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A masked, randomised clinical trial evaluating the efficacy and safety of Lokivetmab compared to saline control in client-owned dogs with allergic dermatitis 一项评估比较洛基维特单抗与盐水对照对患过敏性皮肤病的家养犬的疗效和安全性的盲选随机临床试验 作者：Leen Van Brussel , Hilde Moyaert , Monica Escalada, Sean P. Mahabir and Michael R. Stegemann 翻译：郑江涛
Background – Interleukin (IL)-31 is an important mediator in canine atopic dermatitis (cAD) and also may be dysregulated in other allergic diseases. Hypothesis/Objectives – To demonstrate the efficacy and safety of Lokivetmab (canine anti-IL-31 monoclonal antibody) for treatment of pruritus associated with allergic dermatitis in dogs. Animals – Dogs that were at least moderately pruritic with a presumptive diagnosis of allergic dermatitis were enrolled in Portugal, Hungary, France and Germany by 12 primary care practitioners and two veterinary dermatology referral specialists. Methods and materials – Dogs were randomised to receive either placebo (saline) or Lokivetmab (1.0–3.3 mg/kg) by subcutaneous injection on Day (D)0. Owners evaluated pruritus using a validated Visual Analog Scale (pVAS) daily until D7 and then weekly until D28. The severity of dermatitis was assessed by the investigators using a modified VAS on D0, D7, D14 and D28.
Results – Beginning at D1, owner-assessed pVAS least square means were significantly reduced in the treatment group versus the placebo group (57.7% versus 21.8% reduction on D28). For all time points, investigator assessed VAS means were significantly reduced in the Lokivetmab group versus the placebo group (57.1% versus 20.5% reduction on D28). Overall, the occurrence of adverse health events during the evaluation period was comparable between the two groups. Conclusions and clinical importance – Lokivetmab is a safe and efficacious treatment for dogs with allergic dermatitis. 背景-白细胞介素（IL）-31是犬特应性皮炎（CAD）的重要介质，也可能在其他过敏性疾病中失调。 假设/目的-证明洛基维特单抗（犬用IL-31单克隆抗体）治疗犬过敏性皮炎相关瘙痒的有效性和安全性。 动物——在葡萄牙、匈牙利、法国和德国，由12名初级保健医生和两名兽医皮肤病转诊专家招募了至少有中度瘙痒并被推定诊断为过敏性皮炎的犬。 方法和材料-犬随机接受安慰剂（盐水）或洛基维特单抗（1.0-3.3 mg/kg），在第0天皮下注射。主人使用经验证的视觉瘙痒评分表（PVAS），每天评分直到第7天，然后每周评分直到第28天。研究人员在第0天、第7天、第14天和第28天使用改良的VAS评估皮炎的严重程度。 结果–从第1天开始，与安慰剂组相比，治疗组的宠主评估PVAS最小二乘均值显著降低（第28天分别降低57.7%和21.8%）。在所有时间点，研究者评估的VAS平均值在洛基维特单抗组与安慰剂组相比显著降低（第28天分别降低57.1%和20.5%）。总体而言，两组在评估期间发生的不良健康事件具有可比性。 结论和临床意义——洛基维特单抗是一种安全有效的治疗过敏性皮炎的药物。
Introduction 介绍 The pro-inflammatory cytokine interleukin (IL)-31 is produced by activated T lymphocytes in multiple species and its pruritogenic nature has been well-described. By binding to receptors on neurons (receptor complex consisting of IL-31 receptor A and oncostatin M receptor β), IL-31 triggers the activation of Janus kinases, which in turn signal to the brain, triggering an itch response and inducing scratching behaviour. In addition, IL-31 can stimulate the production of inflammatory mediators by promoting epithelial cell responses as demonstrated in transgenic mice over-expressing IL-31, a model in which severe pruritus as well as alopecia and skin lesions are induced. Anti-IL-31 antibodies have been demonstrated in NC/Nga mice (a mouse model for human atopic dermatitis) to reduce or eliminate the pruritic effects of IL-31. 促炎细胞因子白介素（IL）-31是由多种物种的活化T淋巴细胞产生的，其致痒性已被充分描述。通过与神经元上的受体（由IL-31受体A和抑瘤素M受体β组成的受体复合物）结合，IL-31触发Janus激酶的激活，Janus激酶反过来向大脑发出信号，触发瘙痒反应并诱导抓挠行为。此外，IL-31可以通过促进上皮细胞应答来刺激炎性介质的产生，如在过度表达IL-31的转基因小鼠中所证明的，诱导严重瘙痒以及脱毛和皮肤病变的模型。已经在NC/NGA小鼠（人类特应性皮炎的小鼠模型）中证实抗IL-31抗体可减少或消除IL-31的瘙痒作用。
A comprehensive global programme has been conducted and reported to demonstrate both safety and efficacy of Lokivetmab in dogs with atopic dermatitis (AD), which led to its registration for treatment of clinical manifestations of canine AD (cAD). The mode of action of Lokivetmab combined with postmarketing studies on its use in pruritic skin diseases other than cAD, have suggested that it could be a valuable treatment alternative for dogs suffering from other allergic dermatoses. The objective of the study, therefore, was to demonstrate the efficacy and safety of Lokivetmab for the treatment of pruritus associated with allergic dermatitis of various aetiologies in dogs. 一项全面的全球计划已经开展并报道了洛基维特单抗在特应性皮炎患犬中的安全性和有效性（AD），这导致其注册用于治疗犬AD（CAD）的临床表现。洛基维特单抗的作用模式与其用于除CAD以外的瘙痒性皮肤病的上市后研究相结合，对于患有其他过敏性皮肤病的犬来说，这可能是一种有价值的治疗选择。因此，本研究的目的是证明洛基维特单抗治疗与各种病因的过敏性皮炎相关的犬瘙痒症的有效性和安全性。
Methods and materials 方法和材料 The main procedures for the study were similar to previous studies of oclacitinib and Lokivetmab, and summarised below. 该研究的主要程序与之前的奥拉替尼和洛基维特单抗研究相似，总结如下。
