeeding discussion), and four dogs on placebo at day 14 as a result of lack of efficacy. There were no on-treatment data for the dog in the HCA group, so last treatment carried forward ITT analyses were performed using data from 15 HCA treated and 13 placebo-treated dogs. There were otherwise no significant protocol deviations in either group.

5只犬被提前退出：HCA组的1只犬在可能的不良反应3天后接受了禁止的药物治疗（见后续讨论），4只犬在第14天因缺乏疗效而服用安慰剂。HCA组的犬没有治疗期间的数据，所以最后一次治疗进行了ITT分析，使用了15只HCA治疗和13只安慰剂治疗的犬的数据。在其他方面，两组中均无显著的方案偏差。

 

 

 

 

 

 

 

CADESI-03

CADESI-03 

The HCA-treated group exhibited a significant reduction in CADESI-03 scores throughout the trial compared to the placebo group (repeated measures ANOVA P < 0.0001) (Table 4 and Figure 1). There was no significant difference between groups at day 0 (P = 0.88). Mean CADESI-03 scores were significantly decreased compared to baseline at days 14 (P = 0.0021) and 28 (P = 0.0001) in the HCA group but not the placebo group (P = 0.37 and P = 0.31). The mean CADESI-03 score in the HCA group was significantly lower than that in the placebo group at day 28 (P = 0.0069) but not at day 14 (P = 0.05). A significantly greater number of dogs achieved a ≥ 50% reduction in CADESI-03 score following HCA treatment compared to placebo at day 28 (Fisher exact test P = 0.02) but not at day 14 (P = 1.0). There was no significant difference in the mean change in CADESI-03 between dogs with short coat (HCA: –73.6, SD 47.2; placebo: –60.4, SD 128.0) and medium/long coats (HCA: –49.6, SD 30.6; placebo: 2.4, SD = 51.4) (repeated-measures ANOVA: HCA P = 0.3; placebo P = 0.64).

与安慰剂组相比，HCA治疗组在整个试验过程中显示出CADESI-03评分的显著降低（重复测量方差分析P<0.0001）（表4和图1）。在第0天，各组间差异无统计学意义（P = 0.88）。与第14天相比，HCA组的平均CADESI-03评分（P = 0.0001）显著下降，但安慰剂组没有显著下降（P = 0.37和P = 0.31）。HCA组的平均CADESI-03评分在第28天显著低于安慰剂组（P = 0.0069），但在第14天则没有降低（P = 0.05）。与安慰剂相比，在第28天，HCA治疗后犬的CADESI-03评分显著降低50%（Fisher精确检验P = 0.02），但在第14天没有（P = 1.0）。短毛犬（HCA：-73.6，SD 47.2；安慰剂：-60.4，SD 128.0）和中/长被毛犬（HCA：-49.6，SD 30.6；安慰剂：2.4，SD=51.4）（重复测量方差分析：HCA P = 0.3；安慰剂P = 0.64），CADESI-03的平均变化无显著差异。

 

Pruritus

瘙痒 

The HCA-treated group exhibited a significant reduction in pruritus scores throughout the trial compared to the placebo group (repeated-measures ANOVA P < 0.0001) (Table 5 and Figure 2).There was no significant difference between groups at day 0 (P = 1.0). Mean pruritus scores were significantly decreased compared to baseline at day 28 (P = 0.018) but not at day 14 (P = 0.12) following the HCA spray. There was no change in the placebo group at day 14 (P = 1.0) or 28 (P = 0.89). Mean pruritus scores in the HCA group were significantly lower than those in the placebo group at day 28 (P = 0.0015) but not at day 14 (P = 0.32). A significantly greater number of dogs achieved a ≥ 50% reduction in pruritus following HCA treatment compared to placebo at day 28 (Fisher exact test P = 0.04) but not at day 14 (P = 0.67). There was no significant difference in the mean change in pruritus score between dogs with short (–3.1, SD 3.6) and medium/long coats (–2.2, SD 3.4) treated with HCA (repeated measures ANOVA P = 0.63), but there was a significant difference between short- (–3.0, SD 2.7) and medium/long-coated dogs (2, SD 3.3) in the placebo group (repeated measures ANOVA P = 0.035).

