0.0584%氢化可的松醋丙酯喷雾剂与口服环孢素治疗犬特应性皮炎的 ...

王帆

Comparable efficacy of a topical 0.0584% hydrocortisone aceponate spray and oral ciclosporin in treating canine atopic dermatitis

0.0584%氢化可的松醋丙酯喷雾剂与口服环孢素治疗犬特应性皮炎的疗效比较

 

作者：Tim J. Nuttall, Neil A. McEwan, Emmanuel Bensignor, Luisa Cornegliani, Christine Lowenstein and Christophe A. Reme

 

Abstract

摘要

This study compared the efficacy of a 0.0584% hydrocortisone aceponate (HCA) spray (Cortavance ; Virbac SA) and ciclosporin (Atopica ; Novartis Animal Health) in canine atopic dermatitis in a single-blind randomized controlled trial. Dogs received HCA (two sprays ⁄ 100 cm2 ; n = 24) or ciclosporin (5 mg ⁄ kg; n = 21). Canine Atopic Dermatitis Extent and Severity Index (CADESI)-03, pruritus (visual analog scale with grade descriptors) and owner scores (5-point scales) were recorded every 28 days for 84 days. Intentionto-treat data were analysed. CADESI-03 and pruritus significantly decreased over time (P < 0.0001), but there was no difference between the treatment groups (P = 0.91 and P = 0.52, respectively). Similar proportions of HCA- and ciclosporin-treated dogs achieved ≥50% reductions in CADESI-03 and pruritus scores at 28 days (CADESI-03 58.3 and 57.1%, P = 0.76; pruritus 33.3 and 38.1%, P = 1.0), 56 days (CADESI-03 70.8 and 81.0%, P = 1.0; pruritus 62.5 and 57.1%, P = 1.0) and 84 days (CADESI-03 75 and 85.7%, P = 0.72; pruritus 65.2 and 57.1%, P = 0.76). The CADESI-03 and pruritus scores were close to equivalence (0.47 and 0.51, respectively). By 84 days, every-otherday or twice-weekly therapy was achieved in 13 of 24 HCA- and 12 of 21 ciclosporin-treated dogs (P = 0.85). There were no significant differences in scores for efficacy (P = 0.82), tolerance (P = 0.62) and ease of administration (P = 0.25). Scores for tolerance (0.49) and administration (0.46) were close to equivalence. The score for efficacy favoured HCA (0.68). Mild adverse events were noted in six of 21 ciclosporin and none of 24 HCA dogs (P = 0.008). Five HCA-treated dogs and three ciclosporin-treated dogs were prematurely withdrawn (P = 0.7). In conclusion, HCA and ciclosporin proved equally effective in treating canine atopic dermatitis for up to 84 days.

本研究使用单盲随机对照试验，比较了一种0.0584%氢化可的松醋丙酯(HCA)喷雾剂(皮乐美)和环孢素(阿托皮卡）对犬特应性皮炎的治疗效果。犬接受HCA(2喷/ 100 cm2;N = 24)或环孢素(5 mg / kg;N = 21)。犬特应性皮炎程度和严重程度指数(CADESI)-03、瘙痒(带等级描述的视觉模拟量表)和宠主评分(5分制)每28天记录一次，共记录84天。分析意向治疗数据。随着时间的推移，CADESI-03和瘙痒明显减少(P < 0.0001)，但两组间无差异(P = 0.91和P = 0.52)。相似比例的HCA和环孢素治疗犬在28天CADESI-03和瘙痒评分降低50% (CADESI-03分别为58.3和57.1%，P = 0.76;瘙痒33.3%和38.1%，P = 1.0)， 56天(CADESI-03 70.8%和81.0%，P = 1.0);瘙痒62.5%和57.1%，P = 1.0)和84天(CADESI-03 75和85.7%，P = 0.72;瘙痒率分别为65.2和57.1%，P = 0.76)。CADESI-03和瘙痒评分接近相等(分别为0.47和0.51)。到84天时，24只HCA治疗犬中的13只和21只环孢素治疗犬中的12只实现了隔日一次或每周两次的治疗(P = 0.85)。两组疗效评分(P = 0.82)、耐受性评分(P = 0.62)、给药难易评分(P = 0.25)差异无统计学意义。耐受性评分(0.49)和给药评分(0.46)接近相等。疗效评分偏向于HCA(0.68)。21只环孢素犬中有6只出现轻度不良反应，24只HCA犬无不良反应(P = 0.008)。5只HCA治疗犬和3只环孢素治疗犬过早退出(P = 0.7)。总之，HCA和环孢素在治疗犬特应性皮炎长达84天的效果是一样的。

 

Introduction

介绍

Canine atopic dermatitis (cAD) is a common, chronic, inflammatory dermatosis.1It has become clear that cAD is a complex, multifactorial disease involving interactions between skin structure, the immune system and environmental influences. The complex pathology makes cAD a challenging disease to manage. Treatment options include managing flare factors, bathing and skin care, allergen avoidance, allergen-specific immunotherapy and essential fatty acids, but many atopic dogs require longterm anti-inflammatory medication.

犬特应性皮炎(cAD)是一种常见的慢性炎症性皮肤病。cAD是一种复杂的多因素疾病，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cAD成为一种具有挑战性的疾病。治疗方案包括控制发病因素、洗澡和皮肤护理、避免过敏原、过敏原特异性免疫疗法和必需脂肪酸，但许多特应性皮炎犬需要长期服用抗炎药物。

 

Ciclosporin (Atopica ; Novartis Animal Health, Basel, Switzerland) is a lipophilic cyclic polypeptide with powerful immunosuppressive properties. It is licensed for the treatment of cAD in many countries. Reviews of therapeutic interventions for cAD have concluded that there is good evidence of high efficacy. Randomized controlled trials (RCTs) have demonstrated that oral ciclosporin at 5 mg ⁄ kg once daily is at least as effective as prednisolone and methylprednisolone. Mean reductions in lesion scores ranged from 52 to 67% and those in pruritus scores from 45 to 78%.  Ciclosporin appears to be well tolerated; adverse effects have been reported in up to 81% of treated dogs, but these are mostly mild to moderate, short-duration gastrointestinal upsets. Less common adverse effects can include persistent anorexia, vomiting and diarrhoea, gingival hyperplasia, hirsutism, verrucose papillomatosis, lameness, insulin resistance, allergic reactions and seizures. These, however, usually resolve on lowering the dose and ⁄ or withdrawing the drug.

