HAVEN: Hydroxychloroquine in ANCA Vasculitis Evaluation, a Phase II Multicentre, Randomised, Double Blind, Placebo Controlled Trial

ANCA血管炎是一种威胁生命的疾病，身体的防御系统变得过度活跃，导致小血管发炎，肾脏、肺部和其他重要器官受到损害。需要新的治疗方法，因为：1)20%的患者对治疗没有反应。2)在有反应的患者中，有一半的患者在药物减少时脉管炎疾病活动加剧。3)药物的副作用会带来比疾病更多的问题。对于非危及生命的ANCA血管炎，需要更安全的药物，因为积极的免疫抑制治疗是不合适的。多年来，羟基氯喹一直被用于治疗狼疮和类风湿性关节炎等相关疾病，其有害影响比传统的免疫抑制药物要小。因此，它是治疗ANCA血管炎的理想候选药物。我们的临床和研究实验室的初步数据表明，羟基氯喹对导致血管和组织炎症的细胞有影响，因此有望用于治疗ANCA血管炎。我们有30名ANCA脉管炎患者的试点数据，表明羟基氯喹耐受性良好，并改善了疾病活动的症状。这一点现在需要在一项对照研究中得到证实。羟基氯喹减少感染、癌症、血栓和心脏病的潜力是有用的特性，因为与普通公众相比，ANCA脉管炎患者的这些风险更高。据我们所知，目前还没有关于羟氯喹治疗ANCA血管炎的研究，尽管羟基氯喹在狼疮和类风湿性关节炎等相关疾病中的益处是显而易见的。我们建议的研究旨在证明，羟氯喹可以减少疾病活动性和症状，减少类固醇的需求及其副作用，减少对重要器官的损害，并提高生活质量。符合试验进入标准的76名非严重ANCA脉管炎患者将被邀请参加。在给予知情同意后，患者将被计算机随机分配(就像扔硬币一样)，在他们通常的药物(38名患者)或两片安慰剂(虚拟的)片剂(38名患者)和他们的常用药物的基础上，再获得2片羟基氯喹。治疗将持续一年，为了提高研究的质量，医生和患者都不知道他们是在服用羟基氯喹还是安慰剂。在研究的前三个月和最后三个月，患者将每月接受一次血液测试和安全评估，在一年的时间里，每三个月一次。我们计划在研究完成后测量血液中羟氯喹的水平，以评估研究药物的依从性。这些信息还将允许与疾病对治疗的反应相关。如果试验显示出没有统计学意义的小益处，但提供了羟氯喹有效的证据，我们将继续进行一项有更多患者参加的更大规模的研究(第三阶段试验)。然而，如果我们的研究显示羟基氯喹有很大的益处，类似于在狼疮患者中看到的效果，那么就不需要进行更大规模的试验，羟基氯喹可能成为ANCA血管炎患者的标准治疗方法。这将代表着对这些患者的护理方面的重大进步。鉴于羟基氯喹是一种相对便宜的治疗方法，医疗服务的总体成本可能会降低。

ANCA vasculitis is a life-threatening disease where the body's defence system becomes overactive, causing inflammation of small blood vessels and damage to the kidneys, lungs and other vital organs. New treatments are needed because: 1) 20% of patients do not respond to treatment. 2) In half the patients who respond, vasculitis disease activity flares when medicines are reduced. 3) The side effects of medicines can cause more problems than the disease. Safer medicines are needed for non-life threatening ANCA vasculitis, where aggressive immune suppressing treatment is not appropriate. Hydroxychloroquine has been used for many years to treat related diseases such as lupus and rheumatoid arthritis with fewer harmful effects than conventional immune suppressing drugs. It is therefore an ideal candidate to treat ANCA vasculitis. We have preliminary data from our clinics and research laboratories showing that hydroxychloroquine has effects on cells which cause inflammation of blood vessels and tissues and is therefore expected to work in treating ANCA vasculitis. We have pilot data on 30 patients with ANCA vasculitis, showing that hydroxychloroquine is well tolerated and improves symptoms of disease activity. This now needs to be confirmed in a controlled study.The potential of hydroxychloroquine to reduce infections, cancer, blood clots and heart disease are useful properties, as these risks are higher in ANCA vasculitis patients compared to the general public. To our knowledge, no studies have been published on hydroxychloroquine in ANCA vasculitis, although the benefits of hydroxychloroquine in related diseases such as lupus and rheumatoid arthritis are clear. Our proposed study aims to demonstrate that hydroxychloroquine reduces disease activity and flares, the need for steroids and their side effects, damage to vital organs and improves quality of life. 76 patients with non-severe ANCA vasculitis who meet the entry criteria for the trial will be invited to participate. After giving their informed consent, patients will be allocated by chance (like tossing a coin) by a computer to receive 2 tablets of hydroxychloroquine in addition to their usual medications (38 patients) or two placebo ("dummy") tablets (38 patients) and their usual medications. Treatment will continue for 1 year and, in order to improve the quality of the study, neither the doctors nor the patients will know if they are taking hydroxychloroquine or placebo. Patients will be seen and have blood tests and safety assessments monthly for the first and last 3 months of the study and every 3 months in between for 1 year. We plan to measure blood levels of hydroxychloroquine to assess adherence to the study medication after the study has been completed. This information will also allow correlations with the response of the disease to treatment.If the trial shows a small beneficial effect that is not statistically significant, but provides evidence that hydroxychloroquine could work, we will proceed to a larger study with more patients (Phase III trial). However, if our study shows a large beneficial effect of hydroxychloroquine, similar to that seen in lupus patients, a larger trial would not be needed and hydroxychloroquine could become part of the standard treatment for ANCA vasculitis patients. This would represent a significant advance in the care of these patients. Given that hydroxychloroquine is a relatively inexpensive treatment, the overall cost to the health service could be reduced.