Selexipag for the Treatment of Pulmonary Arterial Hypertension

Olivier Sitbon, Richard N. Channick, Kelly M Chin, Aline Frey, Sean P. Gaine, Nazzareno Galiè, Hossein-Ardeschir Ghofrani, Marius M. Hoeper, Irene M. Lang, Ralph Preiss, Lewis J. Rubin, Lilla Di Scala, Victor F. Tapson, Igor Adzerikho, Jinming Liu, Olga Moiseeva, Xiaofeng Zeng, Gérald Simonneau, Vallerie V. McLaughlin, GRIPHON Investigators

Research output: Contribution to journalArticle

Abstract

BACKGROUND: In a phase 2 trial, selexipag, an oral selective IP prostacyclin-receptor agonist, was shown to be beneficial in the treatment of pulmonary arterial hypertension.

METHODS: In this event-driven, phase 3, randomized, double-blind, placebo-controlled trial, we randomly assigned 1156 patients with pulmonary arterial hypertension to receive placebo or selexipag in individualized doses (maximum dose, 1600 μg twice daily). Patients were eligible for enrollment if they were not receiving treatment for pulmonary arterial hypertension or if they were receiving a stable dose of an endothelin-receptor antagonist, a phosphodiesterase type 5 inhibitor, or both. The primary end point was a composite of death from any cause or a complication related to pulmonary arterial hypertension up to the end of the treatment period (defined for each patient as 7 days after the date of the last intake of selexipag or placebo).

RESULTS: A primary end-point event occurred in 397 patients--41.6% of those in the placebo group and 27.0% of those in the selexipag group (hazard ratio in the selexipag group as compared with the placebo group, 0.60; 99% confidence interval, 0.46 to 0.78; P<0.001). Disease progression and hospitalization accounted for 81.9% of the events. The effect of selexipag with respect to the primary end point was similar in the subgroup of patients who were not receiving treatment for the disease at baseline and in the subgroup of patients who were already receiving treatment at baseline (including those who were receiving a combination of two therapies). By the end of the study, 105 patients in the placebo group and 100 patients in the selexipag group had died from any cause. Overall, 7.1% of patients in the placebo group and 14.3% of patients in the selexipag group discontinued their assigned regimen prematurely because of adverse events. The most common adverse events in the selexipag group were consistent with the known side effects of prostacyclin, including headache, diarrhea, nausea, and jaw pain.

CONCLUSIONS: Among patients with pulmonary arterial hypertension, the risk of the primary composite end point of death or a complication related to pulmonary arterial hypertension was significantly lower with selexipag than with placebo. There was no significant difference in mortality between the two study groups. (Funded by Actelion Pharmaceuticals; GRIPHON ClinicalTrials.gov number, NCT01106014.).

Original languageEnglish
Pages (from-to)2522-33
Number of pages12
JournalNew England Journal of Medicine
Volume373
Issue number26
DOIs
Publication statusPublished - Dec 24 2015
Externally publishedYes

Fingerprint

Pulmonary Hypertension
Placebos
Therapeutics
selexipag
Epoprostenol Receptors
Phosphodiesterase 5 Inhibitors
Epoprostenol
Jaw
Nausea
Headache
Disease Progression
Cause of Death
Diarrhea
Hospitalization
Confidence Intervals
Pain
Mortality

Keywords

  • Acetamides
  • Aged
  • Disease Progression
  • Double-Blind Method
  • Drug Administration Schedule
  • Female
  • Hospitalization
  • Humans
  • Hypertension, Pulmonary
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Prodrugs
  • Pyrazines
  • Clinical Trial, Phase III
  • Journal Article
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

Cite this

Sitbon, O., Channick, R. N., Chin, K. M., Frey, A., Gaine, S. P., Galiè, N., ... GRIPHON Investigators (2015). Selexipag for the Treatment of Pulmonary Arterial Hypertension. New England Journal of Medicine, 373(26), 2522-33. https://doi.org/10.1056/NEJMoa1503184

Selexipag for the Treatment of Pulmonary Arterial Hypertension. / Sitbon, Olivier; Channick, Richard N.; Chin, Kelly M; Frey, Aline; Gaine, Sean P.; Galiè, Nazzareno; Ghofrani, Hossein-Ardeschir; Hoeper, Marius M.; Lang, Irene M.; Preiss, Ralph; Rubin, Lewis J.; Di Scala, Lilla; Tapson, Victor F.; Adzerikho, Igor; Liu, Jinming; Moiseeva, Olga; Zeng, Xiaofeng; Simonneau, Gérald; McLaughlin, Vallerie V.; GRIPHON Investigators.