环孢素(阿托皮卡)是一种亲脂性环状多肽，具有强大的免疫抑制特性。它在许多国家被许可用于治疗cAD。对cAD治疗干预的回顾已经得出结论，有充分的证据表明其疗效高。随机对照试验(RCT)表明，口服环孢素5 mg / kg，每日一次，至少与泼尼松龙和甲基泼尼松龙一样有效。病变评分的平均下降幅度为52%至67%，瘙痒评分的平均下降幅度为45%至78%。环孢素似乎耐受性良好;据报道，在接受治疗的犬中，高达81%的犬出现了不良反应，但这些反应大多是轻度至中度的、短时间的胃肠道不适。不太常见的不良反应包括持续性厌食、呕吐和腹泻、牙龈增生、多毛、疣状乳头状瘤病、跛行、胰岛素抵抗、过敏反应和癫痫发作。然而，这些问题通常通过降低剂量或停药来解决。

 

The topical diester glucocorticoid hydrocortisone aceponate (HCA; Cortavance ; Virbac SA, Carros, France) is a 0.0584% spray formulation licensed in many countries (although not in the Americas) for up to 70 days treatment of pyotraumatic dermatitis, flea allergic dermatitis and other inflammatory dermatoses in dogs. Nonhalogen ated, diester topical glucocorticoids avoid many of the adverse effects seen with traditional topical glucocorticoids by virtue of their metabolism into largely inactive moieties within the skin. The absence of a halogen at C6, C9 or C21 is associated with better local and systemic tolerance, acetate esterification at C21 increases stability, and propionate esterification at C17 enhances anti-inflammatory activity. Double esterification also enhances penetration of the drug through the stratum corneum and ensures specific metabolism in the deep dermis. This minimizes effects on hair follicles, dermal fibroblasts and blood vessels, decreasing the likelihood of local cutaneous and systemic adverse effects. An RCT demonstrated good efficacy in cAD; mean reductions in lesion scores and pruritus were 61.4 and 38.8%, respectively, with the majority of dogs achieving >50% reductions. Hydrocortisone aceponate appears to be well tolerated; no adverse effects were seen after 70 days treatment in the RCT or after 8 weeks treatment of healthy dogs, but a significant decrease in dermal thickness was noted after 14 days treatment in another study. Recent practice guidelines recommended the use of this product in managing both acute and chronic cAD.

外用一种0.0584%的二酯糖皮质激素氢化可的松醋丙酯(HCA;皮乐美)是喷雾制剂，已在许多国家(但不是在美国)获得许可，用于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长达70天。无卤素、双酯外用糖皮质激素避免了传统外用糖皮质激素的许多副作用，因为它们在皮肤内代谢成大部分不活跃的部分。C6、C9或C21处无卤素与更好的局部和全身耐受性有关，C21处醋丙酯化增加了稳定性，C17处丙酸酯化增强了抗炎活性。双重酯化也增强了药物通过角质层的渗透，并确保了真皮深层的特定代谢。这最大限度地减少了对毛囊、真皮成纤维细胞和血管的影响，降低了局部皮肤和全身不良反应的可能性。一项随机对照试验显示对cAD有良好的疗效;病变评分和瘙痒的平均降幅分别为61.4%和38.8%，大多数犬的降幅大于50%。氢化可的松醋丙酯似乎耐受性良好;在RCT中，治疗70天后或健康犬治疗8周后未见不良反应，但在另一项研究中，治疗14天后皮肤厚度显着下降。最近的实践指南推荐使用本品管理急性和慢性cAD。

 

The RCT, however, evaluated HCA against a placebo spray. Comparison against a placebo can overestimate treatment effect, and it is useful to compare novel treatments against an established active control of known efficacy. The aim of this single-blind RCT, therefore, was to compare the efficacy of HCA and ciclosporin in the treatment of cAD. Ciclosporin was chosen as the active control because it is licensed for the management of cAD and has a known, published evidence base for efficacy and safety. Comparison with a 1% triamcinolone spray (Genesis ; Virbac Animal Health, Fort Worth, TX, USA) would have been useful, but this product is not licensed or available in Europe. Systemic glucocorticoids were not included as an active control because of the risk of adverse effects and owner reluctance to use this medication.

然而，RCT将HCA与安慰剂喷雾进行了对比。与安慰剂比较可能会高估治疗效果，将新疗法与已知疗效的既定积极对照进行比较是有用的。因此，这项单盲随机对照试验的目的是比较HCA和环孢素治疗cAD的疗效。选择环孢素作为主动对照，是因为它被许可用于cAD的管理，并且有已知的、已发表的有效性和安全性的证据基础。与1%曲安奈德喷雾剂进行对比可能是有用的，但该产品在欧洲没有许可或可用。由于存在不良反应的风险以及宠主不愿使用这种药物，全身性糖皮质激素未被纳入主动对照。

 

Materials and methods

材料与方法

Study patients

研究对象

The study was performed in accordance with ethical guidelines laid down by The University of Liverpool and Virbac SA. Dogs with a clinical diagnosis of cAD according to accepted criteria17,18 were recruited from five European dermatology referral centres (in the UK, Germany, France and Italy). It was estimated that with a mean baseline Canine Atopic Dermatitis Extent and Severity Index (CADESI)-0319 score of 120 and a mean 60% reduction in the treatment groups with an SD of ±30%, 25 dogs in each group would be required to detect significant differences in response with >95% power. With the actual CADESI-03 outcomes and intention-to-treat data, the calculated power of the study was 94%.

