TY - JOUR
T1 - Macitentan for the treatment of portopulmonary hypertension (PORTICO)
T2 - a multicentre, randomised, double-blind, placebo-controlled, phase 4 trial
AU - Sitbon, Olivier
AU - Bosch, Jaume
AU - Cottreel, Emmanuelle
AU - Csonka, Denes
AU - de Groote, Pascal
AU - Hoeper, Marius M.
AU - Kim, Nick H.
AU - Martin, Nicolas
AU - Savale, Laurent
AU - Krowka, Michael
N1 - Funding Information:
This study was sponsored by Actelion Pharmaceuticals Ltd (Allschwil, Switzerland). The sponsor participated in the conception and design of the study, analysis and interpretation of the data, drafting and critical revision of the report, and approved submission of the manuscript. All authors had access to the data, reviewed and edited the manuscript, approved the final draft, and were involved in the decision to submit the manuscript for publication. All authors vouch for the accuracy and completeness of the analyses and for the fidelity of this report to the study protocol. The corresponding author was involved in the trial design, collection and interpretation of the data, and prepared the first draft of the manuscript with editorial assistance funded by the sponsor.
Funding Information:
OS has received grants, personal fees, and non-financial support from Actelion, Bayer and Merck, grants and personal fees from GlaxoSmithKline, and personal fees from Arena Pharmaceuticals and Acceloron. JB has received grants or personal fees from Actelion, Biovie, Barcelona Liver Bioservices, Brudy, Conatus, Exallenz, and Gilead and non-financial support from Actelion. EC, DC, and NM are employees of Actelion Pharmaceuticals Ltd and received non-financial support from Actelion. PdG reports personal fees and non-financial support from Novartis and Vifor, personal fees from Servier, Bayer and Merck Sharp & Dohme, Shire, and Mylan, and non-financial support from Actelion. MMH has received personal fees from Actelion, Bayer, Gilead, GlaxoSmithKline, Merck Sharp & Dohme, and Pfizer and non-financial support from Actelion. NHK has received personal fees from Actelion, Arena, Bayer, Merck, grants from Bellerphon, Eiger, Gilead, Lung Biotechnology and Soni Vie, and non-financial support from Actelion. LS and MK have received non-financial support from Actelion.
Funding Information:
The authors would like to thank all the patients and investigators who participated in the study. The steering committee members were Jaume Bosch, Marius Hoeper, Michael Krowka, Hyong (Nick) Kim and Olivier Sitbon. The Independent Liver Safety Data Review Board members were Willis Maddrey, Paul Watkins, and James Freston. Statistical analysis was done by Nicolas Martin, and pharmacokinetics analysis by Denes Csonka. Hepatic venous pressure gradient tracings were reviewed by a member of the steering committee (Jaume Bosch). The Independent Liver Safety Data Review Board reviewed patients with Hepatic Adverse Events of Special Interest. Medical writing and submission support were provided by Shuna Gould and Richard McDonald (Watermeadow Medical, an Ashfield Company), funded by Actelion Pharmaceuticals Ltd.