All data were collected in compliance with the principles of the International Cooperation on Harmonisation for Veterinary Medicines (VICH) Good Clinical Practice (GCP) Guideline 9.14 The protocol was reviewed and approved before study initiation by the Sponsor Ethical Review Board, the Hungarian authorities (Budapest, Hungary; authorisation nos. 5300/1431-2/2019 and 5300/2336-1/2019), Portuguese authorities (Lisboa, Portugal; authorisation no. 62/ECVPT/2019), as well as ANSES (Fougeres, France; authorisation no. EC-19-229) and German National Competent Authorities (authorisation no. Cytopoint-001-A). The owners gave written informed consent for their dogs to participate in the study. 所有数据的收集均符合国际兽药协调组织（VICH）药品临床试验质量管理规范（GCP）指南9.14本方案在研究开始前由申办者伦理审查委员会和匈牙利当局、葡萄牙当局，以及ANSES和德国国家主管当局。犬的主人以书面形式同意他们的犬参加这项研究。
In a masked, placebo-controlled field trial, dogs diagnosed with allergic pruritus were recruited from veterinary practices in France, Germany, Hungary and Portugal. Most of the participating investigators were veterinarians with experience in canine primary care medicine, whereas two were veterinary dermatology referral specialists. Animals were allocated randomly to one of two treatment groups in a 1:1 ratio of placebo (saline control) or Lokivetmab at 1.0–3.3 mg/kg body weight. Dogs received one subcutaneous injection of either saline or Lokivetmab on Day (D)0 and were followed for 28 days after treatment. Pruritus was assessed by the owner on a 10.0 cm long validated pruritus Visual Analog Scale (pVAS), and the condition of the skin was assessed by investigators using a severity of dermatitis VAS scale with descriptors adjusted to reflect different severities of the skin lesions (Figure S1). Blood and urine samples were collected at enrolment as well as at the time of study completion. 在一项有安慰剂对照的盲选试验中，从法国、德国、匈牙利和葡萄牙的兽医诊所招募了被诊断患有过敏性瘙痒症的犬。大多数参与调查的人员是具有犬类初级保健医学经验的兽医，而两名是兽医皮肤科转诊专家。动物被随机分配到两个治疗组中的一个，安慰剂（盐水对照）或洛基维特单抗（1.0-3.3 mg/kg体重）的比例为1：1。犬在第0天接受一次皮下注射盐水或洛基维特单抗，并在治疗后随访28天。瘙痒由主人以10.0cm长已验证的瘙痒视觉模拟量评分表（PVAS），研究者使用皮炎严重程度VAS量表评估皮肤状况，并调整描述符以反映皮肤病变不同严重程度（图S1）。在入组时和研究结束时采集血样和尿样。
Sample size estimates were derived from power calculations based on variance and effect sizes observed in a multicentre noninferiority field study with ciclosporin as the control product. With ≥45 Lokivetmab-treated dogs and ≥45 controls, there was ≥80% power to show a 32.72% difference in means for the primary efficacy endpoint of percentage change from baseline owner-assessed pVAS at D28. This outcome assumed mean responses for percentage change from baseline of 16.81% and 49.53% for placebo and Lokivetmab, respectively, using a two-sided 5% significance level for the comparison of treatment means at D28. 在一项以环孢素为对照药物的多中心非劣效性领域研究中，根据观察到的方差和效应大小进行功效计算，得出样本量估计值。对于≥45只接受洛基维特单抗治疗的犬和≥45只对照犬，在第28天时，主要疗效终点（与基线宠主评估的PVAS的百分比变化）的平均值有≥80%的差异。该结果假设安慰剂组和洛基维特单抗组相对于基线的百分比变化的平均反应分别为16.81%和49.53%，使用双侧5%显著性水平比较第28天的治疗平均值。
Inclusion criteria 选入标准 Dogs were client-owned, weighed between 3 and 80 kg on D0, and were in overall good health apart from their diagnosis of allergic dermatitis. A presumptive diagnosis was made to include one or more of the following: adverse reaction to food, flea allergy, contact allergy, suspected AD or unspecified allergic dermatosis. The diagnoses were made at the discretion of the investigators (i.e. specific tests were not imperative) and several presumptive causes could be identified at the same time. A diagnosis of cAD was only allowed in combination with one of the other aetiologies. To be eligible for enrolment, owners had to assess their dogs as having at least moderate pruritus on a categorical assessment form at the initial (D0) assessment. Categories included: normal dog, very mild, mild, moderate, severe and extremely severe pruritus. 家养犬，在D0时体重在3到80公斤之间，除了诊断为过敏性皮炎外，总体健康状况良好。推定诊断包括以下一项或多项：食物不良反应、跳蚤过敏、接触性过敏、疑似AD或未指明的过敏性皮肤病。诊断由研究人员自行决定（即特定测试不是必须的），并且可以同时确定几个假定的原因。CAD的诊断只允许与其他病因之一相结合。为了有资格登记，主人必须在初始（D0）评估时在分类评估表上评估他们的犬至少有中度瘙痒。分类包括：正常犬、极轻度、轻度、中度、重度和极重度瘙痒。
All dogs had to be on flea control for a minimum of four weeks before enrolment with no presence of fleas on D0 [no more than a mild infestation (i.e. flea faeces or debris present at most), no actual fleas visible], and continued use of this flea preventative during the study period was mandatory. Dogs diagnosed with cutaneous adverse reactions to food and that were consuming a hypoallergenic diet were required to have been on this diet for at least six weeks before D0. Regardless of food allergy status, all dogs had to remain on the same diet for the entire duration of the study. Allergenspecific immunotherapy was allowed if the dog had been on therapy for at least eight months before D0, or if the unsuccessful treatment had been discontinued for at least eight weeks before D0. 所有犬必须在登记前接受至少四周的跳蚤控制，在D0时没有跳蚤[不超过轻度感染（即最多有跳蚤粪便或碎片），没有实际可见的跳蚤]，并且在研究期间必须继续使用这种跳蚤预防剂。被诊断为对食物有皮肤不良反应并食用低过敏性饮食的犬需要在D0前至少六周食用这种饮食。无论食物过敏状态如何，所有的犬都必须在整个研究期间保持相同的饮食。如果犬在D0之前已经接受了至少8个月的治疗，则允许进行过敏原特异性免疫治疗。或者如果不成功的治疗在D0之前已经中断了至少八周。