这项研究是按照利物浦大学和Virbac SA制定的道德准则进行的。从五个欧洲皮肤病转诊中心(英国、德国、法国和意大利)招募了根据公认标准临床诊断为cAD的犬。据估计，平均基线犬特应性皮炎程度和严重程度指数(CADESI)-0319评分为120，治疗组平均减少60% (SD为±30%)，每组需要25只犬才能以>95%的功率检测到显著差异。根据CADESI-03的实际结果和意向治疗数据，该研究的计算功率为94%。

 

Trial protocol

试验协议

Dogs with cAD that fulfilled the entry criteria (Table 1) were randomly allocated to receive either 0.0584% HCA or ciclosporin according to a computer-generated random sequence established before the trial. Treatment allocation and compliance assessments were made by a dispenser who did not participate in any clinical assessments. Owners were instructed to apply the spray once daily to affected skin only from 10 cm away at a dose rate of two sprays per 100 cm2 of affected skin. The ciclosporin was administered at 5 mg ⁄ kg orally once daily on an empty stomach, although administration with food was allowed if necessary. Clinical assessments were performed on days 0, 28, 56 and 84 by investigators blinded to the treatment allocation. Each dog was examined by the same investigator throughout the trial to minimize interobserver variability. The investigators were all experienced referral dermatologists recognized by the European College of Veterinary Dermatology and ⁄ or the Royal College of Veterinary Surgeons. The total possible CADESI-03 scores range from 0 to 1260. The scores were used to define severity as follows: remission, 0–15; mild cAD, 16–59; moderate cAD, 60–119; severe cAD, ≥120. If the CADESI-03 decreased to 59 or less (i.e. in remission or mild cAD as assessed by CADESI-03) at the re-examinations on days 28 or 56, the frequency of administration was reduced to every other day and then twice weekly. If the clinical signs subsequently worsened, the frequency of treatment was increased. Investigators performed a thorough clinical examination at each visit, recording and investigating any adverse events as appropriate.

根据试验前计算机生成的随机序列，符合入组标准(表1)的cAD犬被随机分配接受0.0584% HCA或环孢素治疗。治疗分配和依从性评估由不参与任何临床评估的配药人员进行。宠主被要求每天在10厘米外的患病皮肤上喷一次喷雾，剂量率为每100平方厘米喷两次。环孢素以5 mg / kg的剂量空腹口服，每日1次，但必要时允许与食物一起给药。临床评估在第0、28、56和84天进行，研究者对治疗分配不知情。在整个试验过程中，每只犬都由同一名调查员检查，以尽量减少观察者之间的差异。研究人员均为欧洲兽医皮肤科学院或英国皇家兽医外科学院认可的经验丰富的转诊皮肤科医生。CADESI-03总分从0到1260分不等。评分用于定义严重程度如下:缓解，0-15;轻度cAD, 16-59;中等cAD, 60-119;重度cAD，≥120。如果在第28天或第56天复查时，CADESI-03评分降至59分或更低(即CADESI-03评估为缓解或轻度cAD)，则给药频率降至隔日一次，然后改为每周两次。如果临床症状随后恶化，则增加治疗频率。调查人员在每次就诊时进行彻底的临床检查，记录和调查任何适当的不良事件。

 

Outcome measures

结果测量

The outcome measures were the CADESI-03, pruritus and owner global evaluation scores (Table 2). Pruritus was assessed using a vertical 10 cm visual analog scale with grade descriptors (Figure 1). Owners were asked to mark the scale with a short horizontal line according to their perception of their dog’s pruritus over the preceding 24 h. The pruritus score was the distance in millimetres from the bottom edge of the scale to their mark.

结果测量是CADESI-03，瘙痒和宠主整体评估分数(表2)。瘙痒使用带有等级描述的垂直10厘米视觉模拟量表进行评估(图1)。要求宠主根据他们在过去24小时内对犬瘙痒的感知用短水平线标记量表。瘙痒评分是从量表底边到他们标记的距离，以毫米为单位。

 

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 analyses using the last treatment value carried forward.

如果犬需要禁用药物治疗，经历不可接受的不适或依从性差，则会被撤回。宠主可以在任何时候自由地退出他们的动物。使用结转的最后治疗值记录给药结束评估以进行意向治疗分析。

 

Two-way repeated-measures ANOVAs were used to evaluate the changes in CADESI-03 and pruritus scores between the treatment groups from day 0 to 84. Noninferiority was tested using Wilcoxon–Mann–Whitney tests with a simultaneous Wei–Lachin procedure. The benchmark values for equivalence were set at 0.36 and 0.64, which refer to a medium-sized difference, assuming a standardized difference of 0.5.25 The proportions of dogs in each treatment group that could be maintained on daily, every-other-day or twice-weekly therapy were tested with the Mantel–Haenszel test. The time to first antimicrobial and ⁄ or glucocorticoid intervention in each group was described using a survival-type analysis. The proportions of dogs in each treatment group that required treatment with antimicrobials and ⁄ or systemic glucocorticoids were analysed with a Peto’s log rank test. Fisher’s exact tests or chi-squared tests were used to analyse differences in the proportions of dogs that achieved ≥50% reductions in CADESI-03 and pruritus scores from baseline to days 28, 56 and 84, and the frequency of treatment-related adverse events. Fisher’s exact tests and Student’s unpaired t-tests were used to analyse the demographic data. The level of statistical signifi-cance was set at P < 0.05 (two-sided).

采用双向重复测量方差分析(anova)来评估治疗组从第0天到第84天CADESI-03和瘙痒评分的变化。采用Wilcoxon-Mann-Whitney检验并同时采用Wei-Lachin程序进行非劣效性检验。等效基准值分别设为0.36和0.64，即中等差异，假设标准化差异为0.5.25。通过Mantel-Haenszel检验，每个治疗组中可以维持每日、隔日一次或每周两次治疗的犬的比例。使用生存型分析描述各组首次抗菌和/或糖皮质激素干预的时间。通过Peto对数秩检验分析每个治疗组中需要使用抗菌剂和全身糖皮质激素治疗的犬的比例。使用Fisher精确检验或卡方检验来分析从基线到第28、56和84天CADESI-03和瘙痒评分降低≥50%的犬的比例的差异，以及治疗相关不良事件的频率。使用Fisher精确检验和Student非配对t检验来分析人口统计数据。P < 0.05为差异有统计学意义(双侧)。