Publisher Copyright:
© 2019 Elsevier Ltd
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/7
Y1 - 2019/7
N2 - Background: No dedicated randomised clinical trials have evaluated therapies for pulmonary arterial hypertension in patients with portopulmonary hypertension. The endothelin receptor antagonist macitentan has demonstrated long-term efficacy in pulmonary arterial hypertension with a good hepatic safety profile. We aimed to evaluate efficacy and safety of macitentan in patients with portopulmonary hypertension. Methods: PORTICO was a phase 4 study done in 36 centres in seven countries, consisting of a 12-week double-blind period (randomly assigned 1:1 to macitentan 10 mg or placebo once daily) followed by a 12-week open-label period. Adults (≥18 years) with portopulmonary hypertension, a 6-minute walk distance of 50 m or more, and with pulmonary vascular resistance of 320 dyn·s·cm−5 or more without severe hepatic impairment (Child-Pugh class C or model for end-stage liver disease score ≥19) were eligible. The primary endpoint was pulmonary vascular resistance at week 12, expressed as ratio of baseline in the full analysis set. Safety was assessed throughout. This trial is registered at ClinicalTrials.gov, number NCT02382016. Findings: Between June 23, 2015, and July 28, 2017, 85 patients were randomly assigned to macitentan (n=43) or placebo (n=42). At baseline, 54 (64%) were receiving background therapy for pulmonary arterial hypertension. Most patients were WHO functional class II (50, 59%) or III (33, 39%) with a mean 6-minute walk distance of 384·5 m (SD 103·9). At week 12, the geometric mean ratio of baseline pulmonary vascular resistance was 0·63 (95% CI 0·58–0·67) in the macitentan group and 0·98 (95% CI 0·91–1·05) in the placebo group, corresponding to a ratio of geometric mean for pulmonary vascular resistance of 0·65 (95% CI 0·59–0·72, p<0·0001), which in turn represented a 35% (95% CI 28–41) reduction in pulmonary vascular resistance with macitentan versus placebo. During the double-blind period, 36 (84%) macitentan-treated and 33 (79%) placebo-treated patients had adverse events, and nine (21%) and six (14%), had serious adverse events. Four (9%) macitentan-treated patients had an adverse event leading to discontinuation versus none in the placebo group. The most frequent adverse event during the double-blind period was peripheral oedema (11 [26%] in the macitentan group and five [12%] in the placebo group). Interpretation: Macitentan significantly improved pulmonary vascular resistance in portopulmonary hypertension patients, with no hepatic safety concerns. Funding: Actelion Pharmaceuticals Ltd.
AB - Background: No dedicated randomised clinical trials have evaluated therapies for pulmonary arterial hypertension in patients with portopulmonary hypertension. The endothelin receptor antagonist macitentan has demonstrated long-term efficacy in pulmonary arterial hypertension with a good hepatic safety profile. We aimed to evaluate efficacy and safety of macitentan in patients with portopulmonary hypertension. Methods: PORTICO was a phase 4 study done in 36 centres in seven countries, consisting of a 12-week double-blind period (randomly assigned 1:1 to macitentan 10 mg or placebo once daily) followed by a 12-week open-label period. Adults (≥18 years) with portopulmonary hypertension, a 6-minute walk distance of 50 m or more, and with pulmonary vascular resistance of 320 dyn·s·cm−5 or more without severe hepatic impairment (Child-Pugh class C or model for end-stage liver disease score ≥19) were eligible. The primary endpoint was pulmonary vascular resistance at week 12, expressed as ratio of baseline in the full analysis set. Safety was assessed throughout. This trial is registered at ClinicalTrials.gov, number NCT02382016. Findings: Between June 23, 2015, and July 28, 2017, 85 patients were randomly assigned to macitentan (n=43) or placebo (n=42). At baseline, 54 (64%) were receiving background therapy for pulmonary arterial hypertension. Most patients were WHO functional class II (50, 59%) or III (33, 39%) with a mean 6-minute walk distance of 384·5 m (SD 103·9). At week 12, the geometric mean ratio of baseline pulmonary vascular resistance was 0·63 (95% CI 0·58–0·67) in the macitentan group and 0·98 (95% CI 0·91–1·05) in the placebo group, corresponding to a ratio of geometric mean for pulmonary vascular resistance of 0·65 (95% CI 0·59–0·72, p<0·0001), which in turn represented a 35% (95% CI 28–41) reduction in pulmonary vascular resistance with macitentan versus placebo. During the double-blind period, 36 (84%) macitentan-treated and 33 (79%) placebo-treated patients had adverse events, and nine (21%) and six (14%), had serious adverse events. Four (9%) macitentan-treated patients had an adverse event leading to discontinuation versus none in the placebo group. The most frequent adverse event during the double-blind period was peripheral oedema (11 [26%] in the macitentan group and five [12%] in the placebo group). Interpretation: Macitentan significantly improved pulmonary vascular resistance in portopulmonary hypertension patients, with no hepatic safety concerns. Funding: Actelion Pharmaceuticals Ltd.
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U2 - 10.1016/S2213-2600(19)30091-8
DO - 10.1016/S2213-2600(19)30091-8
M3 - Article
C2 - 31178422
AN - SCOPUS:85067648677
VL - 7
SP - 594
EP - 604
JO - The Lancet Respiratory Medicine
JF - The Lancet Respiratory Medicine
SN - 2213-2600
IS - 7
ER -