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Selexipag for the Treatment of Pulmonary Arterial Hypertension

SITBON, Olivier, et al. & GRIPHON Investigators

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, [...]

SITBON, Olivier, et al. & GRIPHON Investigators. Selexipag for the Treatment of Pulmonary Arterial Hypertension. New England Journal of Medicine, 2015, vol. 373, no. 26, p.

2522-2533

DOI : 10.1056/NEJMoa1503184

Available at:

http://archive-ouverte.unige.ch/unige:83660

Disclaimer: layout of this document may differ from the published version.

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This appendix has been provided by the authors to give readers additional information about their work.

Supplement to: Sitbon O, Channick R, Chin KM, et al. Selexipag for the treatment of pulmonary arterial hyperten- sion. N Engl J Med 2015;373:2522-33. DOI: 10.1056/NEJMoa1503184

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SUPPLEMENTARY APPENDIX

Contents

1. LIST OF INVESTIGATORS ... 3

2. LIST OF STEERING COMMITTEE MEMBERS ... 7

3. LIST OF CRITICAL EVENT COMMITTEE MEMBERS ... 8

4. LIST OF DATA AND SAFETY MONITORING COMMITTEE MEMBERS ... 8

5. BLEEDING CASES ADJUDICATORS ... 8

6. GRIPHON STUDY STATISTICAL ANALYSIS PLAN REVIEWERS ... 8

7. FOLLOW-UP OF PATIENTS WHO DISCONTINUED TREATMENT ... 8

8. TREATMENT DISCONTINUATIONS AND SENSITIVITY ANALYSES ... 9

1. Primary end point ... 9

2. All-cause Mortality Up to End of Study ... 11

9. IMPUTATION RULES FOR MISSING 6-MINUTE WALK DISTANCE ... 11

10. FIGURE S1. DOSE ADJUSTMENT (TITRATION) SCHEME ...13

11. FIGURE S2. GRIPHON STUDY DESIGN ...14

11. FIGURE S3. EFFECT OF SELEXIPAG ON THE PRIMARY COMPOSITE END POINT EXCLUDING EVENTS THAT OCCURRED PRIOR TO INCREASING THE SAMPLE SIZE .15 12. FIGURE S4. EFFECT OF SELEXIPAG ON THE PRIMARY COMPOSITE END POINT IN PATIENTS GROUPED BY PRESPECIFIED SELEXIPAG INDIVIDUAL MAINTENANCE DOSE VERSUS PLACEBO ...16

13. FIGURE S5. EFFECT OF SELEXIPAG ON THE PRIMARY COMPOSITE END POINT BY PRESPECIFIED SUBGROUP ...18

14. TABLE S1. SENSITIVITY ANALYSES (A, B, AND C) OF THE PRIMARY ANALYSIS ...19

15. TABLE S2. INDIVIDUAL MAINTENANCE DOSE ...20

16. TABLE S3. ABSENCE OF WORSENING IN FUNCTIONAL CLASS FROM BASELINE TO WEEK 26 ...21

17. TABLE S4. SENSITIVITY ANALYSIS (A) OF THE SECONDARY END POINT ALL- CAUSE MORTALITY UP TO END OF STUDY ANALYSIS ...22

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18. TABLE S5. CHANGE IN N-TERMINAL PRO-BRAIN NATRIURETIC PEPTIDE (NT-

proBNP) FROM BASELINE TO WEEK 26 ...23 19. TABLE S6. PROSTACYCLIN-ASSOCIATED ADVERSE EVENTS REPORTED IN THE DOSE-ADJUSTMENT AND MAINTENANCE PHASES ...24

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1. LIST OF INVESTIGATORS

The prostacyclin (PGI2) receptor agonist in pulmonary arterial hypertension (GRIPHON) Investigators are as follows: Argentina – Hospital Privado de Cordoba, Cordoba: M Amuchastegui; Instituto de Cardiologia, Corrientes: E Perna; Sanatorio San Jose, Buenos Aires: G Bortman; Hospital Britanico, Buenos Aires: FJ Chertcoff; Sanatorio Otamendi y Miroli, Buenos Aires: R Gene; Centro de Investigaciones Cardiovasculares, Buenos Aires:

JO Caneva. Australia – The Royal Hobart Hospital Centre for Clinical Research, Hobart: D Kilpatrick; Royal Adelaide Hospital Cardiovascular Investigation Unit, Adelaide: P Steele;

Flinders Medical Centre, Bedford Park: R Minson; St Vincent’s Hospital, Darlinghurst: E Kotlyar; John Hunter Hospital, New Lambton Heights: G Reeves; Royal Perth Hospital, Perth: M Lavender; The Prince Charles Hospital, Chermside: F Kermeen; St. Vincent’s Hospital (Melbourne), Fitzroy: W Stevens; Royal Melbourne Hospital, Parkville: D

