Stratified adaptive therapeutic studies in pulmonary arterial hypertension caused by mutations in BMPR2

肺动脉高压是一种毁灭性的限制生命的疾病，更有可能影响年轻女性。患者面临日常症状、过早死亡和潜在的肺移植。每4名患者中就有1名患有这种疾病的遗传型。治疗方法还没有解决这种疾病的潜在遗传原因。我们提出了有史以来第一次针对这种疾病的遗传形式的治疗试验，即一种名为骨形态发生2型受体的蛋白质的突变，使用了两种药物，这两种药物在改善患者和动物模型的细胞功能方面显示出了希望；羟氯喹和苯丁酸酯。我们之所以能够做到这一点，是因为MRC和英国心脏基金会之前在世界上最大的肺动脉高压基因研究中进行了投资，这些研究已经确定了英国的患者可能从这些治疗中受益。这项试验使用了一种新的给患者分配药物的方法--适应性设计。随着试验的进行，如果两种药物中的任何一种显示出更大的效果，试验将通过增加患者获得该药物的比例来“适应”这一新信息。这将允许团队一次测试一种以上的药物，但专注于效果更好的药物。这项试验将在英国全国范围内进行，所有7家国家认证的肺动脉高压中心都可以进行。

Pulmonary arterial hypertension is a devastating life-limiting disease more likely to affect young women. Patients face daily symptoms, an early death and potentially lung transplantation. 1 in 4 patients has a genetic form of the disease. Treatments do not address the underlying genetic cause of the disease yet. We propose the first ever trial of treatments aimed at the genetic form of the disease, mutations in a protein called the bone morphogenetic type 2 receptor, using 2 drugs that have shown promise in improving function in cells taken from patients and in animal models; hydroxychloroquine and phenylbutyrate. We have only been able to do this because of previous investment by the MRC and British Heart Foundation in the world's biggest genetic studies in pulmonary arterial hypertension that have identified patients in the UK who might benefit from the treatments. The trial uses a new way of assigning drugs to patients-an adaptive design. As the trial progresses if either drug is showing a bigger effect, the trial will "adapt" to this new information by increasing the proportion of patients who get the drug. This will allow the team to test more than one drug at a time but concentrate on drugs that are having bigger effects. The trial will be available all across the UK running from all 7 of the nationally accredited pulmonary hypertension centres.