Adding antibiotics to usual care does not improve outcomes for people with the lung disease idiopathic pulmonary fibrosis (IPF), according to the findings from a multi-center, phase 3 clinical trial sponsored by Weill Cornell Medicine.

Importantly, the investigators note that although the trial had negative findings, the novel way it was designed and conducted could pave the way for future studies that are less expensive and easier to conduct. The research was published May 11 in JAMA: The Journal of the American Medical Association.

“IPF is a rare but fatal disorder that has a prognosis worse than most cancers and, unfortunately, has very limited therapeutic options,” said lead author Dr. Fernando J. Martinez, the Bruce Webster Professor of Internal Medicine at Weill Cornell Medicine and chief of pulmonary and critical care medicine at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center. “There has been a lot of interest in trying to develop a better mechanistic insight that might lead to new therapeutic options.”

IPF develops when the lungs become damaged or scarred, making it difficult to breathe. While outcomes vary, the disease generally progresses over time. Increasingly, investigators have developed an understanding of the etiology and natural history of IPF, particularly why it may behave differently in different people.

Multiple investigative groups have suggested that the makeup of the microbiota in the lungs may have an effect. (The microbiota is the collection of all bacteria and other microbes that live on or inside someone’s body.) With that idea in mind, the collaborators developed the trial, which they named CleanUP-IPF, to study the effects of treating patients with antibiotics that are expected to alter the lung microbiota.

The trial, which was conducted in collaboration with Duke Clinical Research Institute, Three Lakes Foundation, the IPF Foundation, Veracyte, Inc., 35 clinical centers across the United States, and the National Heart, Lung, and Blood Institute, part of the National Institutes of Health (NIH), included 513 adults with IPF. About half had either co-trimoxazole (commonly known as Bactrim) or doxycycline added to their treatment. The rest received no additional treatment beyond standard care. The patients were followed until they died or experienced a lung-related hospitalization. After an average follow-up time of just over a year, the difference in the time to disease progression among the three groups was not statistically significant.

“The role of the bacteria in the lung in IPF disease progression has been a long-standing question,” said Dr. James Kiley, director of the Division of Lung Diseases at the National Heart, Lung, and Blood Institute, part of the NIH. “It is helpful to clinicians to know that the common antibiotics used in this study to modify the bacteria did not delay hospitalizations or deaths for people living with idiopathic pulmonary fibrosis. However, the possibility remains open that other antimicrobial or immunomodulatory treatments may benefit patients living with this progressive lung condition.”

“This trial was the first pragmatic trial successfully conducted in patients suffering from IPF,” Martinez said. Pragmatic trials are aimed at evaluating the effectiveness of treatments in real-life settings, with the idea that their findings are more applicable to routine clinical practice. They are becoming more common in certain fields, including cardiology and rheumatology, in part because they are less expensive to carry out and because patients can be enrolled more quickly.

One feature of this pragmatic trial was that there were very few exclusion criteria, allowing many IPF patients to participate. Additionally, the choice of which antibiotic to use was based on doctor and patient preference, not the parameters of the trial. Participating institutions included both academic medical centers and smaller community hospitals. The trial completed patient enrollment ahead of schedule, something that’s very unusual, according to Martinez.

He noted that a recent trial conducted by collaborators in the UK using a traditional placebo-controlled approach also examined co-trimoxazole for treating IPF. Importantly, “the findings for this particular antibiotic were remarkably similar to CleanUP-IPF,” Martinez said. “This suggests that the less complex and intrusive structure of CleanUP-IPF did not negatively affect its outcomes and supports the concept that the pragmatic trial is a valid trial design.”