Smallwood. Austria – Medical University of Vienna, Vienna: I Lang; Medical University of Graz, Graz: H Olschewski. Belarus – Minsk Regional Clinical Hospital, Minsk: I Adzerikho;

9th Clinical Hospital, Minsk: N Soroka; Republican Scientific and Practical Center

“Cardiology,” Minsk: L Polonetsky. Belgium – Erasme Hospital, Brussels: J-L Vachiéry;

University Hospital Gasthuisberg, Leuven: M Delcroix. Canada – Hôpital Laval, Québec City, QC: S Provencher; Health Sciences Center, Winnipeg, MB: Z Bshouty; Toronto General Hospital, Toronto, ON: J Granton; Royal University Hospital, Saskatoon, SK: K Laframboise;

University of Ottawa Heart Institute, Ottawa, ON: L Mielniczuk; Vancouver General Hospital, Vancouver, BC: J Swiston; University of Alberta Hospital, Edmonton, AB: D Lien; Jewish General Hospital, Montreal, QC: D Langleben. Chile – Hospital Clínico de la Universidad Católica, Santiago: P Castro Galvez; Clinica Tabancura, Santiago: P Sepúlveda Varela;

Asesorias e Investigaciones Medicas TASOL Ltda., Santiago: M Zagolín. China – Peking Union Medical College Hospital, Beijing: X Zeng; Shanghai Pulmonary Hospital, Shanghai: J Liu; Fuwai Hospital, Beijing: J He; Guangdong General Hospital, Guangdong: H Yao; Renjii Cardiology, Shanghai: J Shen; Renji Hospital, Shanghai: C Bao; Beijing Shijitan Hospital, Beijing: Y Wang. Colombia – Fundacion Clinica Shaio, Bogota: J Rubén Dueñas; Fundacion

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Cardio Infantil, Bogota: C Aguirre. Czech Republic – General Faculty Hospital, Prague: P Jansa. Denmark – Aarhus University Hospital, Aarhus: JE Nielsen-Kudsk; Copenhagen University Hospital, Copenhagen: J Carlsen. France – Bicêtre Hospital, Le Kremlin-Bicêtre:

X Jaïs; Hospital Côte De Nacre, Caen: E Bergot; Hospital Larrey, Toulouse: L Têtu; Hospital Huriez, Lille: E Hachulla; Nouvel Hôpital Civil, Strasbourg: M Canuet; Hospital Louis Pradel, Bron: V Cottin. Germany – University of Greifswald, Greifswald: R Ewert; University Hospital Dresden, Dresden: G Höffken; DRK Kliniken Berlin Köpenick, Berlin: C Opitz; Klinik

Löwenstein, Löwenstein: G Staehler; Universitätsklinikum Regensburg, Regensburg: T Lange; Medizinische Hochschule Hannover, Hannover: M Hoeper; Universitätsklinikum Giessen, Giessen: H-A Ghofrani; Universitätsklinikum Heidelberg, Heidelberg: E Grünig;

Praxis Leipzig, Leipzig: J Winkler; Universitätsklinikum Köln Herzzentrum, Cologne: S Rosenkranz. Greece – Onasseio Cardiosurgical Hospital, Athens: V Voudris. Hungary – Semmelweis University, Budapest: K Karlócai; University of Pécs, Pécs: A Komócsi; Kenézy Gyula Hospital and Clinic, Debrecen: I Czuriga; University of Szeged Clinical Center,

Szeged: T Forster; Gottsegen Gyorgy National Cardiological Institute, Budapest: A Temesvári. India – Apollo Indraprastha Hospitals, New Delhi: V Kohli; Apollo Hospitals Chennai, Chennai: A Oomman; Care Hospitals Nampally, Hyderabad: BKS Sastry; Sanjivani Hospital Cardiology, Ahmedabad: K Sharma; Frontier Lifeline Hospitals, Chennai: R

Subramanyan. Ireland – Mater Misericordiae Hospital, Dublin: S Gaine. Israel – Hadassah Medical Center, Jerusalem: N Berkman; Chaim Sheba Medical Center, Tel-Hashomer: I Ben- Dov; Kaplan Medical Center – Pulmonary Institute, Rehovot: G Fink; Rabin Medical Centre, Petach Tikvah: M Kramer; Carmel Medical Center, Haifa: Y Adir. Italy – Second University of Naples, Naples: G Valentini; Sant’Orsola-Malpighi Polyclinic, Bologna: N Galiè;