与安慰剂组相比，HCA治疗组在整个试验过程中瘙痒评分显著降低（重复测量分析P<0.0001）（表5和图2）。在第0天，各组间无显著性差异（P = 1.0）。在HCA喷雾剂使用后的第28天（P = 0.018），但在第14天，平均瘙痒评分没有显著下降（P = 0.12）。安慰剂组在第14天（P = 1.0）和第28天（P = 0.89）时均无变化。HCA组的平均瘙痒评分在第28天显著低于安慰剂组（P = 0.0015），但在第14天则没有降低（P = 0.32）。与安慰剂相比，在第28天，HCA治疗后的犬类瘙痒明显减少50%（Fisher精确检验P = 0.04），但在第14天没有（P = 0.67）。HCA治疗组的犬短被毛（-3.1，SD3.6）和中/长被毛（-2.2，SD3.4）的瘙痒评分平均变化没有显著差异（重复测量方差P = 0.63），但在安慰剂组短被毛（-3.0，SD2.7）和中/长被毛犬（2，SD 3.3）的瘙痒评分有显著差异（重复测量方差P = 0.035）。

 

 

 

Figure 2. Mean (SD) pruritus rating (14 cm visual analogue scale [VAS]) during treatment with 0.0584% HCA spray (n = 15) and placebo (n = 13).

图2.使用0.0584% HCA喷雾剂（n = 15）和安慰剂（n = 13）治疗期间的平均（SD）瘙痒评分(14 cm视觉模拟量表（VAS]）。

 

 

Figure 3. Maintenance treatment with 0.0584% HCA spray in 21 atopic dogs. HCA group – dogs previously treated with HCA spray in part one of the trial; Placebo group – dogs previously treated with placebo spray in part one of the trial.

图3.使用0.0584% HCA喷剂对21只特应性患犬犬的维持治疗。HCA组-在试验第一部分中使用HCA喷雾剂的犬；安慰剂组-在试验第一部分中使用安慰剂喷雾剂的犬。

 

 

 

Owners’ global efficacy score

宠主整体疗效评分

The global efficacy score was significantly higher in the HCA treated compared to the placebo group throughout the trial (repeated measures ANOVA P < 0.0001). Significant differences between the two groups were seen at both days 14 (P = 0.0009) and 28 (P = 0.0001), but there were no significant differences for the scores within each group between days 14 and 28 (HCA P = 0.48; placebo P = 0.95) (Table 6). There was no difference in the owners’ global efficacy score between short- (HCA = 2.7, SD 1.3; placebo = 2.4, SD 0.9) and medium/long-coated dogs (HCA: 3.1, SD 0.8; placebo: 2.1, SD 1.0) in either group (repeated measures ANOVA: HCA P = 0.46; placebo P = 0.62).

在整个试验过程中，HCA治疗组的整体疗效评分显著高于安慰剂组（重复测量方差分析P < 0.0001）。两组在第14天（P = 0.0009）和第28天（P = 0.0001）均有显著差异，但第14天和第28天的评分无显著差异（HCA P = 0.48；安慰剂P=0.95）（表6）。短被毛-（HCA=2.7，SD 1.3；安慰剂= 2.4，SD 0.9)和中/长被毛犬（HCA：3.1，SD 0.8；安慰剂：2.1，SD 1.0）在两组（重复测量方差分析：HCA P = 0.46；安慰剂P = 0.62)之间的宠主整体疗效评分无差异。

 

Maintenance treatment with HCA spray

使用HCA喷雾剂进行维护治疗

Eight dogs were withdrawn during or after part one of the study at the owners’ request for poor efficacy (four dogs from the placebo group) or for nontreatment related reasons (one dog from the HCA group with a possible adverse reaction [see succeeding discussion] and three other dogs from the HCA group). Of the remaining 21 dogs, three required daily therapy, seven required every other treatment and six could be maintained on twiceweekly treatment. Five dogs could not be maintained on daily HCA spray alone and required additional treatment (Figure 3). There was a significant difference in long-term control between those dogs on HCA and those on placebo in part one of the trial. Dogs originally on HCA were more likely to be maintained on every other day or twice-weekly therapy, and all of the dogs that required additional therapy had been on placebo (chi-squared test P = 0.01). There was no difference in the proportion of short- and medium/ long-coated dogs that required daily, every other day or twice-weekly therapy maintenance therapy in either group (HCA: P = 0.8; placebo: P = 0.12).

