Background Conducting randomized controlled trials to investigate survival in a rare disease like pulmonary arterial hypertension has considerable ethical and logistical constraints. In many studies, such as the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) randomized controlled trial, evaluating survival is further complicated by bias introduced by allowing active therapy among placebo-treated patients who clinically deteriorate. Methods and Results SERAPHIN enrolled and followed patients in the same time frame as the US Registry to Evaluate Early And Long-term PAH Disease Management, providing an opportunity to compare observed survival for SERAPHIN patients with predicted survival had they received real-world treatment as in the Registry to Evaluate Early And Long-term PAH Disease Management. From the Registry to Evaluate Early And Long-term PAH Disease Management (N=3515), 734 patients who met SERAPHIN eligibility criteria were selected and their data used to build a prediction model for time to death up to 3 years based on 10 baseline prognostic variables. The model was used to predict a survival curve for each of the 742 SERAPHIN patients via their baseline variables. The average of these predicted survival curves was compared with observed survival of the placebo (n=250) and macitentan 10 mg (n=242) groups using a log-rank test and Cox proportional hazard model. Observed mortality risk for patients randomized to placebo, 62% of whom were taking background pulmonary arterial hypertension therapy, tended to be lower than that predicted for all SERAPHIN patients (16% lower; P=0.259). The observed placebo survival curve closely approximated the predicted survival curve for the first 15 months. Beyond that time, observed risk of mortality decreased compared with predicted mortality, potentially reflecting the impact of crossover of patients in the placebo group to active therapy. Over 3 years, risk of mortality observed with macitentan 10 mg was 35% lower than predicted mortality ( P=0.010). Conclusions These analyses show that, in a rare disease, real-world observational data can complement randomized controlled trial data to overcome some challenges associated with assessing survival in the setting of a randomized controlled trial. Clinical Trial Registration https://www.clinicaltrials.gov . Unique identifiers: NCT00660179 and NCT00370214.

APHP Centre de Référence de l'Hypertension Pulmonaire Service de Pneumologie et Soins Intensifs Université Paris Sud Hôpital de Bicêtre Le Kremlin Bicêtre France

Biostatistics Actelion Pharmaceuticals Ltd Allschwil Switzerland

Canada Respirology Division London Health Sciences Centre ON

Cardiopulmonary Department Ignacio Chávez National Heart Institute Mexico City Mexico

Clinicial Department of Cardiology and Angiology 1st Faculty of Medicine Charles University Prague Czech Republic

Department of Biostatistics Harvard University Boston MA

Department of Pneumology University Hospitals Leuven Belgium

Department of Pulmonary Circulation and Thromboembolic Diseases and Cardiology Centre of Postgraduate Medical Education European Health Centre ECZ Otwock Poland

Division of Cardiology CARE Hospitals Hyderabad India

Division of Cardiovascular Diseases Allegheny General Hospital Pittsburgh PA

Division of Pulmonary and Critical Care Medicine University of California San Diego Medical School

Epidemiology and Observational Studies Actelion Pharmaceuticals Ltd Allschwil Switzerland

Global Medical Affairs Actelion Pharmaceuticals Ltd Allschwil Switzerland

INCOR Heart Institute University of Sao Paulo Brazil

Pulmonary Center Boston University School of Medicine MA

University of California Los Angeles

University of Giessen and Marburg Lung Center Germany member of the German Center of Lung Research and Department of Medicine Imperial College London United Kingdom

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Walkley SU, Davidson CD, Jacoby J, Marella PD, Ottinger EA, Austin CP, Porter FD, Vite CH, Ory DS. Fostering collaborative research for rare genetic disease: the example of niemann-pick type C disease. Orphanet J Rare Dis. 2016;11:161. doi: 10.1186/s13023-016-0540-x. PubMed PMC

Institute of Medicine (US) Committee on Accelerating Rare Diseases Research Orphan Product Development. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: National Academies Press (US); 2010.

Behera M, Kumar A, Soares HP, Sokol L, Djulbegovic B. Evidence-based medicine for rare diseases: implications for data interpretation and clinical trial design. Cancer Control. 2007;14:160–166. doi: 10.1177/107327480701400209. PubMed

Temple R, Ellenberg SS. Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 1: ethical and scientific issues. Ann Intern Med. 2000;133:455–63. doi: 10.7326/0003-4819-133-6-200009190-00014. PubMed

Holubkov R, Dean JM, Berger J, Anand KJ, Carcillo J, Meert K, Zimmerman J, Newth C, Harrison R, Willson DF, Nicholson C Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Is “rescue” therapy ethical in randomized controlled trials? Pediatr Crit Care Med. 2009;10:431–438. doi: 10.1097/PCC.0b013e318198bd13. PubMed PMC

Jönsson L, Sandin R, Ekman M, Ramsberg J, Charbonneau C, Huang X, Jönsson B, Weinstein MC, Drummond M. Analyzing overall survival in randomized controlled trials with crossover and implications for economic evaluation. Value Health. 2014;17:707–713. doi: 10.1016/j.jval.2014.06.006. PubMed

White IR, Bamias C, Hardy P, Pocock S, Warner J. Randomized clinical trials with added rescue medication: some approaches to their analysis and interpretation. Stat Med. 2001;20:2995–3008. doi: 10.1002/sim.927. PubMed

Farber HW, Miller DP, Poms AD, Badesch DB, Frost AE, Muros-Le Rouzic E, Romero AJ, Benton WW, Elliott CG, McGoon MD, Benza RL. Five-year outcomes of patients enrolled in the REVEAL Registry. Chest. 2015;148:1043–1054. doi: 10.1378/chest.15-0300. PubMed

Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonssagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT) Eur Respir J. 2015;46:903–975. doi: 10.1183/13993003.01032-2015. PubMed

Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M ESC Scientific Document Group. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37:67–119. doi: 10.1093/eurheartj/ehv317. PubMed

Pulido T, Adzerikho I, Channick RN, Delcroix M, Galiè N, Ghofrani HA, Jansa P, Jing ZC, Le Brun FO, Mehta S, Mittelholzer CM, Perchenet L, Sastry BK, Sitbon O, Souza R, Torbicki A, Zeng X, Rubin LJ, Simonneau G SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369:809–818. doi: 10.1056/NEJMoa1213917. PubMed

Galiè N, Barberà JA, Frost AE, Ghofrani HA, Hoeper MM, McLaughlin VV, Peacock AJ, Simonneau G, Vachiery JL, Grünig E, Oudiz RJ, Vonk-Noordegraaf A, White RJ, Blair C, Gillies H, Miller KL, Harris JH, Langley J, Rubin LJ AMBITION Investigators. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015;373:834–844. doi: 10.1056/NEJMoa1413687. PubMed

McLaughlin VV, Channick R, Ghofrani HA, Lemarie JC, Naeije R, Packer M, Souza R, Tapson VF, Tolson J, Al Hiti H, Meyer G, Hoeper MM. Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension. Eur Respir J. 2015;46:405–413. doi: 10.1183/13993003.02044-2014. PubMed

Sitbon O, Channick R, Chin KM, Frey A, Gaine S, Galiè N, Ghofrani HA, Hoeper MM, Lang IM, Preiss R, Rubin LJ, Di Scala L, Tapson V, Adzerikho I, Liu J, Moiseeva O, Zeng X, Simonneau G, McLaughlin VV GRIPHON Investigators. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med. 2015;373:2522–2533. doi: 10.1056/NEJMoa1503184. PubMed

European Medicines Agency. European Public Assessment Report: Opsumit (macitentan). http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002697/WC500160900.pdf. Accessed March 16, 2018.

Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, Tapson VF, Bourge RC, Brundage BH, Koerner SK, Langleben D, Keller CA, Murali S, Uretsky BF, Clayton LM, Jöbsis MM, Blackburn SD, Shortino D, Crow JW Primary Pulmonary Hypertension Study Group. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334:296–301. doi: 10.1056/NEJM199602013340504. PubMed

Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, Coffey CS, Frost A, Barst RJ, Badesch DB, Elliott CG, Liou TG, McGoon MD. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation. 2010;122:164–172. doi: 10.1161/CIRCULATIONAHA.109.898122. PubMed

Benza RL, Gomberg-Maitland M, Miller DP, Frost A, Frantz RP, Foreman AJ, Badesch DB, McGoon MD. The REVEAL Registry risk score calculator in patients newly diagnosed with pulmonary arterial hypertension. Chest. 2012;141:354–362. doi: 10.1378/chest.11-0676. PubMed

CORE: Center for Outcomes Research and Evaluation, 2018. The Yoda Project, Yale University. http://yoda.yale.edu/welcome-yoda-project. Accessed May 5, 2019.

McGoon MD, Krichman A, Farber HW, Barst RJ, Raskob GE, Liou TG, Miller DP, Feldkircher K, Giles S. Design of the REVEAL registry for US patients with pulmonary arterial hypertension. Mayo Clin Proc. 2008;83:923–931. doi: 10.4065/83.8.923. PubMed

Kishnani PS, Corzo D, Nicolino M, Byrne B, Mandel H, Hwu WL, Leslie N, Levine J, Spencer C, McDonald M, Li J, Dumontier J, Halberthal M, Chien YH, Hopkin R, Vijayaraghavan S, Gruskin D, Bartholomew D, van der Ploeg A, Clancy JP, Parini R, Morin G, Beck M, De la Gastine GS, Jokic M, Thurberg B, Richards S, Bali D, Davison M, Worden MA, Chen YT, Wraith JE. Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease. Neurology. 2007;68:99–109. doi: 10.1212/01.wnl.0000251268.41188.04. PubMed

Nicolino M, Byrne B, Wraith JE, Leslie N, Mandel H, Freyer DR, Arnold GL, Pivnick EK, Ottinger CJ, Robinson PH, Loo JC, Smitka M, Jardine P, Tatò L, Chabrol B, McCandless S, Kimura S, Mehta L, Bali D, Skrinar A, Morgan C, Rangachari L, Corzo D, Kishnani PS. Clinical outcomes after long-term treatment with alglucosidase alfa in infants and children with advanced Pompe disease. Genet Med. 2009;11:210–219. doi: 10.1097/GIM.0b013e31819d0996. PubMed

D’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT, Levy PS, Pietra GG, Reid LM, Reeves JT, Rich S, Vreim CE, Williams GW, Wu M. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115:343–349. PubMed

McLaughlin VV, Sitbon O, Badesch DB, Barst RJ, Black C, Galiè N, Rainisio M, Simonneau G, Rubin LJ. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J. 2005;25:244–249. doi: 10.1183/09031936.05.00054804. PubMed

Klein JP, Rizzo JD, Zhang MJ, Keiding N. Statistical methods for the analysis and presentation of the results of bone marrow transplants. Part 2: Regression modeling. Bone Marrow Transplant. 2001;28:1001–1011. doi: 10.1038/sj.bmt.1703271. PubMed

Hlatky MA, Califf RM, Harrell FE, Jr, Lee KL, Mark DB, Pryor DB. Comparison of predictions based on observational data with the results of randomized controlled clinical trials of coronary artery bypass surgery. J Am Coll Cardiol. 1988;11:237–245. PubMed

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ClinicalTrials.gov
NCT00660179, NCT00370214