Mediterranean Institute for Transplantation and Advanced Specialized Therapies, Palermo: P Vitulo. Malaysia – Institut Jantung Negara, Kuala Lumpur: D Chew. Mexico – Instituto Nacional De Cardiologia, Mexico City: TR Pulido Zamudio; Instituto Nacional De Ciencias Medicas y Nutricion Salvador, Mexico City: JL Hernández-Oropeza. The Netherlands – Academic Hospital Maastricht, Maastricht: H-P Brunner-La Rocca; VU University Medical

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Center, Amsterdam: A Boonstra; Erasmus University Medical Center, Rotterdam: L van den Toorn; St. Antonius Ziekenhuis, Nieuwegein: RJ Snijder. Peru – Centro De Investigación Enfermedades Respiratorio, Lima: M Camere; Hospital Nacional Edgardo Rebagliati Martins, Lima: JG Matheus. Poland – University Clinical Centre, Gdańsk: G Raczak; John Paul II Hospital, Kraków: P Podolec; European Health Centre, Otwock: A Torbicki; Wojewódzki Specjalistyczny Szpital im. dr. Wł. Biegańskiego, Łódź: J Kasprzak. Republic of Korea (South) – Severance Hospital, YonSei University Health System, Seoul: H-J Chang; Gachon University Gil Medical Center, Incheon: W-J Chung; Catholic University of Korea, Seoul: HO Jung; Seoul National University Hospital, Seoul: H-K Kim; Samsung Medical Center, Seoul:

S-A Chang. Romania – National Institute of Pneumology “Marius Nasta,” Bucharest: MA Bogdan; Iasi Pneumophtisiology Clinical Hospital, Iasi: T Mihaescu. Russian Federation – Federal Almazov Medical Research Centre, Institute of Cardiology Centre, St Petersburg: OM Moiseeva; State Institution Rams, Moscow: ML Stanislav; Institution of Clinical Cardiology, Moscow: I Chazova; Institute Of Pulmonology, Moscow: AG Chuchalin; Tomsk Regional, Tomsk: L Lenskaya; Regional Clinical Hospital #1, Ekaterinburg: M Arkhipov; Kemerovo Cardiology, Kemerovo: O Barbarash; Cardiology Scientific Research Institute, Tomsk: A Evtushenko; City Hospital #5, Barnaul: TI Martynenko; Consultative Diagnostic Center

“Healthy Joints,” Novosibirsk: E Zonova. Serbia – Clinical Centre of Serbia, Belgrade: S Radovanovic; Clinical Hospital Center Zemun, Belgrade: B Putniković. Singapore – National Heart Centre, Singapore: ST Lim. Slovakia – Eastern Slovak Institute of Cardiovascular Diseases, Košice: M Studenčan; National Institute of Cardiovascular Diseases, Bratislava: E Goncalvesová. Spain – Hospital Clinic of Barcelona, Barcelona: JA Barbera; Vall d’Hebron University Hospital, Barcelona: A Roman; University Hospital 12 Octubre, Madrid: MAG Sanchez. Sweden – Sahlgrenska University Hospital, Göteborg: B Rundqvist; Linköping University Hospital, Garnisonsvägen: L Hübbert; Umeå University Hospital, Umeå: S Söderberg; Uppsala University Hospital, Uppsala: G Wikström. Switzerland – University Hospital Basel, Basel: M Tamm; University Hospital Geneva, Geneva: T Rochat; Cantonal Hospital St Gallen, St Gallen: M Brutsche. Taiwan – National Taiwan University Hospital,

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Taipei: HH Hsu; Kaohsiung Veterans General Hospital, Kaohsiung: CC Cheng. Thailand – Srinagarind Hospital, Khon Kaen Province: R Nanagara. Turkey – Dokuz Eylul University Hospital, Izmir: B Akdeniz; Çukurova University, Balcali: M Demir; Istanbul University

Cardiology Institute, Istanbul: S Kucukoglu; Marmara University School of Medicine, Istanbul:

B Mutlu. Ukraine – Lviv Regional Clinical Hospital, Lviv: L Solovey; Dnipropetrovsk Medical Academy, Dnepropetrovsk: GV Dzyak; National Institute of Phthisiology and Pulmonology Yanovskiy AMS, Kyiv: V Gavrysyuk; Kharkiv City Clinical Hospital 13, Kharkiv: V Blazhko. UK – Golden Jubilee National Hospital, Glasgow: A Peacock; Hammersmith Hospital, London: S Gibbs; Royal Free Hospital, London: G Coghlan. USA – Massachusetts General Hospital, Boston, MA: R Channick; University of Michigan Health System, Ann Arbor, MI: M Rubenfire;

UT Southwestern Medical Center, Dallas, TX: K Chin; Arizona Pulmonary Specialists Ltd, Phoenix, AZ: J Feldman; Christiana Care Health Services Inc., Newark, DE: G O’Brien;