八只犬因为治疗期间或部分研究后的宠主认为治疗疗效不佳而退出（安慰剂组四只犬）或非治疗相关原因（HCA组1只犬伴有一种可能的不良反应[见成功讨论]和HCA组其他3只犬）。在剩下的21只犬中，3只需要每日一次治疗，7只需要每次其他的治疗，6只可以维持20周的治疗。有5只犬不能单独使用每日的HCA喷雾剂，需要额外的治疗（图3）。在试验的第一部分中，那些服用HCA和服用安慰剂的犬在长期控制方面有显著差异。最初接受HCA治疗的犬更有可能隔日一次或每周两次接受治疗一次，所有需要额外治疗的犬都服用了安慰剂（卡方检验P = 0.01）。在两组中，需要每日、隔日一次或每周两次治疗维持治疗的比例无差异（HCA：P = 0.8；安慰剂：P = 0.12）。

 

Safety and tolerance

安全性和耐受性

Both treatments were very well tolerated throughout the study. One dog was withdrawn from the HCA group after 3 days after receiving prohibited medication for severe pedal dermatitis and otitis, although it is unclear whether this was treatment related or an exacerbation of the AD. Adverse events in the HCA group were otherwise limited to short-term, self-resolving diarrhoea (two dogs), pyrexia and vomiting (one dog) and persistent oestrus (one dog). These were not thought to be related to treatment. Four dogs were withdrawn from the placebo group in part one of the trial as a result of lack of efficacy but no adverse events were reported.

在整个研究过程中，两种治疗方法的耐受性都很好。1只犬在接受治疗严重足皮炎和耳炎的禁止药物治疗3天后退出HCA组，但尚不清楚这是与治疗相关还是与AD恶化有关。除此之外，HCA组的不良事件仅限于短期的、自限性腹泻（两只犬）、发热和呕吐（一只犬）和持续发情（一只犬）。这些都不被认为与治疗有关。在试验的第一部分中，有4只犬由于缺乏疗效而从安慰剂组中退出，但没有任何不良事件的报道。

 

There were complete on-trial blood analysis and ACTH stimulation data for nine dogs in the HCA group and seven dogs in the placebo group. The reasons for the missing data included investigator error, lack of owner consent and lost samples. There were no significant abnormalities on haematology and biochemistry. Most dogs had values within normal ranges at baseline and throughout the study. There were marginally increased neutrophil counts in seven dogs (four HCA and three placebo treated) at day 0 and two HCA dogs at day 28, elevated AP at days 0 (450 iμ/L; normal range 0–100) and 28 (370 iμ/L) in one HCA-treated dog, and mildly elevated creatinine at day 0 in four (two HCA and two placebo) dogs (126–150 μmol/L; normal range 20–110) and three (one HCA and two placebo) dogs at day 28 (120– 128 μmol/L). There were no abnormalities seen at day 70 in any of the tested dogs. All tested dogs had pre- and post-ACTH cortisol levels within normal ranges throughout the study (Table 7).

对HCA组的9只犬和安慰剂组的7只犬进行了完整的试验中血液分析和ACTH刺激数据。数据缺失的原因包括调查员的错误、缺乏宠主同意和样本丢失。血液学、生化检查未见明显异常。在基线时和整个研究过程中，大多数犬的实验值都在正常范围内。第0天，7只犬（4只HCA和3只安慰剂治疗）的中性粒细胞计数略有增加，第28天，2只HCA犬的中性粒细胞计数增加，第0天AP升高(450 iμ/L；HCA犬0-100）和28只（370 iμ/L），第0天（2只HCA和2只0μmol/L（120-110）；第28天，3只（1只HCA和2只安慰剂）犬（120-128μmol/L）的肌酐轻度升高。在第70天，任何测试犬都没有发现异常。在整个研究过程中，所有被测试的犬在ACTH前后的皮质醇水平都在正常范围内（表7）。

 

 

 

 