 

 

Table 1. Inclusion and exclusion criteria

表1纳入和排除标准

Inclusion criteria纳入标准

1. At least 18 months of age 1:至少18月龄

2. History of perennial pruritus 2：全年性瘙痒病史 3. Clinical diagnosis of atopic dermatitis 3：临床诊断为特应性皮炎

4. No response to a minimum 6 week novel (home-cooked or commercial) or hydrolysed exclusion diet. Dogs should be stabilized on their usual diet for at least 2 weeks prior to the trial, which should be maintained during the study 4：对至少6周的新奇蛋白(家庭自制或商业化)或水解粮食物排查无反应。试验前至少2周应保持犬日常饮食稳定，并在研究期间保持

5. No response to a veterinary-approved flea-control regimen for at least 8 weeks and monthly flea control maintained throughout the trial 5：对兽医批准的跳蚤控制方案至少8周没有反应，并且在整个试验期间保持每月跳蚤控制

6. Sarcoptic mange excluded by trial therapy and ⁄ or negative serology 6：经试验治疗或血清学阴性排除疥螨病

7. CADESI ≥6 (i.e. at least mild atopic dermatitis as assessed by CADESI-03) 7. CADESI≥6(即至少轻度特应性皮炎，由CADESI-03评估)

8. Allergen-specific immunotherapy permitted if used for >12 months, the dose remains unchanged for 6 months, the clinical signs are stable and the regimen is maintained during the trial 8：如果使用>12个月，允许使用过敏原特异性免疫治疗，剂量保持6个月不变，临床症状稳定，在试验期间维持该方案

9. Essential fatty acids permitted if in use for >8 weeks, the clinical signs are stable and the dosing regimen is maintained during the trial 9：必需脂肪酸允许使用>8周，临床症状稳定，试验期间维持给药方案

10. Owner’s written informed consent has been obtained 10：已取得业宠主的书面知情同意

Exclusion criteria排除标准

1. Clinical evidence of ectoparasite infestation 1：临床证明有外寄生虫感染

2. Clinical evidence of bacterial or fungal infections 2：临床证明有细菌或真菌感染

3. Antimicrobial therapy or prostaglandins within 7 days 3：7天内使用过抗生素治疗或前列腺素治疗

4. Antihistamines within 14 days 4：14天内使用过抗组胺药

5. Oral or topical glucocorticoids or ciclosporin within 21 days 5:21天内口服或外用过糖皮质激素或环孢素

6. Parenteral depot glucocorticoids within 56 days 6：56天内注射过糖皮质激素

7. Initiated or discontinued essential fatty acids within 56 days 7:56天内早期使用或持续使用过EFA

8. Allergen-specific immunotherapy discontinued within 6 months or initiated within 12 months 8:6个月内或12个月内早期时进行过ASIT治疗

9. Pregnancy or breeding activity 9：怀孕期或哺乳期

10. Concurrent condition that may deteriorate during the study 10：研究期间出现可能加重的并发病

 

 

 

Figure 1. Visual analog scale with grade descriptors to evaluate pruritus. The owners were asked to mark the vertical line with a short horizontal line at the point they felt most closely matched their perception of their dog’s pruritus over the preceding 24 h.

图1。带有等级描述的视觉模拟量表来评估瘙痒。宠主们被要求在他们认为与之前24小时内他们对犬瘙痒的感觉最接近的点上画一条短水平线。。

 

Results

结果

Demographic data

统计数据

Twenty-five dogs from 15 breeds and crosses were enrolled in the HCA group, and 23 dogs from 10 breeds and crosses in the ciclosporin group. The range of breeds did not appear to differ between the groups, but the low numbers of each breed prevented statistical analysis. There were no significant differences in age (HCA, mean 5.3 years, range 1.5–12; and ciclosporin, mean 6.0 years, range 1.1–10; Student’s unpaired t-test, P = 0.33), sex (HCA, 9 female, 14 male; and ciclosporin, 11 female, 10 male; Fisher’s exact test, P = 0.55) or weight (HCA, mean 24.5 kg, range 4.2–68; and ciclosporin, mean 17.4 kg, range 3.8–46; Student’s unpaired t-test, P = 0.1). Apart from flea control, none of the dogs received any concomitant therapy throughout the trial.

来自15个品种和杂交的25只犬被纳入HCA组，来自10个品种和杂交的23只犬被纳入环孢素组。两组之间的品种范围似乎没有差异，但每个品种的数量都很低，无法进行统计分析。年龄差异无统计学意义(HCA，平均5.3岁，范围1.5-12;环孢素，平均6.0年，范围1.1-10;学生非配对t检验，P = 0.33)，性别(HCA，雌性9只，雄性14只;环孢素，雌性11只，雄性10只;Fisher精确检验，P = 0.55)或体重(HCA，平均24.5 kg，范围4.2-68;环孢素平均17.4 kg，范围3.8-46;学生非配对t检验，P = 0.1)。在整个试验过程中，除了跳蚤控制外，没有一只犬接受任何联合治疗。

 

Intention-to-treat analyses

意向处理分析

Eight dogs were prematurely withdrawn at the owner’s request, on grounds of poor efficacy and ⁄ or for requiring treatment with a prohibited medication, as follows: HCA group, one dog between days 0 and 28, two dogs between days 28 and 56, and two dogs between days 56 and 84; and ciclosporin group, one dog between days 0 and 28, and two dogs between days 56 and 84 (Fisher’s exact test, P = 0.7). On-treatment data were used for intention-to-treat analyses using the last treatment carried forward technique. One HCA-treated dog and two ciclosporin-treated dogs were excluded because of insufficient on-treatment data. There were no other significant protocol deviations in either group.