University of Arizona, Tuscon, AZ: F Rischard; Doylestown Cardiology Associates-VIAA, Doylestown, PA: R Sangrigoli; UC Davis Medical Center, Sacramento, CA: R Allen; Cedars- Sinai Medical Center, Los Angeles, CA: G Chaux; University of Texas Houston Health Center, Houston, TX: B Patel; Columbia University Medical Center, New York, NY: E Rosenzweig;

University of Wisconsin Hospital, Madison, WI: J Runo; Henry Ford Hospital, Detroit, MI: H Cajigas; Johns Hopkins University Medical Center, Baltimore, MD: P Hassoun; LSU Health Sciences Center, New Orleans, LA: B deBoisblanc; Vanderbilt University Medical Center, Nashville, TN: I Robbins; Lindner Clinical Trial Center, Cincinnati, OH: PJ Engel; University of California San Diego Medical Center, La Jolla, CA: DS Poch; Penn Presbyterian Medical Center, Philadelphia, PA: JS Fritz; Vanderbilt University Medical Center, Cincinnati, OH: J Elwing; Kentuckiana Pulmonary Associates, Louisville, KY: JW McConnell; Ohio State University Medical Center, Columbus, OH: N Sood; Boston University School of Medicine, Boston, MA: HW Farber; Washington University School of Medicine, St Louis, MO: M

Chakinala; Georgia Health Sciences University, Augusta, GA: J Gossage; Newark Beth Israel Medical Center, Newark, NJ: C Migliore; William Beaumont Hospital Troy PH Center, Troy, MI: S Allen; Baylor College of Medicine, Houston, TX: A Frost; Clarian North Hospital,

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Carmel, IN: W Harvey; Duke University Medical Center, Durham, NC: T Fortin; St Luke’s Medical Center, Milwaukee, WI: R Tumuluri; Tufts Medical Center, Boston, MA: I Preston; Liu Center for the Study and Treatment of Pulmonary Hypertension, Torrance, CA: R Oudiz;

Oregon Pulmonary Associates, Portland, OR: J Butler; Emory University School of Medicine, Atlanta, GA: M Fisher; GLVA Healthcare Center, Los Angeles, CA: S Shapiro; Montefiore Medical Center – JD Weiler Hospital, Bronx, NY: J Taurus; Thomas Jefferson University Hospital, Philadelphia, PA: M Scharf; University Hospitals – Case Medical Center, Cleveland, OH: R Schilz; Georgia Clinical Research, Austell, GA: C Miller; University of Iowa Hospitals and Clinics, Iowa City, IA: L Cadaret; Froedtert Hospital, Milwaukee, WI: K Presberg.

2. LIST OF STEERING COMMITTEE MEMBERS

Austria – Medical University of Vienna, Vienna: I Lang. France – Hôpital Universitaire de Bicêtre, Université Paris-Sud, Le Kremlin Bicêtre: G Simonneau and O Sitbon. Germany – Universitätsklinikum Giessen, Giessen: H-A Ghofrani; Medizinische Hochschule Hannover, Hannover: M Hoeper. Ireland – Mater Misericordiae Hospital, Dublin: S Gaine. Italy – DIMES, University of Bologna, Bologna: N Galiè. USA – Massachusetts General Hospital, Boston, MA: R Channick; UT Southwestern Medical Center, Dallas, TX: K Chin; University of Michigan Health System, Division of Cardiovascular Medicine, Ann Arbor, MI: V McLaughlin;

Division of Pulmonary and Critical Care Medicine, University of California, San Diego, CA: L Rubin;

Cedars-Sinai Medical Center, Los Angeles, CA: V Tapson.

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3. LIST OF CRITICAL EVENT COMMITTEE MEMBERS

South Africa – Milpark Hospital, Johannesburg: PG Williams (reviewer); Switzerland – Hôpital des Enfants, Geneva: M Beghetti (chairman and reviewer until November 7, 2012);

UK – Institute of Cellular Medicine Newcastle University and The Newcastle upon Tyne Hospitals NHS Foundation Trust: P Corris (reviewer since November 7, 2012); Papworth Hospital, Cambridge: J Pepke-Zaba (reviewer since study start and chairperson since November 7, 2012).

4. LIST OF DATA AND SAFETY MONITORING COMMITTEE MEMBERS

Brazil – University of São Paulo, São Paulo: R Souza; USA – University of Wisconsin, Madison, WI: DL DeMets; University of Chicago, Chicago, IL: M Gomberg-Maitland; University of California, San Diego, CA: BH Greenberg.

5. BLEEDING CASES ADJUDICATORS

Canada – Thrombosis Service McMaster Clinic HHS - General Hospital, Hamilton, ON: S Schulman (reviewer and chairman); Department of Medicine, Division of General Internal Medicine, St. Joseph’s Healthcare, Hamilton, ON: J Douketis (reviewer).

