Ambassador Blog Series: WSU Medical Students, Colleen & Lakshman, on a landmark trial in Pulmonary Fibrosis

December 17, 2014

Lakshman Swamy

 Lakshman Swamy Doctor Docphin Ambassador

Colleen McCormick 

Colleen Mccormick

Institution: Wright State University
Training Level: Medical Students

Trial: Prednisone, Azathioprine, and N-Acetylcysteine for Pulmonary Fibrosis
The Idiopathic Pulmonary Fibrosis Clinical Research Network
Journal: New England Journal of Medicine
Date: May 24, 2012
URL: https://www.docphin.com/articledetail.aspx?articleID=750754

Summary by Lakshman Swamy and Colleen McCormick, WSU-BSOM students

Idiopathic pulmonary fibrosis is a chronic, fatal disease, with average life expectancy of 2-5 years.  A 2005 published trial of combination therapy (prednisone, azathioprine and N-acetylcysteine) showed improved pulmonary function when compared to a two-drug regimen of prednisone and azathioprine; however, the study design has been criticized.

The landmark clinical trial Prednisone, Azathioprine, and N-Acetylcysteine: A Study That Evaluates Response in Idiopathic Pulmonary Fibrosis (PANTHER-IPF) tested common therapies for idiopathic pulmonary fibrosis but was stopped in 10/2011 due to harm caused by the experimental arm of the group (prednisone and azathioprine).

This trial is particularly relevant to me because of a specific patient experience I had. I was on a pulmonary elective where we cared for a patient admitted for a severe pneumonia. She was on the combination immunosuppressive therapy listed here. When I spoke with her outside pulmonologist, the physician acknowledged this study but said “she had been doing well for so long; I didn’t want to change anything.” Our interpretation was different: she was doing well for so long despite a continual risk of infection due to being immunosuppressed, which finally caught up with her. In that situation, my attending said it was almost malpractice to keep patients on these drugs after seeing the data from this trial. 

Key Takeaways:
·      Halfway through the trial, interim analysis revealed there was an increased rate of death (8 vs 1 in placebo, p=0.01) and hospitalization (23 vs. 7, P<0.001) in the experimental (combination therapy) group vs. placebo. The trial was terminated at this point due to patient harm.
·      No identifiable physiologic or clinical benefit of the combined treatment
·      There are 3 reasons why this trial is perhaps more valid than previous studies. First, they used multidisciplinary assessment to confirm diagnosis of IPF. Second, they were methodical about dosage, going so far as to measure TPMT levels (predictive of azathioprine toxicity). Third, their azathioprine dose was itself lower than previous trials.
·      This is a great example of a study having immediate implications for clinical care. Patients on the combination therapy are at risk and should be removed; new patients should not be advised to start the therapy.

Potential Limitations of Trial:

One study limitation includes the high rate of termination of the combination therapy: 20/77 patients discontinued the combination treatment, compared to 3/78 patients in the placebo group. We are also looking forward to seeing the results from the continuation of the N-acetylcysteine arm of the PANTHER-IPF trial.

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