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

HAVEN：羟氯喹用于 ANCA 血管炎评估，一项 II 期多中心、随机、双盲、安慰剂对照试验

• 批准号: MR/R006253/1
• 负责人: David D'Cruz
• 金额: $ 100.85万
• 依托单位: Guy's and St Thomas' NHS Foundation Trust
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR006253%2F1
• 关键词: HAVEN; Hydroxychloroquine; ANCA; Vasculitis; Evaluation

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.

ANCA 血管炎是一种危及生命的疾病，身体的防御系统变得过度活跃，导致小血管发炎并对肾脏、肺和其他重要器官造成损害。需要新的治疗方法是因为：1) 20% 的患者对治疗没有反应。 2) 在一半有反应的患者中，当药物减少时，血管炎疾病活动加剧。 3）药物的副作用比疾病引起的问题更多。对于不危及生命的 ANCA 血管炎，需要更安全的药物，在这种情况下，积极的免疫抑制治疗是不合适的。羟氯喹多年来一直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更少。因此，它是治疗 ANCA 血管炎的理想候选药物。我们的诊所和研究实验室的初步数据显示，羟氯喹对引起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 血管炎患者的试点数据，表明羟氯喹耐受性良好，可改善疾病活动症状。现在这一点需要在对照研究中得到证实。羟氯喹减少感染、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 血管炎患者的这些风险更高。据我们所知，尚未发表关于羟氯喹治疗 ANCA 血管炎的研究，尽管羟氯喹对狼疮和类风湿性关节炎等相关疾病的益处是明确的。我们提出的研究旨在证明羟氯喹可以减少疾病活动和发作、类固醇的需求及其副作用、对重要器官的损害并提高生活质量。将邀请76名符合试验入选标准的非严重ANCA血管炎患者参加。在给予患者知情同意后，计算机将随机（如抛硬币）分配患者在常用药物（38 名患者）之外服用 2 片羟氯喹或两片安慰剂（“假药”）片剂（38 名患者）以及他们常用的药物。治疗将持续一年，为了提高研究质量，医生和患者都不会知道他们服用的是羟氯喹还是安慰剂。在研究的前 3 个月和最后 3 个月，每月对患者进行一次血液检查和安全性评估，期间每 3 个月进行一次，持续 1 年。我们计划在研究完成后测量羟氯喹的血液水平，以评估对研究药物的依从性。这些信息还将与疾病对治疗的反应建立相关性。如果试验显示出一个小的有益效果，虽然在统计上不显着，但提供了羟氯喹可能有效的证据，我们将进行一项涉及更多患者的更大规模的研究（第三阶段）审判）。然而，如果我们的研究显示羟氯喹具有与狼疮患者相似的巨大有益作用，则不需要进行更大规模的试验，羟氯喹可能成为 ANCA 血管炎患者标准治疗的一部分。这将代表这些患者护理方面的重大进步。鉴于羟氯喹是一种相对便宜的治疗方法，卫生服务的总体成本可以降低。

项目成果

The HAVEN study-hydroxychloroquine in ANCA vasculitis evaluation-a multicentre, randomised, double-blind, placebo-controlled trial: study protocol and statistical analysis plan.

• DOI: 10.1186/s13063-023-07108-3
• 发表时间: 2023-04-06
• 期刊: Trials
• 影响因子: 2.5