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

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.