Discussion

讨论

This study shows that the 0.0584% HCA spray is an effective and well-tolerated treatment for canine AD. Using the standard dosing regimen, the mean decrease in CADESI-03 score was 61.4% with the majority of dogs achieving ≥ 50% reduction, the point conventionally used to denote a significant clinical improvement.16 The improvement in pruritus was less marked, with a mean reduction of 38.8%, with 7 of 15 dogs experiencing a ≥ 50% decrease. The clinical response was quite rapid, with an improvement from baseline evident by 14 days, with further improvement at 28 days. The second part of the trial demonstrated that 13 of 21 dogs could be maintained for 2–4 weeks on HCA spray alone administered every other day or less often. The owners’ global efficacy ratings corroborated these results, although several owners that rated the clinical efficacy and tolerance very high found the spray difficult to apply. It would therefore be better to separate these factors into three owner scores in future trials.

本研究表明，0.0584% HCA喷雾剂是一种有效且耐受性良好的犬AD治疗方法。使用标准给药方案，CADESI-03评分平均下降61.4%，大多数犬达到≥下降50%，这个点通常用于表示显著的临床改善。瘙痒症的改善不那么明显，平均减少了38.8%，15只犬中有7只犬的≥下降了50%。临床反应相当迅速，与基线相比，在14天明显改善，在28天进一步改善。试验的第二部分表明，21只犬中的13只可以隔日一次或更少地单独使用HCA喷雾剂来维持2-4周。宠主的整体疗效评级证实了这些结果，但一些对临床疗效和耐受性评级非常高的宠主发现喷雾剂很难应用。因此，在未来的试验中，最好将这些因素分为三个宠主分数。

 

The coat length did not appear to influence the response to treatment, ease of application or tolerance of the HCA spray, although pruritus scores were significantly lower in short-coated dogs treated with placebo compared to medium/long-coated dogs. The reason for this is not known, and it is possible that stratification of the data reduced group sizes and statistical power resulting in a type 1 error. The spray is formulated to penetrate the hair coat, minimizing the effect of coat length. In addition, although dogs were not preselected by lesion type or distribution, AD classically affects the less well-haired parts of the body facilitating topical treatment.

被毛长度似乎没有影响HCA喷雾剂的治疗反应、应用的方便性或耐受性，但用安慰剂治疗的短被毛犬的瘙痒评分明显低于中/长被毛犬。其原因尚不清楚，而且数据的分层可能减少了组的规模和统计能力，从而导致了第1类错误。喷雾的配方是穿透被毛，最大限度地减少毛长度的影响。此外，虽然犬没有根据病变类型或分布预先选择，但AD通常会影响机体毛发不佳部位，从而也促进了外用治疗。

 

HCA was very well tolerated in this study with no adverse events attributable to treatment. This is generally a better safety profile than reported for other anti-inflammatory agents such as antihistamines, arofylline, misoprostol, cyclosporine and systemic glucocorticoids. There was no clinical evidence of cutaneous atrophy or secondary infection and no significant changes to blood parameters or adrenal function following treatment for up to 70 days. This indicates that there is minimal systemic absorption of active compound following topical administration. This is in marked contrast to traditional topical glucocorticoids, which are absorbed systemically, resulting in significant local and systemic adverse effects following long-term and/or extensive application. This study, however, only followed dogs for a maximum of 70 days, and as AD is usually a life-long condition, longer-term studies of safety are warranted. The assessment of cutaneous atrophy, furthermore, was subjective and did not employ more objective measures that might have detected minor changes. Recent studies using repeated histopathology, however, detected no changes in epidermal or dermal thickness, or hair follicles at treated sites in healthy dogs over three months (C. Reme, personal communication). Nevertheless, HCA is not licensed for long-term treatment, and clinicians should carefully monitor treated animals for adverse effects. The longer-term response to HCA treatment was variable between dogs. Variation in the frequency of long-term medication has been noted for cyclosporine and glucocorticoids. This may be caused by inherent severity of condition, environment (e.g. allergen or irritant exposure), genotypic differences in response to drug therapy or compliance. Interesting, all five of the dogs that required additional therapy in part two of the trial received placebo in part one. This suggests that although significant clinical remission was evident by 14–28 days, continued further improvement enabled a reduction in the frequency of therapy. These results are encouraging as monotherapy is not normally recommended.3 It is therefore possible that adjunct treatments such as skin barrier care, allergen avoidance and ASIT will permit less frequent treatment in more dogs.

