A large pragmatic study in idiopathic pulmonary fibrosis (IPF) found that antimicrobial therapy did not have a statistically significant effect on respiratory hospitalization or death compared with usual care alone.
IPF is a chronic, progressive lung disease that causes scar tissue to form in the lungs, interfering with oxygen uptake. Alteration in lung microbes is associated with disease progression. IPF has an estimated prevalence of 13 to 20 per 100,000 people worldwide. Around 100,000 people in the United States have IPF, and 30,000 to 40,000 new cases are diagnosed each year.[1] IPF has a poor prognosis, with an estimated average survival time of 2 to 5 years after diagnosis.[2]
The results of the CleanUP IPF for the Pulmonary Trials Cooperative (CleanUP-IPF) trial were published recently in JAMA.[3] This pragmatic, randomized, unblinded clinical trial was conducted across 35 U.S. sites and included 513 adults with IPF aged over 40. Adding co-trimoxazole (trimethoprim-sulfamethoxazole) or doxycycline to usual care led to a rate of first nonelective respiratory hospitalization or death of 20.4 events per 100 person-years—a statistic that is calculated by dividing the total years of follow-up by the number of participants who received active treatment. This compared to a rate of 18.4 events per 100 person-years for usual care alone, a difference that was not statistically significant. There was also no statistically significant difference between the effect of co-trimoxazole and doxycycline on the primary end point of time to first nonelective respiratory hospitalization or all-cause mortality.
The study was designed to follow up on earlier data linking disease progression in IPF with microbial imbalance in the lungs, and the resulting immune response. Earlier trials with methodological shortcomings had suggested improved outcomes in IPF patients treated with either sulfamethoxazole/trimethoprim or doxycycline. Innovative features of CleanUP-IPF included: 1) a pragmatic randomized trial design; 2) collection of targeted biological samples to allow future exploration of ‘personalized’ therapy; and 3) developing a strong partnership between the National Heart, Lung, and Blood Institute, a broad range of investigators, industry, and philanthropic organizations.
As a pragmatic study, participants in both treatment arms had limited in-person visits with the enrolling clinical center. Visits were limited to assessments of lung function and other clinical parameters at time points prior to randomization and at months 12, 24, and 36. All participants were followed until the study completion for the assessment of clinical endpoints related to hospitalization and mortality events.
Patients were randomized from August 2017 to June 2019, with final follow-up in January 2020. Participants were randomized 1:1 to receive either antimicrobials and usual care or usual care alone. On December 18, 2019, the study was terminated for futility or inability to achieve its objectives.
DCRI was the data coordinating center for the CleanUP-IPF trial, and Kevin Anstrom, PhD, Professor in the Duke Department of Biostatistics and Bioinformatics, and DCRI Therapeutic Area Lead for Statistics and Data Science, was one of three lead investigators. The others were based at Weill Cornell Medicine and the University of Virginia. This is the largest IPF randomized trial to date involving the DCRI, and possibly the largest ever.
“The findings of CleanUP-IPF do not support treatment with these antimicrobials for underlying IPF,” Anstrom said. “It was unfortunate that the treatment turned out not to be effective in these patients with high unmet needs. Future studies may need to be more closely targeted to identify potentially responsive subpopulations. However, this study did verify the utility of the PRECIS-2 tool to achieve the targeted enrollment.” This tool – the PRagmatic Explanatory Continuum Indicator Summary – helps trialists design pragmatic studies that are fit for purpose.
“From a pulmonologist’s perspective, it was groundbreaking to be able to do a pragmatic study in IPF,” said DCRI’s Laurie D. Snyder, MD, MHS, who was a medical monitor for the study. “This has changed the way we think about IPF studies, allowing us to manage them in a very patient-centric way as part of their routine care.”
“This trial benefited from a very large participating network,” said DCRI statistician Eric Yow, MS. “In addition, IPF trials typically have more burdensome endpoints, such as measuring forced expiratory volume which requires several clinic visits for the participants. CleanUP-IPF used an endpoint that reflected how the patient feels and functions.”
The design of CleanUP-IPF is described in an earlier paper in Respiratory Research.[4] DCRI’s Anstrom, Snyder and Yow were among the authors.
A second study of the impact of antimicrobials on patients with IPF, carried out in the UK and published in JAMA in December 2020, reached similar conclusions. The authors wrote that “co-trimoxazole compared with placebo did not improve a composite clinical outcome among patients with moderate or severe IPF.”[5] This study did not involve the DCRI.
The DCRI has been making strides in IPF research since 2005, when it became the coordinating center for IPFnet, a network of 26 clinical sites that conducted clinical trials in the IPF space, as described in an earlier article posted on DCRI.org.
DCRI authors of the JAMA CleanUP-IPF study results paper were Yow, Snyder, Anstrom and Michael T. Durheim, MD, who is also affiliated with the Department of Respiratory Medicine, Oslo University Hospital–Rikshospitalet, Oslo, Norway.
Sources
[1] https://medlineplus.gov/genetics/condition/idiopathic-pulmonary-fibrosis/#frequency
[2] https://www.medscape.com/answers/301226-95979/what-is-the-mortality-rate-of-idiopathic-pulmonary-fibrosis-ipf
[3] Martinez FJ, Yow E, Flaherty KR, et al. Effect of Antimicrobial Therapy on Respiratory Hospitalization or Death in Adults With Idiopathic Pulmonary Fibrosis: The CleanUP-IPF Randomized Clinical Trial. JAMA. 2021;325(18):1841–1851. doi:10.1001/jama.2021.4956. Available at: https://jamanetwork.com/journals/jama/article-abstract/2779827
[4] Anstrom KJ, Noth I, Flaherty KR, et al; CleanUP-IPF Study Team. Design and rationale of a multi-center, pragmatic, open-label randomized trial of antimicrobial therapy—the study of clinical efficacy of antimicrobial therapy strategy using pragmatic design in Idiopathic Pulmonary Fibrosis (CleanUP-IPF) clinical trial. Respir Res. 2020;21(1):68. doi:10.1186/s12931-020-1326-1. Available at https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-020-1326-1
[5] Wilson AM, Clark AB, Cahn T, et al. Effect of Co-trimoxazole (Trimethoprim-Sulfamethoxazole) vs Placebo on Death, Lung Transplant, or Hospital Admission in Patients With Moderate and Severe Idiopathic Pulmonary Fibrosis: The EME-TIPAC Randomized Clinical Trial. JAMA. 2020;324(22):2282–2291. doi:10.1001/jama.2020.22960
https://jamanetwork.com/journals/jama/article-abstract/2773680