Prohibited and conditionally allowed medications and therapies 禁止和有条件允许的药物和治疗方式 Withdrawal times for prohibited medications such as (and not limited to) oral and injectable corticosteroids, oclacitinib, ciclosporin and long-acting injectable antibacterials, were as described by Moyaert et al.6 (Table S1). Some treatments were allowed, under the condition that the owners, investigators and other study personnel adhered to minimal use and frequency of use guidelines for the concomitant medication (Table S1). 禁用药物的停药时间，例如（但不限于）口服和注射用皮质类固醇、奥拉替尼、环孢素和长效注射用抗生素。如Moyaert等人6所述（表S1）。在宠主、研究者和其他研究人员遵守合并用药的最低使用和使用频率指南的条件下，允许进行一些治疗（表S1）。
Exclusion criteria included prior treatment with Lokivetmab, signs of uncontrolled disease unrelated to allergic dermatitis, signs of immune suppression, and presence of active skin infection or infestation including (and not limited to) demodectic and sarcoptic acariasis, bacterial pyoderma and Malassezia dermatitis. Lactating bitches and any dog intended for use as a breeding animal also were excluded. 排除标准包括既往使用洛基维特单抗治疗、与过敏性皮炎无关的未控制疾病症状、免疫抑制症状、以及存在活跃的皮肤感染或寄生虫感染，包括（但不限于）蠕形螨病和疥螨病、细菌性脓皮病和马拉色菌皮炎。哺乳期母犬和任何打算用作繁殖动物的犬也被排除在外。
Randomisation and masking 随机化跟掩蔽 Each animal was randomly allocated to either placebo (saline) or Lokivetmab (Cytopoint, Zoetis Belgium SA; Louvain-la-Neuve, Belgium) treatment in a 1:1 ratio. Animals were randomised on D0 according to a randomised complete block design with one-way treatment structure replicated in multiple clinics. Within each study site the dogs were blocked on order of enrolment. Within each block, dogs were allocated at random to treatment groups, with each treatment occurring at least once. Investigators and all site personnel, with the exception of the treatment dispenser, were masked to the treatment group assignments as were owners and the laboratory personnel.The treatment dispenser drew up the correct dose of injectable treatment (Lokivetmab or saline, with identical appearance) into a syringe and provided it to the investigator for administration. 将每只动物随机分配至安慰剂（盐水）或洛基维特单抗（赛妥敏）治疗1：1比率。根据具有在多个诊所中重复的单向治疗结构的随机完全区组设计，在第0天将动物随机分组。在每个研究地点内，犬按登记顺序被封锁。在每个区块内，犬被随机分配到治疗组，每种治疗至少进行一次。除治疗配药员外，研究者和所有现场人员以及宠主和实验室人员均被蒙蔽至治疗组分配。治疗配药员将正确剂量的可注射治疗（洛基维特单抗或盐水，外观相同）注入注射器，并提供给研究者用于给药。
The demographic dataset on D0 was not analysed statistically because animals were blocked on order of enrolment within a study site and treatment groups were assigned randomly. Any potential differences for demographics on D0 between treatment groups could occur by chance and would mimic normal field conditions. 未对D0的人口统计学数据集进行统计学分析，因为动物按研究地点内的入组顺序进行分组，并且随机分配治疗组。处理组之间的D0人口统计学的任何潜在差异都可能偶然发生，并将模拟正常的现场条件。
Treatment administration 治疗管理 Lokivetmab was provided as per commercial formulation in singleuse vial containing 1 mL that contained no preservative. Vials provided contained solution in one of four concentrations (10, 20, 30 and 40 mg/mL). Based on the dosing chart, each dog was administered 1.0–3.3 mg/kg of Lokivetmab depending upon the dog’s body weight. 洛基维特单抗按照商业配方提供，装在含有1ml不含防腐剂的一次性小瓶中。提供的小瓶含有四种浓度之一的溶液（10、20、30和40毫克/毫升）。根据给药表，根据犬的体重，每只犬使用1.0-3.3 mg/kg的洛基维特单抗。
Study schedule and variables measured 研究时间表和变量测量 Baseline data (demographic, physical examination, initial assessment of pruritus and adherence to inclusion criteria) were collected at enrolment on D0. Owners performed an assessment of the severity of their dog’s itch using the pVAS on D0 (before treatment and repeated approximately 4 h post-treatment), and D1–D7, D14, D21 and D28. This 10 cm long scale had descriptors along its side at 2 cm intervals to help the owners assess the severity of the dog’s pruritus during the past 24 h. The overall condition of the dog’s skin was evaluated by the investigator on a similar 10 cm VAS scale with descriptors at 2 cm increments adjusted to reflect different severities of skin condition: no (normal dog), very mild, mild, moderate, severe and extremely severe dermatitis (Figure S1). Combined with a general physical examination, these investigator-driven assessments were performed on D0, D7, D14 and D28. Dogs were observed for 30 min following administration for signs of immediate adverse reactions to treatment. Abnormal health events (AHE) and/or concomitant treatment reported by owners or identified on physical examination were recorded throughout the study. 基线数据（人口统计学、体检、瘙痒的初步评估和对纳入标准的依从性）在入组时收集。主人在D0（治疗前和治疗后约4小时重复）使用PVAS对他们的犬的瘙痒严重程度进行评估。以及D1–D7、D14、D21和D28。这个10厘米长的量表在其侧面每隔2厘米有一个描述符，以帮助主人评估犬在过去24小时内瘙痒的严重程度。研究人员采用类似的10 cm VAS量表对犬皮肤的整体状况进行评估，并以2 cm为增量对描述信息进行调整，以反映皮肤状况的不同严重程度：无（正常犬）、极轻度、轻度、中度、重度和极重度皮炎（图S1）。结合一般体检，这些研究者主导的评估在D0、D7、D14和D28进行。给药后观察犬30分钟，以观察对治疗的即时不良反应迹象。在整个研究过程中，记录宠主报告的或体检发现的异常健康事件（AHE）和/或伴随治疗。