6. GRIPHON STUDY STATISTICAL ANALYSIS PLAN REVIEWERS

USA – University of Seattle, Seattle, WA: T Fleming; Harvard T.H. Chan School of Public Health, Boston, MA: LJ Wei.

7. FOLLOW-UP OF PATIENTS WHO DISCONTINUED TREATMENT

All patients were followed for vital status. In addition, patients who discontinued treatment (subsequent to a primary end-point event or prematurely) and provided written informed consent for further follow-up were followed for morbidity events, during the posttreatment observation period. The follow-up ran from the time of treatment discontinuation until the end of the study.

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The follow-up schedule consisted of an initial evaluation at the time of study drug

discontinuation, scheduled evaluations every 6 months thereafter, and ad hoc evaluations if clinical worsening was suspected.

The evaluations carried out were as follows: Hospitalization for pulmonary arterial

hypertension worsening since previous visit, WHO functional class, concomitant medications for pulmonary arterial hypertension (including long-term oxygen therapy), and vital status.

8. TREATMENT DISCONTINUATIONS AND SENSITIVITY ANALYSES 1. Primary end point

Of the 1156 patients randomized, 218 patients (88 in the placebo group and 130 in the selexipag group) prematurely discontinued treatment; defined as discontinuing treatment without experiencing a primary end-point event. The median treatment duration was 24.0 weeks for the placebo-treated patients and 16.7 weeks for the selexipag-treated patients. The amount of missing observation time relative to the maximum theoretical

observation time for the primary end point was 16.3% in the placebo group and 18.3% in the selexipag group.

According to the protocol and the statistical analysis plan, all randomized patients were included in, and contributed to, the primary end-point analysis, which is presented in the manuscript and in Table S1. In this analysis, the 218 patients who prematurely discontinued study treatment were censored at the time of treatment discontinuation. Importantly, these patients provided information during their time on study treatment for the Kaplan–Meier estimates and the log-rank tests.

Sensitivity analyses were performed on the primary end point to assess the impact of premature treatment discontinuations on the estimate of the treatment effect, as follows:

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(a) The first sensitivity analysis (Table S1), prespecified in the statistical analysis plan, consisted of imputing a morbidity event in patients with signs of disease progression at the time of premature treatment discontinuation. Patients with signs of disease progression were identified if they met any of the following prospectively-defined criteria:

1) Last available WHO functional class is greater than baseline functional class 2) Last available 6-minute walk distance decreased by at least 15% of the baseline

value with no evidence that this decrease is unrelated to pulmonary arterial hypertension worsening

3) Pulmonary arterial hypertension medication started within 4 weeks prior to treatment discontinuation

4) An adverse event suggestive of ongoing pulmonary arterial hypertension worsening at treatment discontinuation

This analysis identified 67 additional patients with events (placebo, n=32; selexipag, n=35).

This reduced the proportion of patients censored at the time of treatment discontinuation from 19% (218 of 1156) to 13% (151 of 1156).

b) The second sensitivity analysis was conducted post hoc and consisted of imputing a primary end-point event at the time of treatment discontinuation for all 218 patients who prematurely discontinued treatment (Table S1). The assumption for this analysis was that treatment discontinuation was a signal for treatment failure.

(c) The third sensitivity analysis, prespecified in the statistical analysis plan, was conducted as an exploratory end point, whereby the primary outcome measure was analyzed up to the end of the study. Death and morbidity events occurring after treatment discontinuation were collected for the 80 patients who consented to be followed during the posttreatment

observation period. Deaths alone were collected for the 138 patients who did not consent to be followed during the posttreatment observation period (Table S1). This analysis contained the 397 events (placebo, n= 242; selexipag, n=155) collected in the primary analysis and 46

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additional events collected during the posttreatment observation period (placebo n=16;

selexipag, n=30).

2. All-cause Mortality Up to End of Study

At the end of study, vital status was recorded for 1101 patients (placebo, n=552; selexipag, n=549) and was unknown for 55 patients (placebo, n=30; selexipag, n=25). These 55 patients included 45 patients who prematurely discontinued treatment and 10 patients who discontinued treatment subsequent to a primary end point event. Overall, for all-cause mortality up to the end of the study, the amount of missing observation time relative to the maximum theoretical observation time was 3.7% in the placebo group and 2.4% in the selexipag group.

According to the protocol and statistical analysis plan, all randomized patients were included in the analysis set for survival regardless of premature treatment or study discontinuation.

The 55 patients (5%) with unknown vital status at the end of study were censored at the date of last contact. These patients provided information on survival during their time in the study for the Kaplan–Meier estimates and the log-rank tests; these data are presented in the manuscript and Table S4.

