Calibration and Validation of Modeled 5-year Survival Predictions Among People with Cystic Fibrosis Treated with the Cystic Fibrosis Transmembrane Conductance Regulator Modulator Ivacaftor Using United States Registry Data

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2023 Apr 12

PMID 37043485

Authors

Lisa J McGarry

Zahra Bhaiwala

Andrea Lopez

Conor Chandler

Christopher G Pelligra

Jaime L Rubin

Theodore G Liou

Affiliations

Soon will be listed here.

Abstract

Objectives: Cystic fibrosis (CF) is a rare genetic disease characterized by life-shortening lung function decline. Ivacaftor, a CF transmembrane conductance regulator modulator (CFTRm), was approved in 2012 for people with CF with specific gene mutations. We used real-world evidence of 5-year mortality impacts of ivacaftor in a US registry population to validate a CF disease-progression model that estimates the impact of ivacaftor on survival.

Methods: The model projects the impact of ivacaftor vs. standard care in people with CF aged ≥6 years with CFTR gating mutations by combining parametric equations fitted to historical registry survival data, with mortality hazards adjusted for fixed and time-varying person-level characteristics. Disease progression with standard care was derived from published registry studies and the expected impact of ivacaftor on clinical characteristics was derived from clinical trials. Individual-level baseline characteristics of the registry ivacaftor-treated population were entered into the model; 5-year model-projected mortality with credible intervals (CrIs) was compared with registry mortality to evaluate the model's validity.

Results: Post-calibration 5-year mortality projections closely approximated registry mortality in populations treated with standard care (6.4% modeled [95% CrI: 5.3% to 7.6%] vs. 6.0% observed) and ivacaftor (3.4% modeled [95% CrI: 2.7% to 4.4%] vs. 3.1% observed). The model accurately predicted 5-year relative risk of mortality (0.53 modeled [0.47 to 0.60] vs. 0.51 observed) in people treated with ivacaftor vs. standard care.

Conclusions: Modeled 5-year survival projections for people with CF initiating ivacaftor vs. standard care align closely with real-world registry data. Findings support the validity of modeling CF to predict long-term survival and estimate clinical and economic outcomes of CFTRm.

References

Davies J, Wainwright C, Canny G, Chilvers M, Howenstine M, Munck A . Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med. 2013; 187(11):1219-25. PMC: 3734608. DOI: 10.1164/rccm.201301-0153OC. View

Goss C, Burns J . Exacerbations in cystic fibrosis. 1: Epidemiology and pathogenesis. Thorax. 2007; 62(4):360-7. PMC: 2092469. DOI: 10.1136/thx.2006.060889. View

Borowitz D, Baker R, Stallings V . Consensus report on nutrition for pediatric patients with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2002; 35(3):246-59. DOI: 10.1097/00005176-200209000-00004. View

McKone E, Borowitz D, Drevinek P, Griese M, Konstan M, Wainwright C . Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST). Lancet Respir Med. 2014; 2(11):902-910. DOI: 10.1016/S2213-2600(14)70218-8. View

Konstan M, Wagener J, VanDevanter D, Pasta D, Yegin A, Rasouliyan L . Risk factors for rate of decline in FEV1 in adults with cystic fibrosis. J Cyst Fibros. 2012; 11(5):405-11. PMC: 4086189. DOI: 10.1016/j.jcf.2012.03.009. View

Oberije C, De Ruysscher D, Houben R, van de Heuvel M, Uyterlinde W, Deasy J . A Validated Prediction Model for Overall Survival From Stage III Non-Small Cell Lung Cancer: Toward Survival Prediction for Individual Patients. Int J Radiat Oncol Biol Phys. 2015; 92(4):935-44. PMC: 4786012. DOI: 10.1016/j.ijrobp.2015.02.048. View

Buuren S, Boshuizen H, Knook D . Multiple imputation of missing blood pressure covariates in survival analysis. Stat Med. 1999; 18(6):681-94. DOI: 10.1002/(sici)1097-0258(19990330)18:6<681::aid-sim71>3.0.co;2-r. View

Shen W, Sakamoto N, Yang L . Model to predict the survival benefit of radiation for patients with rhabdomyosarcoma after surgery: a population-based study. Int J Oncol. 2014; 45(2):549-57. DOI: 10.3892/ijo.2014.2466. View

Eddy D, Hollingworth W, Caro J, Tsevat J, McDonald K, Wong J . Model transparency and validation: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force--7. Value Health. 2012; 15(6):843-50. DOI: 10.1016/j.jval.2012.04.012. View

10.

Liou T, Adler F, FitzSimmons S, Cahill B, Hibbs J, Marshall B . Predictive 5-year survivorship model of cystic fibrosis. Am J Epidemiol. 2001; 153(4):345-52. PMC: 2198936. DOI: 10.1093/aje/153.4.345. View

11.

Volkova N, Moy K, Evans J, Campbell D, Tian S, Simard C . Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries. J Cyst Fibros. 2019; 19(1):68-79. DOI: 10.1016/j.jcf.2019.05.015. View

12.

De Boeck K, Amaral M . Progress in therapies for cystic fibrosis. Lancet Respir Med. 2016; 4(8):662-674. DOI: 10.1016/S2213-2600(16)00023-0. View

13.

Duckers J, Lesher B, Thorat T, Lucas E, McGarry L, Chandarana K . Real-World Outcomes of Ivacaftor Treatment in People with Cystic Fibrosis: A Systematic Review. J Clin Med. 2021; 10(7). PMC: 8038673. DOI: 10.3390/jcm10071527. View

14.

Levy W, Mozaffarian D, Linker D, Sutradhar S, Anker S, Cropp A . The Seattle Heart Failure Model: prediction of survival in heart failure. Circulation. 2006; 113(11):1424-33. DOI: 10.1161/CIRCULATIONAHA.105.584102. View

15.

Whiting P, Al M, Burgers L, Westwood M, Ryder S, Hoogendoorn M . Ivacaftor for the treatment of patients with cystic fibrosis and the G551D mutation: a systematic review and cost-effectiveness analysis. Health Technol Assess. 2014; 18(18):1-106. PMC: 4780965. DOI: 10.3310/hta18180. View

16.

Mogayzel Jr P, Naureckas E, Robinson K, Mueller G, Hadjiliadis D, Hoag J . Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2013; 187(7):680-9. DOI: 10.1164/rccm.201207-1160oe. View

17.

Moss R, Flume P, Elborn J, Cooke J, Rowe S, McColley S . Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial. Lancet Respir Med. 2015; 3(7):524-33. PMC: 4641035. DOI: 10.1016/S2213-2600(15)00201-5. View

18.

Elborn J . Cystic fibrosis. Lancet. 2016; 388(10059):2519-2531. DOI: 10.1016/S0140-6736(16)00576-6. View

19.

Liou T, Kartsonaki C, Keogh R, Adler F . Evaluation of a five-year predicted survival model for cystic fibrosis in later time periods. Sci Rep. 2020; 10(1):6602. PMC: 7171119. DOI: 10.1038/s41598-020-63590-8. View

20.

Van Goor F, Hadida S, Grootenhuis P, Burton B, Cao D, Neuberger T . Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci U S A. 2009; 106(44):18825-30. PMC: 2773991. DOI: 10.1073/pnas.0904709106. View