On the final day of study (D28, or earlier for dogs withdrawn before D28), the dog’s overall response to treatment (RTT) was assessed by both the owner and the investigator by drawing a vertical line on a horizontal 10 cm scale ranging from ”no improvement” to ”excellent results”. 在研究的最后一天（第28天，或更早，对于在第28天之前退出的犬），犬的主人和研究者通过在水平的10厘米刻度上画一条从“无改善”到“极好结果”的垂直线来评估犬对治疗的总体反应（RTT）。
A physical examination including body weight was performed at each clinic visit. Any signs of ill health that were not preexisting (or any change in severity) were reported on an AHE form. The condition of eyes and ears, and skin and appendages attributable to the preexisting disease of allergic dermatitis was captured on the investigator severity of dermatitis VAS form and treatment differences between both groups reported as such. The investigators were instructed only to report a worsening of the associated clinical signs as an AHE. 在每次门诊就诊时进行包括体重在内的体检。任何不存在的健康不佳迹象（或任何严重程度的变化）在AHE表格上报告。可归因于先前存在的过敏性皮炎疾病的眼睛、耳朵、皮肤和附属物的状况记录在研究者的皮炎严重程度VAS表格中，并记录两组之间的治疗差异。研究人员只需将相关临床症状的恶化报告为AHE。
Blood samples (haematological and serum chemical parameters) and urine samples (urinalysis and protein creatinine ratio) were collected at enrolment and study completion. Blood and urine were collected again at the discretion of the investigator if the dog presented for an AHE. All samples for haematological, serum chemical, urinalysis and urine protein creatinine ratio investigations were sent to the same laboratory. 在入组和研究结束时收集血样（血液学和血清化学参数）和尿样（尿液分析和蛋白肌酐比率）。如果犬出现在AHE中，则由研究者自行决定再次收集血液和尿液。用于血液学、血清化学、尿液分析和尿蛋白肌酐比率调查的所有样本均送往同一实验室。
In cases of suspected secondary bacterial infections, it was recommended to collect a swab sample for standard bacteriological investigation, including antibiogram, through standard veterinary procedures. 在怀疑继发细菌感染的情况下，建议通过标准兽医程序收集拭子样本进行标准细菌学调查，包括抗菌谱。
Efficacy outcome measures 疗效结果测量 The efficacy dataset excluded those dogs that were considered to have had a protocol deviation that affected the collection or integrity of their efficacy data, such as treatment with prohibited medications or visits performed outside the allowed visit windows. Dogs withdrawn from the study before D28 as a consequence of worsening signs of allergic dermatitis (lack of efficacy) were included in the analysis as failing to achieve 50% or 75% reduction from baseline for all subsequent time points after their withdrawal. 疗效数据集排除了那些被认为存在影响其疗效数据收集或完整性的方案偏差的犬，例如使用禁用药物治疗或在允许的就诊窗口之外进行的就诊。在第28天之前因过敏性皮炎症状恶化（缺乏疗效）而退出研究的犬被纳入分析，因为在其退出后的所有后续时间点，未能从基线减少50%或75%。
For the owner pVAS, data were summarised for D0, D0+4 h, D1–D7 ( 1 day), D14 (2 days), D21 (2 days) and D28 (3 days). For investigator VAS, data were summarised for D0, D7 (1 day), D14 (2 days) and D28 (3 days). 对于宠主PVA，总结了D0、D0+4小时、D1–D7（1天）、D14（2天）、D21（2天）和D28（3天）的数据。对于研究者VAS，总结了D0、D7（1天）、D14（2天）和D28（3天）的数据。
The primary efficacy end-point was defined as the reduction from baseline of the owner-assessed pruritus as measured by pVAS, on D28. 主要疗效终点被定义为在第28天通过PVAS测量的宠主评估的瘙痒从基线的减少。
Secondary efficacy end-points included percentage reduction from baseline of owner pVAS and investigator VAS at each time point, proportion of dogs achieving 50% and 75% decrease of ownerassessed pruritus compared at each time point compared to D0, percentage of dogs achieving a ”normal range” on the pVAS on each of the study time points, and assessment of overall RTT from the owner and the investigator at study completion or withdrawal. Using the pVAS, a score of 0–19 mm was assumed to be the best approximation of a ”normal range”. 次要疗效终点包括每个时间点主人PVAS和研究者VAS从基线减少的百分比，每个时间点与D0相比，主人评估的瘙痒减少50%和75%的犬的比例，在每个研究时间点达到PVAS“正常范围”的犬的百分比，以及在研究完成或退出时主人和研究者对总体RTT的评估。使用PVAS，0-19mm的评分被认为是“正常范围”的最佳近似值。
Safety outcome measures 安全性结果测量 Data from all animals were included in the dataset used for the assessment of safety, independent of the occurrence of protocol deviations. Similar to the study reported by Moyaert et al., frequencies of dogs reported to show at least one AHE were summarised by clinical signs, and frequencies of dogs receiving concomitant medication over the course of the study were summarised by an Anatomical Therapeutic Chemical classification system for veterinary medicinal products (ATC) functional use term. 所有动物的数据均包括在用于安全性评估的数据集中，与方案偏差的发生无关。与Moyaert等人报道的研究相似。通过临床症状总结了报告显示至少一种AHE的犬的频率，并通过兽医药品的解剖学治疗化学分类系统总结了研究过程中接受合并用药的犬的频率（ATC）功能使用术语。
Summary statistics (means with standard deviations or medians with ranges) were calculated by treatment and intended day of sampling for each haematological, serum chemical and quantitative urinalysis value, reporting the number of dogs that fell below, within or above the normal range (provided by the laboratory) at each day of sampling for haematological and serum chemical parameters specifically. In addition, shift tables provided the number of dogs that had an increased or decreased shift compared to baseline at each day of sampling. 根据治疗和每个血液学样本的预期日期计算汇总统计数据（平均值和标准差或中位数和范围）。血清化学和定量尿液分析值，报告在血液学和血清化学参数取样的每一天低于、在正常范围内或高于正常范围（由实验室提供）的犬的数量。此外，移位表提供了在取样的每一天，与基线相比，移位增加或减少的犬的数量。
