Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study

Hossein Ardeschir Ghofrani; Gérald Simonneau; Andrea M. D'Armini; Peter Fedullo; Luke S. Howard; Xavier Jaïs; David P. Jenkins; Zhi Cheng Jing; Michael M. Madani; Nicolas Martin; Eckhard Mayer; Kelly Papadakis; Dominik Richard; Nick H. Kim; Irene Lang; Christian Kähler; Marion Delcroix; Zoheir Bshouty; Pablo Sepulveda Varela; Zhi Cheng Jing; Yuanhua Yang; Jinming Liu; Gangcheng Zhang; Nuofu Zhang; Yuhong Mi; Xianyang Zhu; Pavel Jansa; Xavier Jaïs; Grégoire Prévot; Hélène Bouvaist; Olivier Sanchez; Friedrich Grimminger; Matthias Held; Heinrike Wilkens; Stephan Rosenkranz; Ekkehard Grünig; Kristóf Karlócai; András Temesvári; Istvan Edes; Sigita Aidietienė; Skaidrius Miliauskas; Tomas Rene Pulido Zamudio; Carlos Jerjes Sanchez; Anton Vonk Noordegraaf; Jerzy Lewczuk; Piotr Podolec; Jarosław Kasprzak; Tatiana Mularek-Kubzdela; Ryszard Grzywna; Keertan Dheda; Olga Moiseeva; Alexander Chernyavskiy; Vladimir Shipulin; Olga Barbarash; Tamila Martynyuk; Hyung Kwan Kim; Jun Bean Park; Jae Seung Lee; Rudolf Speich; Silvia Ulrich; John David Aubert; Arintaya Phrommintikul; Nattapong Jaimchariyatam; Suree Sompradeekul; Zeynep Pinar Onen; Gulfer Okumus; Lyubomyr Solovey; Volodymyr Gavrysyuk; Luke Howard; Joanna Pepke-Zaba; Robin Condliffe; John McConnell; Kim Kerr; Lan Hieu Nguyen; Nguyen Vinh Pham

doi:10.1016/S2213-2600(17)30305-3

Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study

Hossein Ardeschir Ghofrani, Gérald Simonneau, Andrea M. D'Armini, Peter Fedullo, Luke S. Howard, Xavier Jaïs, David P. Jenkins, Zhi Cheng Jing, Michael M. Madani, Nicolas Martin, Eckhard Mayer, Kelly Papadakis, Dominik Richard, Nick H. Kim, Irene Lang, Christian Kähler, Marion Delcroix, Zoheir Bshouty, Pablo Sepulveda Varela, Zhi Cheng JingYuanhua Yang, Jinming Liu, Gangcheng Zhang, Nuofu Zhang, Yuhong Mi, Xianyang Zhu, Pavel Jansa, Xavier Jaïs, Grégoire Prévot, Hélène Bouvaist, Olivier Sanchez, Friedrich Grimminger, Matthias Held, Heinrike Wilkens, Stephan Rosenkranz, Ekkehard Grünig, Kristóf Karlócai, András Temesvári, Istvan Edes, Sigita Aidietienė, Skaidrius Miliauskas, Tomas Rene Pulido Zamudio, Carlos Jerjes Sanchez, Anton Vonk Noordegraaf, Jerzy Lewczuk, Piotr Podolec, Jarosław Kasprzak, Tatiana Mularek-Kubzdela, Ryszard Grzywna, Keertan Dheda, Olga Moiseeva, Alexander Chernyavskiy, Vladimir Shipulin, Olga Barbarash, Tamila Martynyuk, Hyung Kwan Kim, Jun Bean Park, Jae Seung Lee, Rudolf Speich, Silvia Ulrich, John David Aubert, Arintaya Phrommintikul, Nattapong Jaimchariyatam, Suree Sompradeekul, Zeynep Pinar Onen, Gulfer Okumus, Lyubomyr Solovey, Volodymyr Gavrysyuk, Luke Howard, Joanna Pepke-Zaba, Robin Condliffe, John McConnell, Kim Kerr, Lan Hieu Nguyen, Nguyen Vinh Pham