In: New England Journal of Medicine, Vol. 373, No. 26, 24.12.2015, p. 2522-33.

Research output: Contribution to journalArticle

Sitbon, O, Channick, RN, Chin, KM, Frey, A, Gaine, SP, Galiè, N, Ghofrani, H-A, Hoeper, MM, Lang, IM, Preiss, R, Rubin, LJ, Di Scala, L, Tapson, VF, Adzerikho, I, Liu, J, Moiseeva, O, Zeng, X, Simonneau, G, McLaughlin, VV & GRIPHON Investigators 2015, 'Selexipag for the Treatment of Pulmonary Arterial Hypertension', New England Journal of Medicine, vol. 373, no. 26, pp. 2522-33. https://doi.org/10.1056/NEJMoa1503184
Sitbon O, Channick RN, Chin KM, Frey A, Gaine SP, Galiè N et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. New England Journal of Medicine. 2015 Dec 24;373(26):2522-33. https://doi.org/10.1056/NEJMoa1503184
Sitbon, Olivier ; Channick, Richard N. ; Chin, Kelly M ; Frey, Aline ; Gaine, Sean P. ; Galiè, Nazzareno ; Ghofrani, Hossein-Ardeschir ; Hoeper, Marius M. ; Lang, Irene M. ; Preiss, Ralph ; Rubin, Lewis J. ; Di Scala, Lilla ; Tapson, Victor F. ; Adzerikho, Igor ; Liu, Jinming ; Moiseeva, Olga ; Zeng, Xiaofeng ; Simonneau, Gérald ; McLaughlin, Vallerie V. ; GRIPHON Investigators. / Selexipag for the Treatment of Pulmonary Arterial Hypertension. In: New England Journal of Medicine. 2015 ; Vol. 373, No. 26. pp. 2522-33.
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TY - JOUR

T1 - Selexipag for the Treatment of Pulmonary Arterial Hypertension

AU - Sitbon, Olivier

AU - Channick, Richard N.

AU - Chin, Kelly M

AU - Frey, Aline

AU - Gaine, Sean P.

AU - Galiè, Nazzareno

AU - Ghofrani, Hossein-Ardeschir

AU - Hoeper, Marius M.

AU - Lang, Irene M.

AU - Preiss, Ralph

AU - Rubin, Lewis J.

AU - Di Scala, Lilla

AU - Tapson, Victor F.

AU - Adzerikho, Igor

AU - Liu, Jinming

AU - Moiseeva, Olga

AU - Zeng, Xiaofeng

AU - Simonneau, Gérald

AU - McLaughlin, Vallerie V.