Data analysis 数据分析 Data analysis was performed using SAS v9.4 (SAS Institute; Cary, NC, USA) as described previously. Mixed linear models were fitted using PROC MIXED. Where appropriate, transformations were applied to end-points before statistical analysis as a remedial measure to address violations in the assumptions for the statistical models. The level of significance was set at a = 0.05 (two-sided). 使用SAS v9.4，如前所述。使用Proc Mixed拟合混合线性模型。在适当的地方，在统计分析之前，将转换应用于端点，作为一种补救措施，以解决统计模型假设中的违规问题。显著性水平设定为a=0.05（双侧）。
Results 结果 Sixty animals per treatment group were targeted for enrolment to allow for drop-outs and retention of 45 evaluable cases per treatment on D28. Withdrawals were allowed for missed assessments resulting from owner/investigator oversight and exclusions of data resulting from protocol deviations that could have biased the efficacy assessment. 每个治疗组有60只动物入选，以便在第28天每次治疗有45个可评价的病例退出和保留。对于因宠主/研究者疏忽而导致的评估遗漏，以及因方案偏差而导致的数据排除（可能使疗效评估产生偏差），允许退出。
Demographic data 病例统计数据 A total of 123 dogs (62 saline controls; 61 Lokivetmab-treated) were enrolled from 14 veterinary practices in France (n = 40), Germany (n = 25), Hungary (n = 35) and Portugal (n = 23). Their demographic details are summarised in Table 1. In the control group, the most common breeds were German shepherd dog (9.7%), Labrador retriever (8.1%) and French bulldog (6.5%). Among the Lokivetmab-treated animals, the three most common breeds were French bulldog (13.1%), Labrador retriever (8.2%) and beagle (6.6%). All dogs were free of fleas (flea infestation was recorded as absent) at enrolment. One Lokivetmab-treated animal was observed with a mild flea infestation (presence of flea faeces and identification of some flea bites) on D14, and returned to normal by the next visit (D28). 总共123只犬（62只盐水对照；61只洛基维特单抗治疗犬）分别来自法国（n=40）、德国（n=25）、匈牙利（n=35）和葡萄牙（n=23）。表1总结了患犬详细信息。在对照组中，最常见的品种是德国牧羊犬（9。7%）、拉布拉多猎犬（8.1%）和法国斗牛犬（6.5%）。在洛基维特单抗治疗的动物中，最常见的三个品种是法国斗牛犬（13.1%）、拉布拉多犬（8.2%）和比格犬（6.6%）。所有犬在登记时都没有跳蚤（跳蚤感染被记录为不存在）。观察到一只洛基维特单抗治疗的动物有轻微的跳蚤感染（第14天出现跳蚤粪便并发现一些跳蚤叮咬），并在下一次就诊（第28天）时恢复正常。
Aetiology 病因学 The most common presumptive diagnosis was food allergy (41.5%), followed by AD (33.3%, in combination with other aetiologies) and contact allergy (33.3%). Flea allergy was least reported, with only 13.8% of the enrolled cases represented. Distribution of the different aetiologies was similar in both treatment groups (Table S2). 最常见的假定诊断是食物过敏（41.5%），其次是AD（33.3%，结合其他病因）和接触性过敏（33.3%）。跳蚤过敏的报告最少，仅占登记病例的13.8%。两个治疗组中不同病因的分布相似（表S2）。
Table 1. Demographics of enrolled 123 dogs at Day 0 表1。第0天登记的123只犬的统计数据
For 29.3% of the animals, an allergic component was identified that could not be assigned to any of the predefined categories with the information at hand at the time of enrolment; these were assigned as unspecified allergic dermatitis (in combination or not with any of the other causes). 对于29.3%的动物，确定了一种过敏成分，根据登记时的信息，不能将其分配到任何预定义的类别中；这些被指定为未指明的过敏性皮炎（与任何其他原因结合或不结合）。 Treatment administration 治疗管理 On D0, the Lokivetmab dose ranged between 1.0 and 2.9 mg/kg. Nearly half of the dogs received a dose of 1–1.2 mg/kg (n = 30), 30% (n = 18) received a dose of 1.3–1.5 mg/kg, and only one animal received a dose >2 mg/kg. 在第0天，洛基维特单抗的剂量范围在1.0和2.9 mg/kg之间。近一半的犬接受了1–1.2 mg/kg的剂量（n=30），30%的犬（n=18）接受了1.3–1.5 mg/kg的剂量，只有一只犬接受了>2 mg/kg剂量。 Table 2. Summary of the different efficacy outcomes after treatment with Lokivetmab in atopic and allergic animals for owner assessment of pruritus Visual Analog Scale (pVAS) on Day 28 表2。特应性和过敏性动物接受洛基维特单抗治疗后第28天瘙痒视觉模拟评分（PVAS）的不同疗效结果总结
Assessment of effectiveness 有效性评估 The primary effectiveness dataset at D28 comprised 99 dogs in the owner pVAS dataset (44 control, 55 Lokivetmab-treated animals). Eighteen dogs were excluded/missing from the analysis of owner assessments in the control group, and six in the Lokivetmab-treated group on D28. The datasets for owner pVAS and investigator VAS changed at each time point as a result of early withdrawals, missing assessments because of owner/investigator oversight (e.g. missed assessment at home or visit skipped) or data excluded from the analysis as a result of protocol deviations that could have biased the efficacy assessment (e.g. forbidden medications given or assessment performed outside the allowed window). 第28天的主要有效性数据集包括主人PVAS数据集中的99只犬（44只对照，55只洛基维特单抗治疗犬）。在第28天，18只犬被排除/遗漏在对照组的主人评估分析中，6只犬被排除/遗漏在洛基维特单抗治疗组中。