(a) A sensitivity analysis, conducted post hoc, consisted of imputing a death at the date of last contact for the 55 patients with missing vital status at the end of the study (Table S4).

The assumption for this analysis was that lack of vital status information at the end of the study could indicate that the patient had died.

9. IMPUTATION RULES FOR MISSING 6-MINUTE WALK DISTANCE

Missing 6-minute walk distance values at week 26 were imputed based on the following prespecified rules:

1) For patients unable to walk at week 26, 0 meters was imputed

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2) If the above rule 1) did not apply, 10 meters was imputed. The 10-meter value was the second lowest observed 6-minute walking distance value at week 26, irrespective of study treatment group.

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10. FIGURE S1. DOSE ADJUSTMENT (TITRATION) SCHEME

Figure S1. Dose Adjustment.

Within 28 days after screening, patients were randomly assigned, in a 1:1 ratio stratified by center, to placebo or selexipag. During the 12-week dose-adjustment phase, study drug was initiated at 200 µg twice daily and titrated weekly in 200 µg twice-daily increments until prostacyclin-associated adverse effects such as headache and jaw pain were unmanageable. The dose was then decreased by 200 µg in both daily doses, giving the highest tolerated dose. The maximum dose allowed was 1600 µg twice daily. After 12 weeks, patients entered the maintenance phase of the study. From week 26, doses could be increased at scheduled visits; dose reductions were allowed at any time.

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11. FIGURE S2. GRIPHON STUDY DESIGN

Figure S2. Study Design.

Within 28 days after screening, patients were randomly assigned, in a 1:1 ratio stratified by center, to placebo or selexipag. Study drug was initiated and the dose adjusted as outlined in section 10 above.

The end of treatment was either at the end of the study, after the occurrence of a primary end-point event or occurred prematurely for various reasons, such as an adverse event. The end of treatment differed for each patient and was defined as the last intake of double-blind treatment (placebo or selexipag) plus 7 days. The end of the study was declared when the prespecified number of primary end-point events was reached. Change in 6-minute walk distance, absence of worsening in WHO functional class and change in NT-proBNP were evaluated at week 26. Vital status was recorded at the end of the study.

Patients who discontinued double-blind treatment and provided written informed consent for further follow-up were followed until the end of the study, in the blinded posttreatment observation period (see section 7 above). Patients who had a nonfatal primary end-point event discontinued double-blind treatment and were eligible to receive open-label selexipag or commercially available drugs, as were patients receiving double-blind treatment at the end of the study.

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11. FIGURE S3. EFFECT OF SELEXIPAG ON THE PRIMARY COMPOSITE END POINT EXCLUDING EVENTS THAT OCCURRED PRIOR TO INCREASING THE SAMPLE SIZE

Figure S3. Primary Composite End Point Excluding the 45 Events That Occurred Prior to Increasing the Sample Size (Kaplan–Meier Estimates).

Shown are Kaplan–Meier curves for the primary composite end point of death (from any cause) or a complication related to pulmonary arterial hypertension (disease progression, or worsening of pulmonary arterial hypertension that resulted in hospitalization, initiation of parenteral prostanoid therapy or long-term oxygen therapy, or the need for lung transplantation or balloon atrial septostomy) up to the end of the treatment period in the selexipag and placebo groups, excluding the 45 events that occurred prior to increasing the sample size show a significant treatment effect in favor of selexipag versus placebo (hazard ratio 0.61, 99% CI, 0.46 to 0.81, P<0.001 with the use of a one- sided log-rank test). The analysis took into account all available data, whereas the Kaplan–Meier curve is truncated at 36 months.

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12. FIGURE S4. EFFECT OF SELEXIPAG ON THE PRIMARY COMPOSITE END POINT IN PATIENTS GROUPED BY PRESPECIFIED SELEXIPAG INDIVIDUAL MAINTENANCE DOSE VERSUS PLACEBO

Figure S4. Primary Composite End Point in Patients Grouped by Prespecified Selexipag Individual Maintenance Dose vs. Placebo (Kaplan–Meier Estimates).