AU - GRIPHON Investigators

PY - 2015/12/24

Y1 - 2015/12/24

N2 - BACKGROUND: In a phase 2 trial, selexipag, an oral selective IP prostacyclin-receptor agonist, was shown to be beneficial in the treatment of pulmonary arterial hypertension.METHODS: In this event-driven, phase 3, randomized, double-blind, placebo-controlled trial, we randomly assigned 1156 patients with pulmonary arterial hypertension to receive placebo or selexipag in individualized doses (maximum dose, 1600 μg twice daily). Patients were eligible for enrollment if they were not receiving treatment for pulmonary arterial hypertension or if they were receiving a stable dose of an endothelin-receptor antagonist, a phosphodiesterase type 5 inhibitor, or both. The primary end point was a composite of death from any cause or a complication related to pulmonary arterial hypertension up to the end of the treatment period (defined for each patient as 7 days after the date of the last intake of selexipag or placebo).RESULTS: A primary end-point event occurred in 397 patients--41.6% of those in the placebo group and 27.0% of those in the selexipag group (hazard ratio in the selexipag group as compared with the placebo group, 0.60; 99% confidence interval, 0.46 to 0.78; P<0.001). Disease progression and hospitalization accounted for 81.9% of the events. The effect of selexipag with respect to the primary end point was similar in the subgroup of patients who were not receiving treatment for the disease at baseline and in the subgroup of patients who were already receiving treatment at baseline (including those who were receiving a combination of two therapies). By the end of the study, 105 patients in the placebo group and 100 patients in the selexipag group had died from any cause. Overall, 7.1% of patients in the placebo group and 14.3% of patients in the selexipag group discontinued their assigned regimen prematurely because of adverse events. The most common adverse events in the selexipag group were consistent with the known side effects of prostacyclin, including headache, diarrhea, nausea, and jaw pain.CONCLUSIONS: Among patients with pulmonary arterial hypertension, the risk of the primary composite end point of death or a complication related to pulmonary arterial hypertension was significantly lower with selexipag than with placebo. There was no significant difference in mortality between the two study groups. (Funded by Actelion Pharmaceuticals; GRIPHON ClinicalTrials.gov number, NCT01106014.).

AB - BACKGROUND: In a phase 2 trial, selexipag, an oral selective IP prostacyclin-receptor agonist, was shown to be beneficial in the treatment of pulmonary arterial hypertension.METHODS: In this event-driven, phase 3, randomized, double-blind, placebo-controlled trial, we randomly assigned 1156 patients with pulmonary arterial hypertension to receive placebo or selexipag in individualized doses (maximum dose, 1600 μg twice daily). Patients were eligible for enrollment if they were not receiving treatment for pulmonary arterial hypertension or if they were receiving a stable dose of an endothelin-receptor antagonist, a phosphodiesterase type 5 inhibitor, or both. The primary end point was a composite of death from any cause or a complication related to pulmonary arterial hypertension up to the end of the treatment period (defined for each patient as 7 days after the date of the last intake of selexipag or placebo).RESULTS: A primary end-point event occurred in 397 patients--41.6% of those in the placebo group and 27.0% of those in the selexipag group (hazard ratio in the selexipag group as compared with the placebo group, 0.60; 99% confidence interval, 0.46 to 0.78; P<0.001). Disease progression and hospitalization accounted for 81.9% of the events. The effect of selexipag with respect to the primary end point was similar in the subgroup of patients who were not receiving treatment for the disease at baseline and in the subgroup of patients who were already receiving treatment at baseline (including those who were receiving a combination of two therapies). By the end of the study, 105 patients in the placebo group and 100 patients in the selexipag group had died from any cause. Overall, 7.1% of patients in the placebo group and 14.3% of patients in the selexipag group discontinued their assigned regimen prematurely because of adverse events. The most common adverse events in the selexipag group were consistent with the known side effects of prostacyclin, including headache, diarrhea, nausea, and jaw pain.CONCLUSIONS: Among patients with pulmonary arterial hypertension, the risk of the primary composite end point of death or a complication related to pulmonary arterial hypertension was significantly lower with selexipag than with placebo. There was no significant difference in mortality between the two study groups. (Funded by Actelion Pharmaceuticals; GRIPHON ClinicalTrials.gov number, NCT01106014.).

KW - Acetamides

KW - Aged

KW - Disease Progression

KW - Double-Blind Method

KW - Drug Administration Schedule

KW - Female

KW - Hospitalization

KW - Humans

KW - Hypertension, Pulmonary

KW - Kaplan-Meier Estimate

KW - Male

KW - Middle Aged

KW - Prodrugs

KW - Pyrazines

KW - Clinical Trial, Phase III

KW - Journal Article

KW - Multicenter Study

KW - Randomized Controlled Trial

KW - Research Support, Non-U.S. Gov't

U2 - 10.1056/NEJMoa1503184

DO - 10.1056/NEJMoa1503184

M3 - Article

C2 - 26699168

VL - 373

SP - 2522

EP - 2533

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 26

ER -