HCA在本研究中耐受性非常好，无可归因于治疗的不良事件。这通常比报道的其他抗炎药物，如抗组胺药、阿罗菲林、米索前列醇、环孢素和全身糖皮质激素的安全性更好。治疗后70天后，无临床证据显示皮肤萎缩或继发感染，血液参数或肾上腺功能没有显著变化。这表明，在外用给药后，活性化合物的全身吸收最小。这与传统的外用糖皮质激素形成鲜明对比，后者会被全身吸收，在长期和/或大面积应用后导致显著的外用和全身不良反应。然而，这项研究只对犬进行了最多70天的随访，而且由于AD通常是一种终身的疾病，因此需要进行更长期的安全性研究。此外，对皮肤萎缩的评估是主观的，没有采用更客观的测量，可能已经检测到微小的变化。然而，最近使用重复组织病理学的研究发现，在三个月的时间里，没有发现健康犬的表皮或真皮厚度或毛囊的变化（C. Reme，个人交流）。然而，HCA并没有被批准用于长期治疗，临床医生应该仔细监测接受治疗的动物的不良反应。不同的犬对HCA治疗的长期反应是不同的。环孢素和糖皮质激素长期药物治疗的频率存在差异。这可能是由于固有的条件严重程度、环境（如过敏原或刺激物暴露）、对药物治疗的反应或依从性的基因型差异引起的。有趣的是，在试验的第二部分中，所有需要额外治疗的五只犬在第一环孢素和糖皮质激素长期药物治疗的频率存在差异。这可能是由于固有的条件严重程度、环境（如过敏原或刺激物暴露）、对药物治疗的反应或依从性的基因型差异引起的。有趣的是，在试验的第二部分中，所有需要额外治疗的五只犬在第一部分中都接受了安慰剂。这表明，尽管在14-28天内明显有显著的临床缓解，但持续的进一步改善使治疗频率得以降低。这些结果是令人鼓舞的，因为通常不推荐单一治疗。因此，辅助治疗，如皮肤屏障护理、避免过敏原和ASIT，可能会允许对更多的犬进行更少的治疗。

 

There are a number of possible reasons for the discrepancy between the changes in CADESI and pruritus scores. CADESI scores have been widely used and modified over 10 years to provide objective measures of acute inflammation, chronic inflammation and self-trauma. The CADESI-03 used in this study has been shown to have high intra- and inter-observer reliability, and is a relevant and reliable assessment of clinical severity. Pruritus scores, in contrast, have not been studied or validated to the same extent. Studies have questioned the reliability and repeatability of simple VAS scores, and a combined VAS scale with behavioural descriptors was found to be superior. It is also possible that the change in CADESI-03 score does not correlate with the change in pruritus. It includes excoriation and self-induced alopecia as measures of self-trauma, but despite this it is predominantly a dermatological assessment of cutaneous inflammation and trauma. This can be reliably and objectively assessed, but may not be as relevant to owners and therefore as good a measure of quality of life as pruritus. Limiting the assessment of pruritus to the preceding 24 h may also make this more vulnerable to short-term changes than CADESI scores. An alternative explanation for the discrepant results is that HCA has differential effects on inflammation and pruritus.

CADESI和瘙痒评分之间的差异可能有许多原因。CADESI评分已被广泛使用和修改了10年，以提供急性炎症、慢性炎症和自我损伤的客观测量。本研究中使用的CADESI-03已被证明具有较高的观察者内和观察者间的可靠性，是临床严重程度的相关可靠评估。相比之下，瘙痒症评分还没有得到相同程度的研究或验证。也有可能CADESI-03评分的变化与瘙痒症的变化无关。它包括将抓痕和自损性脱毛作为自损的衡量标准，但尽管如此，它主要是对皮肤炎症和创伤的皮肤学评估。这可以得到可靠和客观的评估，但可能与宠主无关，因此也不像瘙痒一样是衡量生活质量的良好指标。将瘙痒的评估限制在前24小时也可能比CADESI评分更容易受到短期变化的影响。对差异结果的另一种解释是，HCA对炎症和瘙痒有不同的影响。

 

A minority of dogs appeared to respond to the placebo spray, although in contrast to the HCA treated group the 95% confidence intervals for the percentage change in both CADESI-03 and pruritus spanned 0, indicating that there was no overall benefit. One weakness of this study is that placebo controlled trials tend to over-emphasize beneficial responses to active treatments. It will therefore be interesting to compare the efficacy of 0.0584% HCA to other anti-inflammatory treatments, although the unique nature of this product will necessitate a single-blind or double-placebo trial design.