Shown are Kaplan–Meier curves for the primary composite end point of death (from any cause) or a complication related to pulmonary arterial hypertension (disease progression, or worsening of pulmonary arterial hypertension that resulted in hospitalization, initiation of parenteral prostanoid therapy or long-term oxygen therapy, or the need for lung transplantation or balloon atrial septostomy) up to the end of the treatment period in the selexipag and placebo groups, according to prespecified selexipag individual maintenance dose strata: low (200, 400 µg twice daily), medium (600, 800, 1000 µg twice daily), and high (1200, 1400, 1600 µg twice daily). The individualized maintenance dose was defined as the dose that a patient received for the longest duration. The effect of selexipag was consistent in the low (hazard ratio 0.60, 95% CI, 0.41 to 0.88), medium (hazard ratio 0.53, 95% CI, 0.38 to 0.72), and high (hazard ratio 0.64, 95% CI, 0.49 to 0.82) dose strata. The analysis took into

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account all available data, whereas the Kaplan–Meier curve is truncated at 30 months. In the selexipag group, 14 patients discontinued the 200 µg twice-daily dose during the dose-adjustment phase and 1 patient received doses different from the per protocol dosing, all 15 were assigned to 0 µg and are not reported here. The medium dose stratum (n=180) includes one patient treated with 900 µg twice daily.

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13. FIGURE S5. EFFECT OF SELEXIPAG ON THE PRIMARY COMPOSITE END POINT BY PRESPECIFIED SUBGROUP

Figure S5. Effect of Selexipag on the Primary Composite End Point by Prespecified Subgroup.

Shown is the forest plot for the primary composite end point of death (from any cause) or a complication related to pulmonary arterial hypertension (disease progression, or worsening of pulmonary arterial hypertension that resulted in hospitalization, initiation of parenteral prostanoid therapy or long-term oxygen therapy, or the need for lung transplantation or balloon atrial septostomy) up to the end of the treatment period in the selexipag and placebo groups, according to prespecified subgroups. A consistent treatment effect was observed across prespecified subgroups: pulmonary arterial hypertension therapy at baseline, WHO functional class at baseline, sex, age at screening, pulmonary arterial hypertension etiology, and geographical region. The vertical solid line references the overall treatment effect.

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14. TABLE S1. SENSITIVITY ANALYSES (A, B, AND C) OF THE PRIMARY ANALYSIS

Table S1. Sensitivity Analyses (a, b, and c) of the Primary Analysis.

Selexipag vs. Placebo

Hazard Ratio (CI) P Value*

Primary analysis 0.60 (99%, 0.46–0.78) <0.001

Sensitivity analysis (a) 0.65 (95%, 0.54–0.78) <0.001

Sensitivity analysis (b) 0.82 (95%, 0.70–0.96) 0.007

Sensitivity analysis (c)† 0.65 (95%, 0.54–0.79) <0.001

CI denotes confidence interval.

* One-sided unstratified log-rank.

Sensitivity analysis (a): The occurrence of a complication related to pulmonary arterial hypertension (a morbidity event) was imputed for patients with signs of disease progression, at the time of premature treatment discontinuation.

Sensitivity analysis (b): a primary end-point event was imputed for patients who prematurely discontinued treatment, at the time of treatment discontinuation. Three patients who withdrew consent and did not receive study drug were included as having an event on day 1.

† Exploratory end point of time to first primary end-point event up to the end of study. Sensitivity analysis (c) contained the 397 first events collected in the primary end-point analysis and 46 additional events collected during the posttreatment observation period.

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15. TABLE S2. INDIVIDUAL MAINTENANCE DOSE

Table S2. Individual Maintenance Dose.*

Prespecified Dose Strata Twice-daily Dose

Placebo N=582 – no. (%)

Selexipag N=574 – no. (%)

Low-dose stratum 200 µg 15 (2.6) 68 (11.8)

400 µg 18 (3.1) 65 (11.3)

Medium-dose stratum 600 µg 20 (3.4) 62 (10.8)

800 µg 21 (3.6) 82 (14.3)

1000 µg 27 (4.6) 35 (6.1)

High-dose stratum 1200 µg 20 (3.4) 42 (7.3)

1400 µg 55 (9.5) 41 (7.1)

1600 µg 393 (67.5) 163 (28.4)

Other than per-protocol dosing 4 (0.7) 2 (0.3)

* The individual maintenance dose was defined as the twice-daily dose that a patient received for the longest duration in the maintenance period, or, for patients who did not enter the maintenance period, as the highest tolerated twice-daily dose that a patient received during the dose-adjustment period.

Patients (placebo, n=9; selexipag, n=14) in the 200 µg twice-daily dose strata who prematurely discontinued the study were assigned to 0 µg and are not reported here.

(23)

16. TABLE S3. ABSENCE OF WORSENING IN FUNCTIONAL CLASS FROM BASELINE TO WEEK 26

Table S3. Patients With and With No Worsening in WHO Functional Class (FC) from Baseline to Week 26. All patients.

Baseline

Week 26

No worsening N (%)

Selexipag vs.

Placebo Point estimate odds

ratio (99% CI)

P value

FC I N

FC II N

FC III N

FC IV N

Missing*

N

Selexipag N=571

FC I 4 4 - - - -

444 (77.8)

1.16 (0.81–1.66)

FC II 274 7 207 21 - 39

FC III 293 1 67 158 10 57 0.28

Placebo N=574

FC I 5 4 - - - 1

430 (74.9)

FC II 255 7 197 16 - 35

FC III 314 4 37 181 14 78

FC denotes WHO functional class.