8只犬因疗效不佳或需要使用禁用药物治疗而应宠主要求提前退出，如下:HCA组，1只犬在第0至28天，2只犬在第28至56天，2只犬在第56至84天;和环孢素组，0 - 28天1只犬，56 - 84天2只犬(Fisher精确检验，P = 0.7)。使用最后一次治疗结转技术，将治疗数据用于意向治疗分析。由于治疗数据不足，1只HCA治疗犬和2只环孢素治疗犬被排除在外。两组均无其他显著的方案偏差。

 

CADESI-03

The CADESI-03 scores in both treatment groups significantly decreased over time (two-way repeated-measures ANOVA, P < 0.0001; Figure 2). There was, however, no difference in response between the HCA- and ciclosporin-treated dogs (P = 0.91). There was also no significant time–treatment interaction (P = 0.57), indicating that treatment effects were consistent at each time point. Reductions of CADESI-03 scores following treatment with HCA and ciclosporin were nearly equivalent (0.47; lower and upper bounds 0.36–0.58), with no significant difference in treatment effect (Wilcoxon–Mann–Whitney ⁄ Wei–Lachin test, P = 0.67).

两治疗组的CADESI-03评分均随时间显著降低(双向重复测量方差分析，P < 0.0001;图2)。然而，HCA和环孢素治疗犬的反应没有差异(P = 0.91)。也没有显著的时间-治疗相互作用(P = 0.57)，表明治疗效果在每个时间点是一致的。HCA和环孢素治疗后CADESI-03评分的降低几乎相等(0.47;下界0.36 ~ 0.58)，治疗效果差异无统计学意义(Wilcoxon-Mann-Whitney / Wei-Lachin检验，P = 0.67)。

 

Similar proportions of the HCA- and ciclosporin-treated dogs achieved ≥50% reductions in CADESI-03 compared with baseline at days 28, 56 and 84. There were no significant differences in response between the two treatment groups at any time point (Table 3).

类似比例的HCA和环孢素治疗犬在28,56和84天与基线相比，CADESI-03降低≥50%。两个治疗组在任何时间点的疗效均无显著差异(表3)。

 

On day 0, 21 of 23 HCA-treated dogs and 19 of 21 ciclosporin-treated dogs had moderate or severe cAD as assessed by the CADESI-03. By day 84, only three dogs in each group had moderate cAD and only two dogs in each group had severe cAD. Of the dogs that completed the trial (i.e. per-protocol rather than intention-to-treat data), only one HCA-treated dog and two ciclosporin-treated dogs had moderate cAD; the remainder had mild cAD or were in remission.

在第0天，根据CADESI-03评估，23只HCA治疗犬中有21只和21只环孢素治疗犬中有19只出现中度或重度cAD。到第84天，每组中只有3只犬患有中度cAD，每组中只有2只犬患有重度cAD。在完成试验的犬中(即按方案而不是意向治疗数据)，只有一只HCA治疗的犬和两只环孢素治疗的犬患有中度cAD;其余的患有轻度cAD或处于缓解期。

 

Pruritus

瘙痒

The pruritus scores in both the HCA- and the ciclosporintreated dogs significantly decreased over time (two-way repeated-measures ANOVA, P < 0.0001), but there was no difference between the groups (P = 0.52; Figure 3). There was no significant time–treatment interaction (P = 0.46), suggesting that the treatment effects were consistent throughout the trial. The decreases in the pruritus scores were nearly equivalent (0.51; lower and upper bounds 0.35–0.68). There was no significant difference between the treatment effects (P = 0.88), although this finding could not be confirmed, because the lower and upper bounds were out of the predefined benchmarks for equality.

HCA和环孢素治疗犬的瘙痒评分均随时间显著降低(双向重复测量方差分析，P < 0.0001)，但组间无差异(P = 0.52;图3)。没有显著的时间-治疗相互作用(P = 0.46)，表明治疗效果在整个试验中是一致的。瘙痒评分的下降几乎相等(0.51;下界和上界0.35-0.68)。治疗效果之间没有显著差异(P = 0.88)，但这一发现无法得到证实，因为下限和上限超出了预定义的平等基准。

 

Similar proportions of the HCA- and ciclosporin-treated dogs achieved ≥50% reductions in pruritus scores compared with baseline at days 28, 56 and 84. There were no significant differences in response between the two treatment groups at any time point (Table 4).

类似比例的HCA和环孢素治疗犬在第28、56和84天与基线相比，瘙痒评分降低≥50%。两个治疗组在任何时间点的疗效均无显著差异(表4)。

 

Owners’ global evaluation scores

宠主的整体评价分数

The owners’ scores for efficacy (two-way repeated-measures ANOVA, P = 0.008), tolerance (P = 0.02) and ease of administration (P = 0.01) all significantly improved during the trial (Figure 4). There was, however, no significant difference between the HCA and ciclosporin treatment groups (efficacy, P = 0.82; tolerance, P = 0.62; and ease of administration, P = 0.25). There was no significant time–treatment interaction (efficacy, P = 0.72; tolerance, P = 0.52; and ease of administration, P = 1.0), indicating that the changes in scores were consistent at each time point.

在试验期间，宠主的疗效(双向重复测量方差分析，P = 0.008)、耐受性(P = 0.02)和给药方便性(P = 0.01)得分均显著提高(图4)。然而，HCA和环孢素治疗组之间无显著差异(疗效，P = 0.82;公差，P = 0.62;给药难易程度，P = 0.25)。两组间无显著的时间-治疗交互作用(疗效，P = 0.72;公差，P = 0.52;和给药难易程度，P = 1.0)，说明各时间点评分变化一致。

 

On day 84, the owners’ scores for tolerance (0.49; lower to upper bound 0.34–0.64; P = 1.0) and ease of administration (0.46; lower to upper bound 0.30–0.62; P = 0.75) were close to equivalence, although this could not be confirmed because the lower bounds were out of the predefined benchmarks for equality. The score for efficacy favoured HCA (0.68; upper to lower bound 0.53–0.84; P = 0.03).

第84天，宠主容忍度评分(0.49;上下界0.34-0.64;P = 1.0)和给药容易程度(0.46;上下界0.30-0.62;P = 0.75)接近相等，但这不能得到证实，因为下限超出了预定义的相等基准。疗效评分倾向于HCA (0.68;上下限0.53-0.84;P = 0.03)。

 

 

Figure 2. CADESI-03 scores in the hydrocortisone aceponate- (n = 24; HCA) and ciclosporin-treated dogs (n = 21; means ± SD).