IRCCS Fondazione Policlinico San Matteo

Research output: Contribution to journal › Article › peer-review

Abstract

Background Macitentan is beneficial for long-term treatment of pulmonary arterial hypertension. The microvasculopathy of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension are similar. Methods The phase 2, double-blind, randomised, placebo-controlled MERIT-1 trial assessed macitentan in 80 patients with CTEPH adjudicated as inoperable. Patients identified as WHO functional class II–IV with a pulmonary vascular resistance (PVR) of at least 400 dyn·s/cm⁵ and a walk distance of 150–450 m in 6 min were randomly assigned (1:1), via an interactive voice/web response system, to receive oral macitentan (10 mg once a day) or placebo. Treatment with phosphodiesterase type-5 inhibitors and oral or inhaled prostanoids was permitted for WHO functional class III/IV patients. The primary endpoint was resting PVR at week 16, expressed as percentage of PVR measured at baseline. Analyses were done in all patients who were randomly assigned to treatment; safety analyses were done in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02021292. Findings Between April 3, 2014, and March 17, 2016, we screened 186 patients for eligibility at 48 hospitals across 20 countries. Of these, 80 patients in 36 hospitals were randomly assigned to treatment (40 patients to macitentan, 40 patients to placebo). At week 16, geometric mean PVR decreased to 73·0% of baseline in the macitentan group and to 87·2% in the placebo group (geometric means ratio 0·84, 95% CI 0·70–0·99, p=0·041). The most common adverse events in the macitentan group were peripheral oedema (9 [23%] of 40 patients) and decreased haemoglobin (6 [15%]). Interpretation In MERIT-1, macitentan significantly improved PVR in patients with inoperable CTEPH and was well tolerated. Funding Actelion Pharmaceuticals Ltd.

Original language	English
Pages (from-to)	785-794
Number of pages	10
Journal	The Lancet Respiratory Medicine
Volume	5
Issue number	10
DOIs	https://doi.org/10.1016/S2213-2600(17)30305-3
Publication status	Published - Oct 1 2017

ASJC Scopus subject areas

Pulmonary and Respiratory Medicine

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10.1016/S2213-2600(17)30305-3

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Ghofrani, H. A., Simonneau, G., D'Armini, A. M., Fedullo, P., Howard, L. S., Jaïs, X., Jenkins, D. P., Jing, Z. C., Madani, M. M., Martin, N., Mayer, E., Papadakis, K., Richard, D., Kim, N. H., Lang, I., Kähler, C., Delcroix, M., Bshouty, Z., Varela, P. S., ... Pham, N. V. (2017). Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study. The Lancet Respiratory Medicine, 5(10), 785-794. https://doi.org/10.1016/S2213-2600(17)30305-3

Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1) : results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study. / Ghofrani, Hossein Ardeschir; Simonneau, Gérald; D'Armini, Andrea M. et al.

In: The Lancet Respiratory Medicine, Vol. 5, No. 10, 01.10.2017, p. 785-794.

Research output: Contribution to journal › Article › peer-review

Ghofrani, HA, Simonneau, G, D'Armini, AM, Fedullo, P, Howard, LS, Jaïs, X, Jenkins, DP, Jing, ZC, Madani, MM, Martin, N, Mayer, E, Papadakis, K, Richard, D, Kim, NH, Lang, I, Kähler, C, Delcroix, M, Bshouty, Z, Varela, PS, Jing, ZC, Yang, Y, Liu, J, Zhang, G, Zhang, N, Mi, Y, Zhu, X, Jansa, P, Jaïs, X, Prévot, G, Bouvaist, H, Sanchez, O, Grimminger, F, Held, M, Wilkens, H, Rosenkranz, S, Grünig, E, Karlócai, K, Temesvári, A, Edes, I, Aidietienė, S, Miliauskas, S, Zamudio, TRP, Sanchez, CJ, Noordegraaf, AV, Lewczuk, J, Podolec, P, Kasprzak, J, Mularek-Kubzdela, T, Grzywna, R, Dheda, K, Moiseeva, O, Chernyavskiy, A, Shipulin, V, Barbarash, O, Martynyuk, T, Kim, HK, Park, JB, Lee, JS, Speich, R, Ulrich, S, Aubert, JD, Phrommintikul, A, Jaimchariyatam, N, Sompradeekul, S, Onen, ZP, Okumus, G, Solovey, L, Gavrysyuk, V, Howard, L, Pepke-Zaba, J, Condliffe, R, McConnell, J, Kerr, K, Nguyen, LH & Pham, NV 2017, 'Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study', The Lancet Respiratory Medicine, vol. 5, no. 10, pp. 785-794. https://doi.org/10.1016/S2213-2600(17)30305-3

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title = "Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study",

