Adding Antibiotics to Standard Care Fail to Show Benefit in Large IPF Trial

Adding two broad spectrum antibiotics — co-trimoxazole or doxycycline — to standard care does not significantly delay hospitalization or prolong survival in adults with idiopathic pulmonary fibrosis (IPF), according to data from one of the largest clinical trials in IPF.

While several studies have shown that changes in lung bacteria are associated with IPF progression, these findings highlight the complex nature of this potential link.

Based on these findings, which are consistent with data from a previous, similar trial testing co-trimoxazole, the researchers recommended against using these antibiotics to treat IPF.

“We were certainly disappointed in the results. But we remain hopeful that in further downstream analyses, we may yet find groups of patients that were potentially benefiting,” Imre Noth, MD, one of the trial’s researchers and the chief of University of Virginia Health’s division of pulmonary and critical care medicine, said in a press release.

“In the meantime, this study will make sure that no one takes antibiotics without need,” Noth said, making a reference to the growing and global problem of antibiotic resistance due to its unnecessary use.

The study, “Effect of Antimicrobial Therapy on Respiratory Hospitalization or Death in Adults With Idiopathic Pulmonary Fibrosis: The CleanUP-IPF Randomized Clinical Trial,” was published in the Journal of the American Medical Association.

Increasing evidence suggests an association between lung microbes and infections, and IPF development and progression. Particularly, increased bacterial load and/or reduced bacterial diversity has been linked to IPF progression and poorer survival.

This association is also supported by previous research in mouse models of IPF, showing that antibiotic treatment or a lack of microbial populations in germ-free mice lessened lung fibrosis and improved survival.

However, whether antibiotics have a beneficial clinical effect on IPF progression remains largely unclear.

The Phase 3 CleanUp-IPF trial (NCT02759120) was designed to evaluate whether adding broad-spectrum antibiotics — here, co-trimoxazole or doxycycline — to standard care lowered the risk of breathing-related hospitalization or all-cause death in 513 IPF patients, ages 40 and older.

The study, believed to be the largest IPF trial ever conducted, was supported by the National Institutes of Health’s National Heart, Lung and Blood Institute, the Three Lakes Foundation, the IPF Foundation, and Veracyte.

Patients recruited at 35 sites across the U.S. were randomly assigned to either one of the two antibiotics — whichever was most appropriate for their condition — in addition to usual care (254 patients), or to standard care alone (259 patients) for up to three years.

CleanUp-IPF’s pre-planned interim analysis, conducted at a median follow-up of 12.7 months, showed that the time to both breathing-related hospitalization and all-cause death was comparable between the two groups of patients.

Per 100 patient-years, such events occurred 20.4 times in the antibiotics group, while 18.4 events were recorded among those on standard care alone; this difference was not statistically significant. Patient-years is a measure of the number of patients in the study and the amount of time they were followed.

No significant group differences were observed when these events were analyzed separately, and when looking at lung function and patient-reported outcomes.

Notably, when combined with standard care, neither of the antibiotics proved to be superior to usual care alone.

Patients receiving a combination of antibiotics and standard care also had more serious respiratory adverse events, but fewer serious infections, than those on usual care alone.

Overall, adding antibiotics to standard care resulted in no significant benefit, and was associated with a higher rate of respiratory-related hospitalizations and all-cause deaths, and of serious respiratory adverse events “that did not reach statistical significance.”

These interim results, which led to the trial’s early termination on Dec. 18, 2019, were consistent with those of a previous clinical trial conducted in the U.K., called EME-TIPAC (ISRCTN17464641). Data from this study showed that treatment with co-trimoxazole, compared with a placebo, failed to improve clinical outcomes, including delaying the time to hospitalization, transplant, or death, in 342 patients with moderate or severe IPF.

“This study extends the EME-TIPAC findings by suggesting that a broader antimicrobial therapy strategy was not effective in improving clinical outcomes,” the researchers wrote.

They added, however, that these data “do not negate the potential effects of other agents whose preclinical or preliminary clinical work suggest an antifibrotic [anti-scarring] and/or clinical effect.”

It is also possible that a limited number of patients with known disruptions to their lung microorganisms may benefit from antibiotic treatment. Further analysis will clarify this.

These findings “may reflect the complex nature of the lung microbial community in chronic lung disease” and the challenges of proving a causal link between antibiotics and better outcomes, such as significant variability in lung microbes and associated immune responses between patients and even in the same patient, the researchers wrote.

Patients’ biological samples were collected during the study, which the researchers expect will help to advance the understanding and treatment of IPF.

“As the largest single study in IPF ever conducted, I think we are going to learn a lot as we look at things more closely,” said Noth, who specializes in this disease.

“Might our choice of antibiotics have been the right ones? Were there some patients that did better than others? Who should we be targeting for treatment? All things this study will help in the future,” he added.

“I am heartened and hopeful moving forward as this study teaches us a lot for the next one, and each study gets us closer to better treatments and a cure,” Noth said.

He also noted that researchers view the study “as great success” as a National Institutes of Health initiative, in that its “pragmatic design, without blinding patients to treatment, led to rapid enrollment, ahead of schedule and basically ahead of budget, showing that large studies can be accomplished in this uncommon disease.”