图2。氢化可的松醋丙酯治疗组CADESI-03评分(n = 24;HCA)和环孢素治疗组犬(n = 21;平均值±SD)。

 

Figure 3. Pruritus scores in the hydrocortisone aceponate- (n = 24; HCA) and ciclosporin-treated dogs (n = 21; means ± SD).

图3。瘙痒评分在氢化可的松醋丙酯治疗组(n = 24;HCA)和环孢素治疗组犬(n = 21;平均值±SD)。

 

 

表3.氢化可的松醋丙酯治疗组（HCA）和环孢素治疗组犬CADESI-03评分与基线相比降低50%的比例

 

 

 

表4.在每个时间点，氢化可的松醋丙酯治疗组（HCA）和环孢素治疗组的犬瘙痒评分与基线相比降低50%的比例

 

 

Frequency of treatment

治疗频率

The ability to reduce the frequency of dosing while maintaining the dogs in remission was similar in the HCA and ciclosporin treatment groups (Table 5). Overall, 38% of the HCA group and 48% of the ciclosporin group could be maintained on every-other-day treatment from day 28 to 56. From day 56 to 84, 54% of the HCA group and 57% of the ciclosporin group could be maintained on every-other-day or twice-weekly treatment. One dog in each group required an increase in dose frequency following worsening of their clinical signs at day 56. There were, however, no significant differences between the two treatment groups (Mantel–Haenszel test, P = 0.85).

HCA和环孢素治疗组在减少给药频率的同时保持犬缓解状态的能力相似(表5)。总体而言，从第28天到第56天，HCA组的38%和环孢素组的48%可以维持隔日一次的治疗。从第56天到第84天，54%的HCA组和57%的环孢素组可以维持隔日一次或每周两次的治疗。在第56天临床症状恶化后，每组有一只犬需要增加剂量频率。然而，两个治疗组之间无显著差异(Mantel-Haenszel检验，P = 0.85)。

 

Time to first intervention with antimicrobials or glucocorticoids

首次使用抗菌剂或糖皮质激素进行干预的时间

Two dogs in the HCA treatment group received a single course of topical antimicrobial ⁄ glucocorticoid treatment at day 56. One dog in the ciclosporin group received systemic antimicrobial treatment at day 28 and two dogs were treated at day 56. These dogs were excluded at the point of intervention and data carried forward for intention-to-treat analysis (see intention to treat analyses above). No other treatment interventions were reported in either group. There was no significant difference in the frequency or time to intervention between the HCA- and ciclosporin-treated groups (Peto’s log rank test, P = 0.81).

HCA治疗组2只犬在第56天接受单疗程的外用抗菌/糖皮质激素治疗。环孢素组1只犬在第28天接受全身抗菌治疗，2只犬在第56天接受治疗。这些犬在干预点被排除，数据结转用于意向治疗分析(见上文的意向治疗分析)。两组均无其他治疗干预措施的报道。HCA治疗组和环孢素治疗组在干预频率和时间上无显著差异(Peto log rank检验，P = 0.81)。

 

Figure 4. Owner assessments of ease of administration, tolerance and efficacy (0–5 scale; 0 = very poor and 5 = excellent) in the hydrocortisone aceponate (n = 24; HCA) and ciclosporin treatment groups (n = 21; mean ± SD).

图4。宠主对用药难易程度、耐受性和疗效的评估(0-5分);0 =极差，5 =优)HCA组(n = 24;HCA)和环孢素治疗组(n = 21;平均值±SD)。

 

 

Table 5. Frequency of treatment with hydrocortisone aceponate (HCA) spray or ciclosporin required to maintain the treated dogs in remission

表5。用氢化可的松醋丙酯(HCA)喷雾剂或环孢素维持治疗犬缓解所需的治疗频率

 

 

Adverse events

不良事件

Both treatments were very well tolerated throughout the study. No adverse events attributable to the trial therapy were reported in the HCA group, although one dog required treatment for a traumatic limb injury on day 56. Seven adverse events possibly associated with ciclosporin therapy were seen in six dogs, as follows: day 28, vomiting (2), diarrhoea and vomiting (1), vomiting and anorexia (1) and diarrhoea (1); day 56, vomiting (1); and day 84, vomiting (1). The frequency of adverse events was significantly higher in the ciclosporin group (Fisher’s exact test, P = 0.008). All the adverse events, however, were mild and short term, and did not require cessation of therapy or dose adjustment.

在整个研究过程中，两种治疗方法的耐受性都很好。在HCA组中没有报告可归因于试验治疗的不良事件，但有一只犬在第56天因创伤性肢体损伤而需要治疗。在6只犬中观察到可能与环孢素治疗相关的7个不良事件，分别是:第28天，呕吐(2)，腹泻和呕吐(1)，呕吐和厌食(1)和腹泻(1);第56天，呕吐1例;第84天出现呕吐(1)。环孢素组不良事件发生频率显著高于环孢素组(Fisher精确检验，P = 0.008)。然而，所有不良事件都是轻微和短期的，不需要停止治疗或调整剂量。

 

Discussion

讨论

This study shows that a topical 0.0584% HCA spray and systemic ciclosporin are both highly effective treatments for cAD. A majority of dogs in both groups achieved >50% reductions in clinical lesion and pruritus scores, the point conventionally used to denote a significant clinical improvement. Most dogs, furthermore, were classified as having mild cAD or were in clinical remission at the end of the trial. The response to treatment was very similar in both groups, with no significant differences in CADESI-03 scores, pruritus scores and the number of dogs that achieved >50% reductions in CADESI-03 and pruritus scores. There were, furthermore, no significant differences in the time to therapeutic intervention, or owner assessments of efficacy, tolerance and ease of administration. Noninferiority, however, could not be proved for all scores because the lower and upper bounds were out of the predefined benchmarks for equality due to the low power of the study design. This is probably because the study was designed to evaluate the comparative efficacy of HCA spray and ciclosporin in treating cAD. Equivalence studies to prove noninferiority of one intervention compared with another typically require very large numbers of dogs. The owner assessments of efficacy did reveal a small but significant superiority in the HCA group. The owner assessments, however, were not blinded and were therefore vulnerable to detection bias.