abstract = "Background Macitentan is beneficial for long-term treatment of pulmonary arterial hypertension. The microvasculopathy of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension are similar. Methods The phase 2, double-blind, randomised, placebo-controlled MERIT-1 trial assessed macitentan in 80 patients with CTEPH adjudicated as inoperable. Patients identified as WHO functional class II–IV with a pulmonary vascular resistance (PVR) of at least 400 dyn·s/cm5 and a walk distance of 150–450 m in 6 min were randomly assigned (1:1), via an interactive voice/web response system, to receive oral macitentan (10 mg once a day) or placebo. Treatment with phosphodiesterase type-5 inhibitors and oral or inhaled prostanoids was permitted for WHO functional class III/IV patients. The primary endpoint was resting PVR at week 16, expressed as percentage of PVR measured at baseline. Analyses were done in all patients who were randomly assigned to treatment; safety analyses were done in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02021292. Findings Between April 3, 2014, and March 17, 2016, we screened 186 patients for eligibility at 48 hospitals across 20 countries. Of these, 80 patients in 36 hospitals were randomly assigned to treatment (40 patients to macitentan, 40 patients to placebo). At week 16, geometric mean PVR decreased to 73·0% of baseline in the macitentan group and to 87·2% in the placebo group (geometric means ratio 0·84, 95% CI 0·70–0·99, p=0·041). The most common adverse events in the macitentan group were peripheral oedema (9 [23%] of 40 patients) and decreased haemoglobin (6 [15%]). Interpretation In MERIT-1, macitentan significantly improved PVR in patients with inoperable CTEPH and was well tolerated. Funding Actelion Pharmaceuticals Ltd.",

author = "Ghofrani, {Hossein Ardeschir} and G{\'e}rald Simonneau and D'Armini, {Andrea M.} and Peter Fedullo and Howard, {Luke S.} and Xavier Ja{\"i}s and Jenkins, {David P.} and Jing, {Zhi Cheng} and Madani, {Michael M.} and Nicolas Martin and Eckhard Mayer and Kelly Papadakis and Dominik Richard and Kim, {Nick H.} and Irene Lang and Christian K{\"a}hler and Marion Delcroix and Zoheir Bshouty and Varela, {Pablo Sepulveda} and Jing, {Zhi Cheng} and Yuanhua Yang and Jinming Liu and Gangcheng Zhang and Nuofu Zhang and Yuhong Mi and Xianyang Zhu and Pavel Jansa and Xavier Ja{\"i}s and Gr{\'e}goire Pr{\'e}vot and H{\'e}l{\`e}ne Bouvaist and Olivier Sanchez and Friedrich Grimminger and Matthias Held and Heinrike Wilkens and Stephan Rosenkranz and Ekkehard Gr{\"u}nig and Krist{\'o}f Karl{\'o}cai and Andr{\'a}s Temesv{\'a}ri and Istvan Edes and Sigita Aidietienė and Skaidrius Miliauskas and Zamudio, {Tomas Rene Pulido} and Sanchez, {Carlos Jerjes} and Noordegraaf, {Anton Vonk} and Jerzy Lewczuk and Piotr Podolec and Jaros{\l}aw Kasprzak and Tatiana Mularek-Kubzdela and Ryszard Grzywna and Keertan Dheda and Olga Moiseeva and Alexander Chernyavskiy and Vladimir Shipulin and Olga Barbarash and Tamila Martynyuk and Kim, {Hyung Kwan} and Park, {Jun Bean} and Lee, {Jae Seung} and Rudolf Speich and Silvia Ulrich and Aubert, {John David} and Arintaya Phrommintikul and Nattapong Jaimchariyatam and Suree Sompradeekul and Onen, {Zeynep Pinar} and Gulfer Okumus and Lyubomyr Solovey and Volodymyr Gavrysyuk and Luke Howard and Joanna Pepke-Zaba and Robin Condliffe and John McConnell and Kim Kerr and Nguyen, {Lan Hieu} and Pham, {Nguyen Vinh}",

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day = "1",

doi = "10.1016/S2213-2600(17)30305-3",

language = "English",

volume = "5",

pages = "785--794",

journal = "The Lancet Respiratory Medicine",

issn = "2213-2600",

publisher = "Elsevier Limited",

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TY - JOUR

T1 - Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1)

T2 - results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study

AU - Ghofrani, Hossein Ardeschir

AU - Simonneau, Gérald

AU - D'Armini, Andrea M.

AU - Fedullo, Peter

AU - Howard, Luke S.

AU - Jaïs, Xavier

AU - Jenkins, David P.

AU - Jing, Zhi Cheng

AU - Madani, Michael M.

AU - Martin, Nicolas

AU - Mayer, Eckhard

AU - Papadakis, Kelly

AU - Richard, Dominik

AU - Kim, Nick H.

