Clinical trial protocol for TRANSFORM‐UK: A therapeutic open‐label study of tocilizumab in the treatment of pulmonary arterial hypertension

Abstract

Our aim is to assess the safety and potential efficacy of a novel treatment paradigm in pulmonary arterial hypertension (PAH), immunomodulation by blocking interleukin-6 (IL6) signaling with the IL6 receptor antagonist, tocilizumab. Inflammation and autoimmunity are established as important in PAH pathophysiology. One of the most robust observations across multiple cohorts in PAH has been an increase in IL6, both in the lung and systemically. Tocilizumab is an IL-6 receptor antagonist established as safe and effective, primarily in rheumatoid arthritis, and has shown promise in scleroderma. In case reports where the underlying cause of PAH is an inflammatory process such as systemic lupus erythematosus, mixed connective tissue disease (MCTD), and Castleman's disease, there have been case reports of regression of PAH with tocilizumab. TRANSFORM-UK is an open-label study of intravenous (IV) tocilizumab in patients with group 1 PAH. The co-primary outcome measures will be safety and the change in resting pulmonary vascular resistance (PVR). Clinically relevant secondary outcome measurements include 6-minute walk distance, WHO functional class, quality of life score, and N-terminal pro-brain natriuretic peptide (NT-proBNP). If the data support a potentially useful therapeutic effect with an acceptable risk profile, the study will be used to power a Phase III study to properly address efficacy.

Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective

“…In hypoxia-induced PH in mice, the attenuating effect of a blockade of IL-6 was also found [78]. Currently, the TRANSFORM-UK trial is running, in which PAH patients are being treated with anti-IL-6, and results of this study are expected soon [116].…”

Perivascular Inflammation in Pulmonary Arterial Hypertension

“…Transgenic mice deficient in IL-6R in vascular smooth muscle are protected against the development of PAH, whereas the administration of an IL-6R specific antagonist reversed experimental PAH in two rat models [ 28 ]. At present, an open-label study of the IL-6R antagonist tolicizumab for the treatment of pulmonary arterial hypertension (TRANSFORM-UK) is running, and results are expected soon [ 29 ].…”

Targeting inflammation and immunity in pulmonary arterial hypertension: any easier after the CANTOS proof‐of‐concept that anti‐inflammation cuts cardiovascular events?

“…In their manuscript, 10 Hernandez et al. try to overcome some of the limitations as discussed above, with sophisticated statistics, and provide a thorough and expanded explanation.…”