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Rationale and design of the REPLACE trial: Riociguat rEplacing Phosphodiesterase 5 inhibitor (PDE5i) therapy evaLuated Against Continued PDE5i thErapy in patients with pulmonary arterial hypertension

Marius Hoeper


Hossein-Ardeschir Ghofrani

Raymond Benza


Paul Corris

Simon Gibbs

Martha Kingman


James Klinger


David Langleben


Vallerie McLaughlin


Andrew Peacock


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Conference: 2017 PH Professional Network Symposium

Release Date: 10.06.2017

Presentation Type: Abstracts

File Download: 2017 PHPN Abstract 1007

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Abstract presented at the 2017 PH Professional Network Symposium held in Bethesda, MD on October 5-7, 2017

Authors Continued:

  • Stephan Rosenkranz, MD, Department of Cardiology, Heart Center at the University Hospital Cologne, and Cologne Cardiovascular Research Center, Cologne, Germany;
  • Anton Vonk-Noordegraf, PhD, Department of Pulmonary Diseases, VU University Medical Center/ Institute for Cardiovascular Research, Amsterdam, The Netherlands;
  • James White, MD, Division of Pulmonary and Critical Care Medicine and the Mary M. Parkes Center, University of Rochester Medical Center, Rochester, NY, USA;
  • Frank Kleinjung, MD, Bayer AG, Berlin, Germany;
  • Christian Meier, MD, Bayer AG, Berlin, Germany;
  • Gérald Simonneau, MD, Assistance Publique–Hôpitaux de Paris, Service de Pneumologie, Hôpital Bicêtre, Université Paris-Sud, Laboratoire d’Excellence en Recherche sur le Médicament et Innovation Thérapeutique, and INSERM Unité 999, Le Kremlin–Bicêtre, France

Purpose

The REPLACE study (NCT02891850) will investigate the potential efficacy and safety benefits of switching to riociguat versus continued treatment with PDE5i therapy in patients with pulmonary arterial hypertension (PAH).

Background

A significant proportion of patients with PAH fail to achieve or maintain treatment goals with PDE5i therapy. This may indicate impairment of the nitric oxide–soluble guanylate cyclase (sGC) pathway, leading to insufficient endogenous cyclic guanosine monophosphate levels. Data from the single-arm, open-label RESPITE study provided preliminary evidence that these patients may benefit from switching from PDE5i to riociguat, an sGC stimulator.
Methods

REPLACE is a prospective, randomized, international, multicenter, two-arm, 24-week, controlled, open-label study in patients aged 18–75 years with PAH who do not achieve or maintain treatment goals with PDE5i therapy. Insufficient clinical response to PDE5i therapy at screening is determined by: World Health Organization (WHO) functional class (FC) III and 6-minute walking distance (6MWD) 165–440 m, despite stable doses of PDE5i with or without background endothelin receptor antagonists (ERAs). Eligible patients will be randomized to remain on PDE5i treatment (sildenafil 60 mg minimum daily or once-daily tadalafil 20–40 mg) or switch to riociguat up to a maximum of 2.5 mg tid (dose adjusted from a starting dose of 1.0 mg tid) (figure). Riociguat therapy will be initiated following washout periods of 24 and 48 hours for sildenafil and tadalafil, respectively. ERA treatment will be continued at the stable dose in both arms.

Results

The planned enrollment of REPLACE is 218 patients. The primary efficacy endpoint ‘satisfactory clinical response’ will be assessed at Week 24 and is defined as a composite fulfillment of 2 of the 3 parameters – ≥10% or ≥30 m increase from baseline in 6MWD; WHO FC I or II; and ≥30% reduction from baseline N-terminal prohormone of brain natriuretic peptide (NT-proBNP) – in the absence of clinical worsening. This will be reviewed and confirmed by an independent clinical endpoint committee. Secondary efficacy outcomes will comprise change from baseline in 6MWD (blinded assessment), NT-proBNP, WHO FC (blinded assessment), and clinical worsening. Exploratory analyses will include quality of life (Living with Pulmonary Hypertension questionnaire), modified REVEAL risk score, and cardiac magnetic resonance imaging of a subset of patients. Safety will be evaluated by adverse events and all-cause mortality.

Conclusion

The REPLACE study will evaluate whether it is clinically beneficial to switch patients with PAH who do not achieve or maintain treatment goals with PDE5i therapy to riociguat.