少数犬似乎对安慰剂喷雾剂有反应，但与HCA治疗组相比，CADESI-03和瘙痒症的百分比变化的95%置信区间为0，表明没有总体益处。这项研究的一个缺点是，安慰剂对照试验往往过度强调对积极治疗的有益反应。因此，比较0.0584%的HCA与其他抗炎治疗方法的疗效将是很有趣的，但该产品的独特特性将需要一个单盲或双安慰剂试验设计。

 

This study was carried out to good clinical practice standards.Rigorous inclusion and exclusion criteria were established before the trial to ensure an unambiguous diagnosis of AD. Selection bias in breed, age, sex, weight and clinical severity was not apparent. Atopic dogs were sequentially recruited according to the inclusion and exclusion criteria, and willingness and ability of the owners to participate. They were specifically not recruited according to their spectrum or distribution of clinical signs, coat length or perceived suitability for topical treatment to ensure that they were representative of atopic dogs presented to veterinary clinics. Four random treatment identifiers (A, B, C and D) were used to minimize identifi-cation of treatment group by response, which could have influenced the assessment of dogs subsequently assigned to the same treatment. Ideally, each sequential treatment allocation should have a unique code but this proved logistically impossible given the widespread distribution of the trial sites and wide weight range of subjects (2.1–83 kg). Detection bias was otherwise unlikely as the placebo and HCA sprays were identical, and the investigators and owners remained unaware of the treatment allocation throughout the whole trial. Performance bias was also considered unlikely as there were few concomitant treatments apart from flea control, and these appeared to be distributed evenly between the groups. Attrition bias was present in both parts of the study. In part one, five dogs were lost although on-treatment data were available in four cases permitting ITT analyses. In addition to these cases three more dogs were lost prior to part two of the study. Poor efficacy was an issue in five of eight dogs (although four were on placebo in part one) and it is therefore possible that this biased towards a favourable response to treatment.

本研究按照良好的临床实践标准进行。在试验前建立了严格的纳入和排除标准，以确保AD的明确诊断。对品种、年龄、性别、体重和临床严重程度的选择偏倚不明显。根据纳入和排除标准、宠主参与的意愿和能力，依次招募特应性皮炎犬。他们不是根据他们的频谱或临床症状分布、被毛长度或认为适合外用治疗而特别招募的，以确保他们能代表到兽医诊所就诊的特应性皮炎犬。使用4个随机治疗标识符（A、B、C和D）来减少对治疗组的反应识别，这可能会影响随后被分配到同一治疗的犬的评估。理想情况下，每个顺序治疗分配都应该有一个独特的代码，但考虑到试验地点的广泛分布和受试者的体重范围很广（2.1-83公斤），这在逻辑上被证明是不可能的。在其他方面，由于安慰剂和HCA喷雾剂是相同的，研究人员和宠主在整个试验中仍然不知道治疗分配。表现偏差也被认为是不太可能的，因为除了控制跳蚤外，很少有联合治疗，而且这些治疗似乎在两组之间均匀分布。在研究的两部分中都存在损耗偏倚。在第一部分中，5只犬丢失，尽管有4例允许ITT分析的治疗数据。除了这些病例之外，在研究的第二部分之前，又失去了三只犬。8只犬中有5只的疗效不佳（尽管第一部分有4只服用了安慰剂），因此这可能偏向于对治疗的有利反应。

 

Acknowledgements

The authors are grateful for statistical support from Virbac SA and The University of Liverpool National Centre for Zoonosis Research.

致谢

作者感谢来自Virbac SA和利物浦大学国家人畜共患病研究中心的统计支持。

 

 

 

 

 

杨先生