title: Rationale and study design of RESPITE: An open-label, phase 3b study of riociguat in patients with pulmonary arterial hypertension who demonstrate an insufficient response to treatment with phosphodiesterase-5 inhibitors.
abstract: Patients with pulmonary arterial hypertension (PAH) who do not have an adequate response to therapy with phosphodiesterase-5 inhibitors (PDE-5i) may have insufficient synthesis of cyclic guanosine monophosphate (cGMP). These patients may respond to a direct soluble guanylate cyclase (sGC) stimulator such as riociguat. RESPITE (NCT02007629) was an open-label, multicenter, uncontrolled, single-arm phase 3b study of riociguat in patients with PAH who demonstrated an insufficient response to treatment with PDE-5i. Insufficient response was defined as World Health Organization functional class (WHO FC) III despite PDE-5i therapy for at least 90 days; 6-min walk distance (6MWD) of 165-440 m, and right-heart catheterization showing mean pulmonary artery pressure >30 mmHg, cardiac index <3.0 L/min/m2, and pulmonary vascular resistance >400 dyn s cm-5. PAH patients with an insufficient response to stable doses of sildenafil or tadalafil-either as monotherapy or in combination with an endothelin receptor antagonist-for at least 90 days were switched to riociguat for 24 weeks. Starting at 1.0 mg TID, the dose of riociguat was increased during the 8-week titration phase in 0.5-mg increments in 2-week intervals if the patient had no signs or symptoms of hypotension. In the ensuing 16-week maintenance phase, riociguat was continued at the optimal individual dose. All efficacy outcomes were exploratory and include change from baseline to 24 weeks in 6MWD, cardiac index, N-terminal pro-brain natriuretic peptide, WHO FC, and quality of life and the proportion of patients with clinical worsening. The following biomarkers were to be measured: cGMP, asymmetric dimethyl arginine, growth-differentiation factor-15, and ST2. Results from RESPITE will help to determine if PAH patients who do not respond to PDE-5i are likely to benefit from treatment with an sGC stimulator. The study may also identify biomarkers that are able to suggest which patients are more likely to respond to sGC stimulators.
authors.affiliation: Department of Respiratory Medicine and German Center of Lung Research, Hannover Medical School, Hannover, Germany. Electronic address: Hoeper.Marius@mh-hannover.de.
authors.forename: Marius M
authors.initials: MM
authors.lastname: Hoeper
authors.affiliation: Pulmonary Hypertension Center, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Klinger
authors.affiliation: Advanced Heart Failure, Transplant, Mechanical Circulatory Support and Pulmonary Hypertension Section, Allegheny Health Network, Pittsburgh, PA, USA.
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Benza
authors.affiliation: Department of Pneumology and Intensive Care Medicine, Hôpital Kremlin Bicêtre, Paris-Sud University, Orsay, France.
authors.forename: Gerald
authors.initials: G
authors.lastname: Simonneau
authors.affiliation: McGill University, Cardiology Division and Center for Pulmonary Vascular Disease, Jewish General Hospital, Montréal, QC, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Langleben
authors.affiliation: Department of Cardiology, The Free University of Brussels, Brussels, Belgium.
authors.forename: Robert
authors.initials: R
authors.lastname: Naeije
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Corris
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D065128:Endothelin Receptor Antagonists / Q000008:administration & dosage; D020536:Enzyme Activators / Q000008:administration & dosage; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D017063:Outcome Assessment, Health Care; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage*; D011720:Pyrazoles / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D011788:Quality of Life; D000068677:Sildenafil Citrate / Q000008:administration & dosage; D000071756:Soluble Guanylyl Cyclase / Q000378:metabolism; D055815:Young Adult
chemical_list: D065128:Endothelin Receptor Antagonists; D020536:Enzyme Activators; D058986:Phosphodiesterase 5 Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D020097:Natriuretic Peptide, Brain; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D000071756:Soluble Guanylyl Cyclase; C542595:riociguat
keywords: Pulmonary arterial hypertension; Riociguat; Soluble guanylate cyclase; sGC stimulator