Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Oct 1;12(4):e12178.
doi: 10.1002/pul2.12178. eCollection 2022 Oct.

Pulmonary hypertension in interstitial lung disease: Clinical trial design and endpoints: A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative-Group 3 Pulmonary Hypertension

Steven D Nathan  1 , Peter Fernandes  2 , Mitchell Psotka  3 , Patrizio Vitulo  4 , Lucilla Piccari  5 , Katerina Antoniou  6 , Sylvia M Nikkho  7 , Norman Stockbridge  8
Affiliations
Review

Pulmonary hypertension in interstitial lung disease: Clinical trial design and endpoints: A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative-Group 3 Pulmonary Hypertension

Steven D Nathan et al. Pulm Circ. .

Abstract

Pulmonary hypertension (PH) associated with interstitial lung disease (ILD) is an attractive target for clinical trials of PH medications. There are many factors that need to be considered to prime such studies for success. The patient phenotype most likely to respond to the intervention requires weighing the extent of the parenchymal lung disease against the severity of the hemodynamic impairment. The inclusion criteria should not be too restrictive, thus enabling recruitment. The trial should be of sufficient duration to meet the chosen endpoint which should reflect how the patient feels, functions, or survives. This paper summarizes prior studies in PH-ILD and provides a framework of the type of studies to be considered. Inclusion criteria, clinical trial endpoints, and pharmacovigilance in the context of PH-ILD trials are also addressed. Through lessons learnt from prior studies, suggestions and guidance for future clinical trials in PH-ILD are also provided.

Keywords: clinical trial design; interstitial lung disease; pulmonary hypertension.

PubMed Disclaimer

Conflict of interest statement

Steven D. Nathan is a consultant for United Therapeutics, Bellerophon, Third Pole, Roche, Boehringer‐Ingelheim, Merck, and Daewoong. Peter Fernandes is an employee of Bellerophon Pharma; Lucilla Piccari has received research funding from and served as a speaker for Janssen as well as received support for attending congresses from Janssen, MSD and Ferrer, not related to this manuscript; and Sylvia M. Nikkho is an employee of Bayer AG. The remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Endpoints that may have a role in PH‐ILD clinical trials. The closer to the center, the greater the correlation with mortality. Those crossing into both the Phase 2 and Phase 3 circles might be suitable for both types of study phases.  6MWD, 6‐minute walking distance; FC, functional class; HrQOL, health‐related quality of life; SpO2, oxygen saturation as measured by pulse oximetry; QoL, quality of life.
Figure 2
Figure 2
Clinical trial outcome measures that may be considered for inclusion as components of composite endpoints in PH‐ILD trials. Large Δ infers larger changes, while smaller Δ infers lesser changes. Clinical progression composites are heralded by lesser change, while clinical worsening infers greater change or more meaningful events. The NT‐proBNP can be used either with a progression or worsening categorical change event to provide biomarker validation. 6MWD six‐minute walk distance; HrQOL, health‐related quality of life; NT‐proBNP, N‐terminal prohormone of brain natriuretic peptide; QoL, quality of life.
See this image and copyright information in PMC

References

    1. Nikkho SM, Richter MJ, Shen E, Abman SH, Antoniou K, Chung J, Fernandes P, Hassoun P, Lazarus HM, Olschewski H, Piccari L, Psotka M, Saggar R, Shlobin OA, Stockbridge N, Vitulo P, Vizza CD, Wort SJ, Nathan SD. Clinical significance of pulmonary hypertension in interstitial lung disease: a consensus statement from the Pulmonary Vascular Research Institute's innovative drug development initiative—Group 3 pulmonary hypertension. Pulm Circ. 2022;12:e12127. 10.1002/pul2.12127 - DOI - PMC - PubMed
    1. Krowka MJ, Ahmad S, de Andrade JA, Frost A, Glassberg MK, Lancaster LH, Lasky J, Mathier MA, Stocks J. A randomized, double‐blind, placebo‐controlled study to evaluate the safety and efficacy of iloprost inhalation in adults with abnormal pulmonary arterial pressure and exercise limitation associated with idiopathic pulmonary fibrosis. Chest. 2007;132:633A. 10.1378/chest.132.4_MeetingAbstracts.633a - DOI
    1. Zisman DA, Schwarz M, Anstrom KJ, Collard HR, Flaherty KR, Hunninghake GW. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med. 2010;363:620–8. 10.1056/NEJMoa1002110 - DOI - PMC - PubMed
    1. Han MK, Bach DS, Hagan PG, Yow E, Flaherty KR, Toews GB, Anstrom KJ, Martinez FJ. Sildenafil preserves exercise capacity in patients with idiopathic pulmonary fibrosis and right‐sided ventricular dysfunction. Chest. 2013;143:1699–1708. 10.1378/chest.12-1594 - DOI - PMC - PubMed
    1. Corte TJ, Keir GJ, Dimopoulos K, Howard L, Corris PA, Parfitt L, Foley C, Yanez‐Lopez M, Babalis D, Marino P, Maher TM, Renzoni EA, Spencer L, Elliot CA, Birring SS, O'Reilly K, Gatzoulis MA, Wells AU, Wort SJ. Bosentan in pulmonary hypertension associated with fibrotic idiopathic interstitial pneumonia. Am J Respir Crit Care Med. 2014;190:208–17. 10.1164/rccm.201403-0446OC - DOI - PMC - PubMed