本研究表明，外用一种0.0584%的HCA喷雾剂和全身环孢素都是治疗cAD的有效方法。两组中的大多数犬在临床病变和瘙痒评分上都达到了>50%的减少，这是通常用来表示显着临床改善的点。此外，大多数犬在试验结束时被归类为轻度cAD或处于临床缓解期。两组对治疗的反应非常相似，在CADESI-03评分、瘙痒评分以及CADESI-03和瘙痒评分降低>50%的犬的数量方面没有显著差异。此外，在治疗干预的时间，或宠主对疗效，耐受性和给药难易程度的评估方面，没有显着差异。然而，由于研究设计的低功效性，下界和上界超出了预定义的平等基准，因此无法证明所有分数都是非劣效性。这可能是因为该研究旨在评估HCA喷雾剂和环孢素治疗cAD的比较疗效。证明一种干预与另一种干预相比具有非劣效性的等效性研究通常需要大量的犬。宠主对疗效的评估确实显示了HCA组的小而显著的优势。然而，宠主评估不是盲法的，因此容易受到检测偏差的影响。

 

The clinical response was fairly rapid, with most of the improvement in clinical lesions and pruritus noted at day 28. Thereafter, it was possible to reduce the frequency of dosing while maintaining the clinical improvement in most dogs. The majority could be maintained on HCA spray or ciclosporin administered every other day or less often, although the longer term response was variable between dogs. This is similar to results published in other studies. Variation in the frequency of long-term medication needed to maintain remission of cAD may be due to the inherent severity of condition, environment (e.g. allergen or irritant exposure), genotypic differences in response to drug therapy or with medication administration. These results are nevertheless encouraging, because monotherapy for cAD is not normally recommended. It is therefore possible that additional therapy, such as skin barrier care, allergen avoidance and allergen-specific immunotherapy, would permit less frequent treatment in more dogs. It is also possible to maintain remission in dogs treated with ciclosporin by continuing once-daily administration but reducing the dose.It is therefore possible that some of the dogs that required daily ciclosporin in this study could have been maintained on a lower dose. Daily dose reduction was not possible with the HCA spray, and therefore the study design only allowed adjustment of the frequency of treatment to allow comparison between the two treatment groups.

临床反应相当迅速，大部分临床病变和瘙痒在第28天得到改善。此后，有可能减少给药频率，同时保持大多数犬的临床改善。大多数可以维持隔日一次或更少的时间使用HCA喷雾或环孢素，但犬之间的长期反应是不同的。这与其他研究发表的结果相似。维持cAD缓解所需的长期用药频率的变化可能是由于固有的病情严重程度、环境(如过敏原或刺激物暴露)、对药物治疗或药物管理反应的基因型差异。尽管如此，这些结果还是令人鼓舞的，因为cAD的单药治疗通常不被推荐因此，其他治疗，如皮肤屏障护理、过敏原避免和过敏原特异性免疫治疗，可能会减少更多犬的治疗频率。用环孢素治疗的犬也有可能通过继续每天给药一次但减少剂量来维持缓解。因此，在这项研究中，一些每天需要环孢素的犬可能会维持较低的剂量。HCA喷雾不可能减少每日剂量，因此研究设计只允许调整治疗频率，以便在两个治疗组之间进行比较。

 

There were few cases of otitis or pyoderma in the HCA and ciclosporin treatment groups, although 26 of the 48 enrolled dogs had required topical or systemic antimicrobial and ⁄ or glucocorticoid treatment in the 3 months prior to the trial (data not shown). This indicates that these infections are secondary to changes in the cutaneous microenvironment that favour bacterial and ⁄ or Malassezia colonization and infection. Secondary infections are common in cAD, although virtually all infections appear to be associated with commensal organisms. Control of inflammation therefore appears to be important in helping to prevent colonization and infection of the skin. Nonantimicrobial methods of controlling infection will be important in limiting the development of antimicrobial resistance. This apparent antimicrobial effect of antiinflammatory medication therefore warrants further study.

在HCA和环孢素治疗组中，很少有耳炎或脓皮病的病例，但在试验前3个月，48只入组犬中有26只需要外用或全身抗菌和/或糖皮质激素治疗(数据未显示)。这表明，这些感染是继发于皮肤微环境的变化，有利于细菌和/或马拉色菌的定植和感染。继发性感染在cAD中很常见，但几乎所有的感染似乎都与共生微生物有关。因此，控制炎症在帮助防止皮肤定植和感染方面显得很重要。控制感染的非抗生素方法对于限制抗生素耐药性的发展将是重要的。因此，抗炎药物的这种明显的抗菌作用值得进一步研究。

 

It is interesting that the owner scores for ease of administration were similar in each group. The owners did not, therefore, appear to regard topical application of the HCA spray as more onerous than administration of the ciclosporin capsules. The results may, however, have been different in a cross-over study that would have allowed each owner to compare the treatment modalities directly. There was some variation in the scores, which probably represented a spectrum of easy and difficult dogs to medicate in both groups. The equivalence analysis revealed a nonsignificant superiority of ciclosporin at day 28, although no trends were seen at days 56 and 84. It is therefore possible that owners found the spray easier to administer with time, as they and their dogs became more used to it and ⁄ or treatment was required less often.

有趣的是，在每一组中，宠主对易于管理的得分是相似的。因此，宠主似乎并不认为外用HCA喷雾剂比使用环孢素胶囊更麻烦。然而，在交叉研究中，结果可能会有所不同，因为交叉研究允许每个宠主直接比较治疗方式。在得分上有一些变化，这可能代表了两组容易和困难的犬的用药范围。等效性分析显示环孢素在第28天的优势不显著，但在第56天和第84天没有发现趋势。因此，宠主可能会发现随着时间的推移，这种喷雾更容易使用，因为他们和他们的犬变得更习惯了，而且需要的治疗次数也减少了。

 

Both treatments were very well tolerated. There were no adverse events attributable to HCA treatment. Blood parameters or adrenal function were not measured, although no significant changes were seen following treatment for up to 70 days in a previous study.There was no clinical evidence of cutaneous atrophy or secondary infection, as noted in a previous study, although more recently cutaneous atrophy following 14 days treatment has been reported.Adverse events were significantly more frequent in the ciclosporin group, although this is of doubtful clinical significance because these were all minor gastrointestinal upsets that did not require specific therapy or changes to treatment. Gastrointestinal disturbances associated with ciclosporin therapy are well recognized, but the majority are mild and transient. The results of this trial indicate that both HCA spray and ciclosporin have a better benefit:risk profile than other anti-inflammatory agents, such as antihistamines, arofylline, misoprostol, traditional topical glucocorticoids and systemic glucocorticoids. This study, however, only followed dogs for a maximum of 84 days, and as cAD is usually a lifelong condition, good pharmacovigilance and longer term studies of safety are warranted.