AU - Lang, Irene

AU - Kähler, Christian

AU - Delcroix, Marion

AU - Bshouty, Zoheir

AU - Varela, Pablo Sepulveda

AU - Jing, Zhi Cheng

AU - Yang, Yuanhua

AU - Liu, Jinming

AU - Zhang, Gangcheng

AU - Zhang, Nuofu

AU - Mi, Yuhong

AU - Zhu, Xianyang

AU - Jansa, Pavel

AU - Jaïs, Xavier

AU - Prévot, Grégoire

AU - Bouvaist, Hélène

AU - Sanchez, Olivier

AU - Grimminger, Friedrich

AU - Held, Matthias

AU - Wilkens, Heinrike

AU - Rosenkranz, Stephan

AU - Grünig, Ekkehard

AU - Karlócai, Kristóf

AU - Temesvári, András

AU - Edes, Istvan

AU - Aidietienė, Sigita

AU - Miliauskas, Skaidrius

AU - Zamudio, Tomas Rene Pulido

AU - Sanchez, Carlos Jerjes

AU - Noordegraaf, Anton Vonk

AU - Lewczuk, Jerzy

AU - Podolec, Piotr

AU - Kasprzak, Jarosław

AU - Mularek-Kubzdela, Tatiana

AU - Grzywna, Ryszard

AU - Dheda, Keertan

AU - Moiseeva, Olga

AU - Chernyavskiy, Alexander

AU - Shipulin, Vladimir

AU - Barbarash, Olga

AU - Martynyuk, Tamila

AU - Kim, Hyung Kwan

AU - Park, Jun Bean

AU - Lee, Jae Seung

AU - Speich, Rudolf

AU - Ulrich, Silvia

AU - Aubert, John David

AU - Phrommintikul, Arintaya

AU - Jaimchariyatam, Nattapong

AU - Sompradeekul, Suree

AU - Onen, Zeynep Pinar

AU - Okumus, Gulfer

AU - Solovey, Lyubomyr

AU - Gavrysyuk, Volodymyr

AU - Howard, Luke

AU - Pepke-Zaba, Joanna

AU - Condliffe, Robin

AU - McConnell, John

AU - Kerr, Kim

AU - Nguyen, Lan Hieu

AU - Pham, Nguyen Vinh

PY - 2017/10/1

Y1 - 2017/10/1

N2 - Background Macitentan is beneficial for long-term treatment of pulmonary arterial hypertension. The microvasculopathy of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension are similar. Methods The phase 2, double-blind, randomised, placebo-controlled MERIT-1 trial assessed macitentan in 80 patients with CTEPH adjudicated as inoperable. Patients identified as WHO functional class II–IV with a pulmonary vascular resistance (PVR) of at least 400 dyn·s/cm5 and a walk distance of 150–450 m in 6 min were randomly assigned (1:1), via an interactive voice/web response system, to receive oral macitentan (10 mg once a day) or placebo. Treatment with phosphodiesterase type-5 inhibitors and oral or inhaled prostanoids was permitted for WHO functional class III/IV patients. The primary endpoint was resting PVR at week 16, expressed as percentage of PVR measured at baseline. Analyses were done in all patients who were randomly assigned to treatment; safety analyses were done in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02021292. Findings Between April 3, 2014, and March 17, 2016, we screened 186 patients for eligibility at 48 hospitals across 20 countries. Of these, 80 patients in 36 hospitals were randomly assigned to treatment (40 patients to macitentan, 40 patients to placebo). At week 16, geometric mean PVR decreased to 73·0% of baseline in the macitentan group and to 87·2% in the placebo group (geometric means ratio 0·84, 95% CI 0·70–0·99, p=0·041). The most common adverse events in the macitentan group were peripheral oedema (9 [23%] of 40 patients) and decreased haemoglobin (6 [15%]). Interpretation In MERIT-1, macitentan significantly improved PVR in patients with inoperable CTEPH and was well tolerated. Funding Actelion Pharmaceuticals Ltd.

AB - Background Macitentan is beneficial for long-term treatment of pulmonary arterial hypertension. The microvasculopathy of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension are similar. Methods The phase 2, double-blind, randomised, placebo-controlled MERIT-1 trial assessed macitentan in 80 patients with CTEPH adjudicated as inoperable. Patients identified as WHO functional class II–IV with a pulmonary vascular resistance (PVR) of at least 400 dyn·s/cm5 and a walk distance of 150–450 m in 6 min were randomly assigned (1:1), via an interactive voice/web response system, to receive oral macitentan (10 mg once a day) or placebo. Treatment with phosphodiesterase type-5 inhibitors and oral or inhaled prostanoids was permitted for WHO functional class III/IV patients. The primary endpoint was resting PVR at week 16, expressed as percentage of PVR measured at baseline. Analyses were done in all patients who were randomly assigned to treatment; safety analyses were done in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02021292. Findings Between April 3, 2014, and March 17, 2016, we screened 186 patients for eligibility at 48 hospitals across 20 countries. Of these, 80 patients in 36 hospitals were randomly assigned to treatment (40 patients to macitentan, 40 patients to placebo). At week 16, geometric mean PVR decreased to 73·0% of baseline in the macitentan group and to 87·2% in the placebo group (geometric means ratio 0·84, 95% CI 0·70–0·99, p=0·041). The most common adverse events in the macitentan group were peripheral oedema (9 [23%] of 40 patients) and decreased haemoglobin (6 [15%]). Interpretation In MERIT-1, macitentan significantly improved PVR in patients with inoperable CTEPH and was well tolerated. Funding Actelion Pharmaceuticals Ltd.

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Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study

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