Pragmatic Trial Design Provides New Structure for Studies in IPF
According to findings from a multicenter, phase 3 clinical trial sponsored by Weill Cornell Medicine, the addition of antibiotics to usual care does not improve outcomes for individuals with idiopathic pulmonary fibrosis (IPF). However, the investigators note that the trial’s novel design and the way in which it was conducted could pave the way for future studies that are less expensive and easier to conduct. The research was published May 11, 2021, in 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,” says lead author Fernando J. Martinez, MD, MS, Chief of Pulmonary and Critical Care Medicine at NewYork-Presbyterian/Weill Cornell Medical Center and the Bruce Webster Professor of Internal Medicine at Weill Cornell Medicine. “There has been a lot of interest in trying to establish better mechanistic insights that might lead to new therapeutic options.”
Increasingly, investigators have developed an understanding of the biology 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 influence disease genesis and behavior. With that idea in mind, Dr. Martinez and his research colleagues developed the CleanUP-IPF trial to study the effects of treating patients with antibiotics that are expected to alter the lung microbiota.
The trial, which was conducted at 35 clinical centers across the United States, enrolled 513 adults with IPF. About half of the patients received either co-trimoxazole (Bactrim) or doxycycline added to their treatment. The rest received no additional treatment beyond standard care. The patients were followed until they experienced a lung-related hospitalization or passed away. After an average follow-up period of just over a year, the difference in the time to disease progression among the three groups was not statistically significant.
According to James Kiley, MD, Director of the Division of Lung Diseases at the National Heart, Lung, and Blood Institute, the role of the bacteria in the lung in IPF disease progression has been a long-standing question. “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,” says Dr. Kiley. “However, the possibility remains open that other antimicrobial or immunomodulatory treatments may benefit patients living with this progressive lung condition.”
The Potential of Pragmatic Trials
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 conduct and because patients can be enrolled more quickly. “CleanUP-IPF was the first pragmatic trial successfully conducted in patients suffering from a rare lung disorder, idiopathic pulmonary fibrosis,” says Dr. Martinez, who has a long and distinguished record of clinical and scientific achievements in advanced and chronic lung disease. On April 1, 2022, Dr. Martinez was named the new Editor-in-Chief of the prestigious American Journal of Respiratory and Critical Care Medicine.
A key feature of the CleanUP-IPF trial was that the few exclusion criteria allowed many IPF patients to participate. Additionally, the choice of which antibiotic to use was based on doctor and patient preference. 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 Dr. Martinez. “Importantly, a parallel trial conducted by collaborators in the United Kingdom using a traditional placebo-controlled approach also examined co-trimoxazole for treating IPF. The findings for this particular antibiotic were remarkably similar to CleanUP-IPF,” he says. “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.”
Effect of Antimicrobial Therapy on Respiratory Hospitalization or Death in Adults With Idiopathic Pulmonary Fibrosis: The CleanUP-IPF Randomized Clinical Trial. Martinez FJ, Yow E, Flaherty KR, Snyder LD, Durheim MT, Wisniewski SR, Sciurba FC, Raghu G, Brooks MM, Kim DY, Dilling DF, Criner GJ, Kim H, Belloli EA, Nambiar AM, Scholand MB, Anstrom KJ, Noth I; CleanUP-IPF Investigators of the Pulmonary Trials Cooperative. JAMA. 2021 May 11;325(18):1841-1851..
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