两种治疗方法的耐受性都很好。HCA治疗未引起的不良事件。血液参数或肾上腺功能没有被测量，但在之前的研究中，在长达70天的治疗后没有发现明显的变化。没有临床证据表明皮肤萎缩或继发感染，正如先前的研究所指出的，但最近有报道在治疗14天后出现皮肤萎缩。环孢素组的不良事件明显更频繁，但这在临床意义上值得怀疑，因为这些都是轻微的胃肠道不适，不需要特定的治疗或改变治疗。与环孢素治疗相关的胃肠道紊乱是公认的，但大多数是轻微和短暂的。本试验结果表明，HCA喷雾剂和环孢素比其他抗炎药(如抗组胺药、阿罗茶碱、米索前列醇、传统的外用糖皮质激素和全身糖皮质激素)具有更好的获益风险。然而，这项研究只对犬进行了最多84天的随访，由于cAD通常是终身疾病，因此需要良好的药物警惕性和更长期的安全性研究。

 

Where possible, this study used reported and validated outcome measures. The CADESI-03 has high intra- and interobserver reliability, and is a relevant and reliable assessment of clinical severity.  The lesion scores encompass features of acute and chronic inflammation, but only provide an indirect assessment of pruritus through excoriation. Direct pruritus scores, in contrast, have not been studied or validated to the same extent. Studies have questioned the reliability and repeatability of simple visual analog scale scores, and the combined visual analog scale with behavioural descriptors used in this study has been found to be superior. Nevertheless, while validated lesion and pruritus scores are useful for evaluating and comparing treatment, it is likely that quality of life is more important to owners and their dogs. It has been difficult to assess quality of life reliably, and studies have often reported global evaluation scores. These, however, can be misleading; for example, in an earlier trial of the HCA spray, some owners found the global score contradictory because they found the spray efficacious but difficult to apply. This study therefore divided the owners’ evaluation into efficacy, ease of application and tolerance. Very recently, quality-of-life questionnaires have been developed and validated. Future studies of therapeutic interventions should evaluate these alongside clinical lesion and pruritus scores.

在可能的情况下，本研究使用了报告和验证的结果测量。CADESI-03具有较高的观察者内部和观察者之间的可靠性，是临床严重程度的相关和可靠的评估。病变评分包括急性和慢性炎症的特征，但仅通过抓痕提供瘙痒的间接评估。相比之下，直接瘙痒评分尚未得到相同程度的研究或验证。研究质疑简单视觉模拟量表得分的可靠性和可重复性，本研究中使用的视觉模拟量表与行为描述符的组合被发现是优越的。然而，虽然经过验证的病变和瘙痒评分对于评估和比较治疗是有用的，但对于宠主和他们的犬来说，生活质量可能更重要。可靠地评估生活质量一直很困难，研究经常报告全球评估分数。然而，这些可能具有误导性;例如，在HCA喷雾的早期试验中，一些宠主发现整体得分矛盾，因为他们发现喷雾有效但难以使用。因此，本研究将宠主的评价分为功效、使用方便度和耐受性。最近，生活质量调查问卷已经被开发和验证。未来的治疗干预研究应该与临床病变和瘙痒评分一起评估这些。

 

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 cAD. Selection bias in breed, age, sex, weight and clinical severity was not apparent. Randomized treatment allocation was made according to a predetermined allocation code. Detection bias by the investigators was unlikely because they were blinded to treatment allocation, and treatment-related follow up was performed by a dispenser who did not participate in any outcome assessments. Detection bias by the owners, however, was highly likely with the single-blind design of the study. Performance bias was considered unlikely because there were no concomitant treatments apart from flea control. Attrition bias was present, with eight dogs withdrawn, although on-treatment data permitting intention-to-treat analysis was available for five of these dogs. Poor efficacy was an issue, although other reasons for withdrawal included withdrawal at the owners’ request and ⁄ or treatment with prohibited medications. It is therefore possible that this biased towards a favourable response to treatment.

这项研究是按照良好的临床实践标准进行的。在试验前建立了严格的纳入和排除标准，以确保cAD的明确诊断。品种、年龄、性别、体重和临床严重程度的选择偏倚不明显。按照预定的分配代码进行随机分配。研究者不太可能发现偏倚，因为他们对治疗分配是盲目的，与治疗相关的随访是由一名没有参与任何结果评估的分配器进行的。然而，在单盲设计的研究中，宠主的检测偏差极有可能出现。表现偏差被认为不太可能，因为除了跳蚤控制之外没有联合治疗。存在损耗偏差，有8只犬退出，但对其中5只犬的治疗数据允许意向治疗分析。疗效差是一个问题，但停药的其他原因包括应宠主要求停药和使用违禁药物治疗。因此，这可能偏向于对治疗的有利反应。

 

In conclusion, this study demonstrated that a 0.0584% HCA spray and ciclosporin were both highly efficacious and well tolerated in the treatment of cAD. There were no significant differences in clinical improvement or owner assessment, although the study design lacked sufficient power to confirm non-inferiority for all the outcome measures.

综上所述，本研究表明一种0.0584%的HCA喷雾剂和环孢素治疗cAD都是高效且耐受性良好的。尽管研究设计缺乏足够的力量来确认所有结果测量的非劣效性，但在临床改善或宠主评估方面没有显着差异。

 

yalicheng179

侯亚芳

霁月

南海

！！！！！

wat

杨先生