宠主pVAS和研究者VAS的数据集在每个时间点都会发生变化，这是由于提前退出、宠主/研究者疏忽导致的评估缺失例如，在家中错过评估或跳过访问）或由于可能使疗效评估产生偏差的方案偏差而从分析中排除的数据（例如，给出的禁用药物或在允许的窗口之外进行的评估）。 Four animals (one placebo, three Lokivetmab-treated dogs) received forbidden medication during the study period and as a result their efficacy data were excluded from the D28 dataset. Data from one additional placebotreated animal were excluded because the D28 assessment was performed outside of the allowed window (D28 3 days). Data from 16 control animals and three Lokivetmab-treated dogs were not available because they were withdrawn from the study before D28. All withdrawals were to the result of worsening or lack of improvement of clinical signs of allergic dermatitis. 四只动物（一只安慰剂，三只洛基维特单抗治疗的犬）在研究期间接受了禁用药物，因此它们的疗效数据被排除在D28数据集中。另外一只接受安慰剂治疗的动物的数据被排除，因为D28评估是在允许的窗口（D28 3天）之外进行的。16只对照动物和3只接受洛基维特单抗治疗的犬的数据不可用，因为它们在第28天之前退出了研究。所有的退出都是由于过敏性皮炎的临床症状恶化或缺乏改善。 Owner-assessed pVAS 宠主评估的pVAS On D0, the pre-treatment mean pruritus score was 69 in the control group versus 70 in the Lokivetmab-treated group. On D28, the least-square (LS) mean percentage reduction from baseline was significantly higher in the Lokivetmab-treated animals (57.7%) compared to the placebo group (21.8%; P < 0.0001). 在第0天，对照组的治疗前平均瘙痒评分为69，而洛基维特单抗治疗组为70。在第28天，洛基维特单抗治疗组动物的最小平方（LS）平均百分比从基线显著降低（57.7%）与安慰剂组（21.8%；P<0.0001）。 For all other time points (beginning with D1), the percentage reduction from baseline of owner-assessed pVAS LS means was significantly greater (P ≤ 0.0109) in the group of animals treated with Lokivetmab versus the group of animals treated with saline, ranging from a 14.5% difference between treatment groups on D1 to a maximum of 37.2% on D14 (Figure 1). 对于所有其他时间点（从D1开始），宠主评估的pVAS LS平均值相对于基线的百分比下降显著更大（P≤0。0109），在第1天治疗组之间的差异为14.5%，在第14天治疗组之间的差异最大为37.2%（图1）。 At every study time point beyond D1 (for 50% reduction) and/or D2 (for 75% reduction), the proportion of animals achieving ≥50% or 75% reduction in pVAS was significantly higher in the treatment group than the control group (P ≤ 0.0213 for 50%; P ≤ 0.0451 for 75%). Treatment success defined as ≥50% reduction in pVAS, achieved a maximum 26% on D6 in the control group, and decreased thereafter. In the Lokivetmab-treated group, a maximum of 73% was reached on D14 and averaged between 66 and 70% during the last two weeks of the study period (Figure 2). In the control group, ≤1% of the dogs achieved 75% reduction at any of the time points, while in the Lokivetmab-treated group, the percentage of dogs achieving 75% reduction varied between 2% on D0 (4 h post-dosing) to 32% of the animals on D21 (Figure 3). 在超过D1（减少50%）和/或D2（减少75%）的每个研究时间点，治疗组中PVAS减少≥50%或75%的动物比例显著高于对照组（50%P≤0.02 13；75%P≤0.0451）。治疗成功定义为PVAS减少≥50%，对照组在第6天达到最大值26%，之后有所下降。在洛基维特单抗治疗组中，在第14天达到最大值73%，在研究期间的最后两周平均在66%和70%之间（图2）。.在对照组中，≤1%的犬在任何时间点都实现了75%的减少，而在洛基维特单抗治疗组中，实现75%减少的犬的百分比在第0天（给药后4小时）的2%和第21天的32%之间变化（图3）。 At all time points after D0, the percentage of dogs achieving a ”normal” VAS score was numerically higher in the Lokivetmab-treated group compared to the control group. By D28, 45.5% of the Lokivetmab-treated dogs were scored as ”normal” in terms of level of pruritus versus 6.8% of the saline-treated dogs (Figure 4). 在D0后的所有时间点，与对照组相比，洛基维特单抗治疗组中达到“正常”VAS评分的犬的百分比在数值上更高。到第28天，就瘙痒水平而言，45.5%的洛基维特单抗治疗组的犬被评为“正常”，而盐水治疗组的犬只有6.8%（图4）。
图1。自主评估的瘙痒视觉模拟评分（PVAS）相对于基线的减少百分比（治疗最小平方数图）。 见图2。自基线起，宠主评估的瘙痒症视觉模拟评分（PVAS）减少50%的曲线图（反向转换治疗最小平方均值）。 图3。从基线减少75%的宠主评估的瘙痒症视觉模拟量表（PVAS）（反向转换治疗最小平方平均值）。 见图4。在评估的每一天，通过治疗，瘙痒视觉模拟评分（PVAS）在“正常”范围（0-19 mm）内的动物的百分比图。 Investigator severity of dermatitis VAS 研究者皮炎严重程度VAS Similar to the pruritus assessment, a reduction in the VAS score reflected an improvement in the condition of the skin. For all time points, the percentage reduction from baseline of investigator-assessed skin condition VAS LS means was significantly higher (P < 0.0001) in the Lokivetmab-treated group compared to the control group. In the control group, dogs achieved 14.1%, 20.6% and 20.5% reduction on D7, D14 and D28, respectively, compared to D0. In the Lokivetmab-treated dogs, the corresponding reductions in percentages were 41.3%, 55.8% and 57.1%. 与瘙痒评估类似，VAS评分的降低反映了皮肤状况的改善。对于所有时间点，研究者评估的皮肤状况VAS LS平均值从基线降低的百分比显著更高（与对照组相比，洛基维特单抗治疗组中P<0.0001）。在对照组中，与D0相比，D7、D14和D28分别减少了14.1%、20.6%和20.5%。在洛基维特单抗治疗组中，相应的减少百分比分别为41.3%、55.8%和57.1%。
Response to treatment (RTT) 治疗反应（RTT） Owner and investigator RTT were significantly higher (P < 0.0001) in the treatment group than the control group. Means were 67.8% and 70.1%, respectively, for treated dogs, and 33.1% and 29.9%, respectively, for controls. 治疗组的宠主和研究者RTT显著高于对照组（P<0.0001）。治疗组的平均值分别为67.8%和70.1%，对照组的平均值分别为33.1%和29.9%。
Adverse health events and concomitant medications: 不良健康事件和合并用药： Overall, the occurrence of AHEs was comparable between both treatment groups: 14.5% in the control group (n = 9) versus 11.5% in the Lokivetmab-treated group (n = 7; Table S3). 总体而言，两个治疗组之间的AHE发生率相当：对照组为14.5%（n=9），洛基维特单抗治疗组为11.5%（n=7；表S3）。