* Missing data at week 26 were included in the analysis as worsening.

(24)

17. TABLE S4. SENSITIVITY ANALYSIS (A) OF THE SECONDARY END POINT ALL-CAUSE MORTALITY UP TO END OF STUDY ANALYSIS

Table S4. Sensitivity Analysis (a) of the Secondary End Point All-cause Mortality up to End of Study Analysis.

Selexipag vs. Placebo

Hazard Ratio (95% CI) P Value*

All-cause mortality, protocol-defined analysis 0.97 (0.74–1.28) 0.42

Sensitivity analysis (a) 0.95 (0.74–1.21) 0.33

CI denotes confidence interval.

* P values were calculated with the use of a one-sided unstratified log-rank test.

Sensitivity analysis (a): death was imputed at the date of last contact for patients who prematurely discontinued treatment without a primary end-point event or discontinued treatment with a nonfatal primary end-point event and had missing survival status at the end of the study.

(25)

18. TABLE S5. CHANGE IN N-TERMINAL PRO-BRAIN NATRIURETIC PEPTIDE (NT-proBNP) FROM BASELINE TO WEEK 26 Table S5. Change in N-terminal pro-brain natriuretic peptide (NT-proBNP)* from Baseline to Week 26.

Placebo N=449

Selexipag

N=460 Selexipag vs. placebo

Median at Baseline – ng per liter

(Q1, Q3)

Median at 26 weeks – ng per liter

(Q1, Q3)

Median Change†

– ng per liter (Q1, Q3)

Median at Baseline – ng per liter

(Q1, Q3)

Median at 26 weeks – ng per liter

(Q1, Q3)

Median Change†

– ng per liter (Q1, Q3)

Treatment Effect (95% CI)

P Value

470.0 (170.0, 1359.0) 582.0 (172.0, 1551.0) 18.0 (-87.0, 325.0) 514.5 (166.0, 1356.0) 369.5 (120, 1177.0) -34.5 (-237.0, 90.0) -123 (-175 to -78) <0.001

* NT-proBNP was quantified using Elecsys® 2010 (Roche Diagnostics, Indianapolis, IN).

† Absolute median change was calculated on paired data.

Only patients with a non-missing value at both the baseline and week 26 are included.

(26)

19. TABLE S6. PROSTACYCLIN-ASSOCIATED ADVERSE EVENTS REPORTED IN THE DOSE-ADJUSTMENT AND MAINTENANCE PHASES

Table S6. Prostacyclin-associated Adverse Events Reported in the Dose-Adjustment and Maintenance Phases.*

Dose Adjustment Maintenance

Placebo (N=577)

Selexipag (N=575)

P Value Placebo (N=508)

Selexipag (N=509)

P Value Patients with ≥1 prostacyclin-associated

adverse event – no. (%) 303 (52.5) 499 (86.8) <0.001 238 (46.9) 367 (72.1) <0.001

Adverse event – no. (%)

Headache 163 (28.2) 363 (63.1) <0.001 99 (19.5) 203 (39.9) <0.001

Diarrhea 67 (11.6) 205 (35.7) <0.001 67 (13.2) 151 (29.7) <0.001

Nausea 79 (13.7) 163 (28.3) <0.001 51 (10.0) 100 (19.6) <0.001

Pain in jaw 22 (3.8) 140 (24.3) <0.001 20 (3.9) 105 (20.6) <0.001

Myalgia 26 (4.5) 86 (15.0) <0.001 16 (3.1) 48 (9.4) <0.001

Vomiting 25 (4.3) 86 (15.0) <0.001 28 (5.5) 39 (7.7) 0.21

Pain in extremity 29 (5.0) 84 (14.6) <0.001 31 (6.1) 66 (13.0) <0.001

Flushing 22 (3.8) 60 (10.4) <0.001 16 (3.1) 52 (10.2) <0.001

Dizziness 51 (8.8) 57 (9.9) 0.55 58 (11.4) 53 (10.4) 0.62

Arthralgia 30 (5.2) 41 (7.1) 0.18 27 (5.3) 47 (9.2) 0.02

Musculoskeletal pain 5 (0.9) 17 (3.0) 0.01 10 (2.0) 11 (2.2) 1.00

Temporomandibular joint syndrome 2 (0.3) 3 (0.5) 0.69 1 (0.2) 3 (0.6) 0.62

* Of the patients randomized to placebo, four did not receive study drug and were excluded from the safety analysis, and one received a single dose of eight tablets of selexipag and was assigned to the selexipag group for the safety analysis.

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