Two dogs in each group were sampled for bacteriological culture owing to a suspected skin or ear infection, and one in each group subsequently was treated with systemic antimicrobials. For a control dog, a skin infection resulted in withdrawal before D28. Because this animal was withdrawn due to worsening signs of allergic dermatitis (lack of efficacy), it was treated as failing to achieve 50% and 75% reduction from baseline for all subsequent time points. One dog in the treatment group also received systemic antimicrobial therapy and was excluded from the efficacy analysis at all subsequent time points. 由于怀疑皮肤或耳部感染，每组中的两只犬被取样进行细菌培养，随后每组中的一只犬接受全身性抗生素治疗。对于对照犬，皮肤感染导致在第28天前停药。由于该动物因过敏性皮炎症状恶化（缺乏疗效）而退出研究，因此在随后的所有时间点，该动物均被视为未能从基线减少50%和75%。治疗组中的一只犬还接受了全身性抗生素，并在随后的所有时间点被排除在疗效分析之外。
Overall, use of concomitant medication was comparable between both treatment groups. In the control group, 15 dogs were treated with oclacitinib at the time of early withdrawal due to lack of efficacy. In the Lokivetmab treatment group, three dogs received oclacitinib as rescue treatment at the time of early withdrawal. 总体而言，两个治疗组的合并用药情况具有可比性。在对照组中，有15只犬在因缺乏疗效而提前停药时接受了奥拉替尼治疗。在洛基维特单抗治疗组中，3只犬在早期停药时接受了奥拉替尼作为补救治疗。
Haematological and serum chemical investigation,and urinalysis 血液学和血清化学检查，以及尿液分析 For various serum chemical parameters, increasing and/or decreasing shifts were observed, yet these were not clinically significant and generally occurred in both groups. The mean serum chemical values remained within reference ranges at all study time points from D0 onwards. 对于各种血清化学参数，观察到增加和/或减少的变化，但这些变化没有临床意义，并且通常在两组中都发生。从D0开始，所有研究时间点的平均血清化学值均保持在参考范围内。
Increasing and/or decreasing shifts were observed equally in both treatment groups for haematological parameters. Overall, mean values remained within reference range at all study time points from D0 onwards, except for MCHC (mean corpuscular haemoglobin concentration) where the mean value was below the reference range (32.6–39.2 g/dL) for both control animals (32.3 g/dL) and Lokivetmab-treated dogs (32.5 g/dL) on D0, and in the control group (32.5 g/dL) on D28. This was not considered clinically relevant. 在两个治疗组中同样观察到血液学参数的增加和/或减少变化。总体而言，除MCHC（平均红细胞血红蛋白浓度）外，从D0开始的所有研究时间点的平均值均保持在参考范围内。第0天，对照组动物（32.3 g/dL）和洛基维特单抗治疗组犬（32.5 g/dL）的平均值均低于参考范围（32.6–39.2 g/dL），第28天，对照组动物（32.5 g/dL）的平均值也低于参考范围。这被认为与临床无关。
Urinalysis did not reveal any concerns for potential treatment-related abnormalities. 尿液分析未发现任何与治疗相关的潜在异常。
Discussion 讨论 The objective of this study was to demonstrate the efficacy and safety of Lokivetmab for the treatment of pruritus associated with an allergic dermatitis in dogs. The targeted population included dogs with presumptive diagnoses of food allergy, flea allergy, contact allergy and AD in any combination, or unspecified allergic pruritus. Diagnoses were established at the discretion of the investigators, who were mainly primary care veterinarians. This approach was deliberately selected to reflect field conditions in general practice, in which Lokivetmab might be prescribed and administered. In a recent study following a similar design (with presumptive diagnoses), a comparable distribution of disease aetiology was reported, with approximately 45% of the dogs diagnosed as suffering from contact allergy. It is likely that more rigorous diagnostic criteria would have altered the distribution of the diagnoses, as the prevalence of allergic contact dermatitis is much lower when assessed exclusively by dermatology specialists. 本研究的目的是证明洛基维特单抗治疗犬过敏性皮炎相关瘙痒的有效性和安全性。实验对象包括假定诊断为食物过敏、跳蚤过敏、接触性过敏和AD的任何组合，或未指明的过敏性瘙痒症的犬。诊断由研究人员自行决定，他们主要是初级保健兽医。这种方法是特意选择的，以反映一般实践中的现场条件，其中可以处方和施用洛基维特单抗。在最近的一项研究中，按照类似的设计（假定诊断），报告了疾病病因的可比分布，大约45%的犬被诊断为患有接触性过敏。更严格的诊断标准可能会改变诊断的分布，因为当由皮肤科专家专门评估时，过敏性接触性皮炎的患病率要低得多。
Results of this study showed significant reduction of owner-assessed pruritus after treatment with Lokivetmab compared to placebo (saline) control. The results are comparable to a prior study which enrolled only dogs with a diagnosis of AD (Table 2). 这项研究的结果显示，与安慰剂（盐水）对照相比，使用洛基维特单抗治疗后，宠主评估的瘙痒症显著减少。该结果与先前的一项仅纳入诊断为AD的犬的研究相比较（表2）。
In this study, a 53% reduction in pruritus was observed 6 days after the start of Lokivetmab treatment which is in line with what was previously reported for oclacitinib (55%). Equally, a peak in pruritus reduction was observed 14 days after injection of Lokivetmab treatment The antipruritic activity of Lokivetmab remained unchanged after D14, and on D28 there was still a 58% reduction in pruritus in the treated animals. In a nine month field study in dogs with AD, the pruritus score decreased further with subsequent injections and reached a plateau after four consecutive monthly injections. A 50% reduction from baseline of mean pruritus score represents a clinically relevant threshold above which owners are satisfied with treatment. This percentage has been used subsequently as a standard for assessing the efficacy of treatments for pruritus. The proportion of animals exhibiting a 50% pruritus decrease on D14 (73%) in this study is nearly identical to the percentage reported for oclacitinib when treating a very similar population of animals diagnosed with allergic dermatitis. 在该研究中，在洛基维特单抗治疗开始后6天观察到瘙痒减少53%，这与先前报道的奥拉替尼（55%）一致。同样，在注射洛基维特单抗治疗后14天观察到瘙痒减轻的峰值。洛基维特单抗的止痒活性在第14天后保持不变，在第28天，治疗动物的瘙痒仍减少58%。在对患有AD的犬进行的为期9个月的现场研究中，瘙痒评分在随后的注射中进一步降低，并在连续4个月注射后达到稳定水平。平均瘙痒评分从基线降低50%代表临床相关阈值，高于该阈值，宠主对治疗感到满意。该百分比随后被用作评估瘙痒症治疗效果的标准。在第14天表现出50%瘙痒减少的动物的比例（73%）几乎与报告的奥拉替尼在治疗诊断为过敏性皮炎的非常相似的动物群体时的百分比相同。
Another mechanism for determining efficacy is implementation of a threshold for what is considered to be a ”normal” animal, where ”normal” is defined as obtaining a pVAS score of <2 cm as proposed by Rybnicek et al. The percentage of dogs with pruritus scores in the ”normal” range on D28 was 45.5% for Lokivetmab-treated dogs compared with 6.8% for placebo-treated dogs. This is in line with what has been reported for atopic dogs treated with Lokivetmab, where 39% of the animals was assessed as ”normal” on D28. Therefore, it appears that neutralisation of IL-31 has an antipruritic effect in a broader population of pruritic dogs than just those with a confirmed diagnosis of AD. The data therefore suggest an association between allergic dermatoses in general and IL-31 dysregulation, as reported previously in humans. 确定疗效的另一种机制是对被认为是“正常”的动物实施阈值，其中“正常”被定义为获得Rybnicek等人提出的<2cm的PVAS评分。在D28天，瘙痒评分在“正常”范围内的犬的百分比,洛基维特单抗治疗组为45.5%，安慰剂治疗的犬为6.8%。这与用洛基维特单抗治疗的特应性犬的报道一致，其中39%的动物在第28天被评估为“正常”。因此，IL-31的中和似乎在更广泛的瘙痒犬群中具有止痒作用，而不仅仅是那些确诊为AD的犬群。因此，这些数据表明，一般过敏性皮肤病与IL-31失调之间存在关联，正如先前在人类中报道的那样。
In addition to owner-assessed pruritus, the investigators assessed the severity of skin lesions using an unvalidated VAS, as has been described previously. Validated scales which have been developed for scoring cAD were not employed, because they are specific for cAD. The results of the investigator-assessed dermatitis VAS mirrored the findings of the owners’ pVAS scores, similar to what was observed with oclacitinib. This also is consistent with results obtained in dogs with cAD, where Lokivetmab treatment had a positive effect on cutaneous inflammation as assessed by reduction of Canine Atopic Dermatitis Extent and Severity Index (CADESI)-03 scores. 除宠主评估的瘙痒外，研究人员还使用未经验证的VAS评估了皮肤病变的严重程度，如前文所述。没有采用为CAD制定的已验证的评分表，因为它们是专门针对CAD的。研究者评估的皮炎VAS的结果反映了宠主的PVAS评分结果，与使用奥拉替尼观察到的结果相似。这也与在患有CAD的犬中获得的结果一致，其中洛基维特单抗治疗对皮肤炎症具有积极作用，这是通过降低犬特应性皮炎程度和严重性指数（CADESI）-03评分来评估的。
In total, 19 dogs were withdrawn from the study before D28: 16 in the control group and three in the treatment group. All were withdrawn owing to progressive or static clinical signs. Treatment failures are to be expected when managing dogs with allergic skin disease, and even drugs with broader modes of action – such as methylprednisolone and ciclosporin – failed to control clinical signs of some dogs with cAD in a trial reported previously. 在第28天之前，总共有19只犬退出了研究：对照组16只，治疗组3只。所有患犬均因进行性或静止性临床症状而退出。在治疗患有过敏性皮肤病的犬时，治疗失败是可以预料的，即使是具有更广泛作用模式的药物——如甲基泼尼松龙和环孢素——在先前报道的一项试验中也未能控制一些患有CAD的犬的临床症状。
The occurrence of abnormal health events was low and comparable between the treatment and placebo groups, and the nonremarkable haematological and serum chemical data also support the safety of Lokivetmab, even when used with a wide variety of medicines and vaccines commonly used in canine practice. It is acknowledged that the duration of this clinical trial was limited to 28 days. However, the long-term safety and efficacy of Lokivetmab has been demonstrated previously in field trials where dogs with cAD were treated and evaluated for up to nine months. 在治疗组和安慰剂组之间，异常健康事件的发生率较低且具有可比性，并且非显著的血液学和血清化学数据也支持洛基维特单抗的安全性。即使与犬临床中常用的各种药物和疫苗一起使用。公认的是，该临床试验的持续时间限制为28天。然而，洛基维特单抗的长期安全性和有效性已在先前的现场试验中得到证实，在这些试验中，患有CAD的犬接受了长达9个月的治疗和评估。
In conclusion, the results of this study demonstrate that neutralisation of IL-31 has an antipruritic effect in a broader population of dogs than just those with a confirmed diagnosis of cAD. In addition to alleviating pruritus, Lokivetmab also reduces inflammatory skin lesions. It therefore is a safe and efficaceous therapy for the treatment of dogs with various allergic dermatitides. 总之，本研究的结果表明，IL-31的中和在更广泛的犬群中具有止痒作用，而不仅仅是那些确诊为CAD的犬群。除了缓解瘙痒，洛基维特单抗还能减少炎性皮肤病变。因此，它是治疗患有各种过敏性皮炎的犬的一种安全有效的疗法。
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发表于 2022-7-1 15:37:26
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