A critical step in the design of any clinical trial is picking the right primary endpoint, the result that will usually make or break the study. That’s more difficult than it sounds – one’s hope is to cure a disease or relieve a patient’s symptoms, but choosing the best specific measure for those goals is something of a guessing game. Further, the process can be made even more difficult for diseases that do not have a long history of clinical research and thus no established endpoints.
Idiopathic pulmonary fibrosis, an unexplained and very serious scarring of the lung tissue, is one such disease. Because of the extremely poor prognosis for patients with IPF, where most patients die within five years of symptoms first appearing, no large-scale clinical trials were tried until 1999, said Imre Noth, Associate Professor of Medicine at the University of Chicago Medical Center. Even today, some groups of IPF patients are still left out of clinical trials.
“The area that has been neglected by far and away are the severe patients,” Noth said. “The rationale beyond most biologics that have been looked at is you need to start early to make an impact.”
But the results of a promising clinical trial of a new treatment for severe IPF patients was published last week in the New England Journal of Medicine. The bad news? The primary outcome chosen for the study – improvement in a patient’s walking distance during a 6-minute test – failed to improve in the group treated with drug. Nevertheless, the trial was greeted with an optimism unusual for the IPF field, Noth said, thanks to a silver lining of secondary successes and promising near-misses.
“This has been a very frustrating disease for pulmonologists,” said Noth, a member of the Idiopathic Pulmonary Fibrosis Clinical Research Network, which designed and administered the trial. “The sense is, ‘Finally something we can give to our patients,’ because at least you can make them feel better, which is a great first step.”
The drug itself is an interesting story. Called sildenafil, it has already been marketed by Pfizer under the name Revatio as a treatment for pulmonary arterial hypertension. But most readers probably know sildenafil by its other commercial name: Viagra. The drug’s more famous use was actually an unintentional side effect, as it was originally developed to be a hypertension treatment. Trying sildenafil for IPF is going back to those primary intentions, capitalizing upon the drug’s ability to improve blood supply to the lungs.
For IPF, which Noth described as feeling like trying to breathe with a tightly-bound chest, a vasodilator such as sildenafil could potentially relieve symptoms and slow disease progression. Even a small effect would be huge for a disease that has no established, proven treatment other than lung transplant.
“Our only assignment was to make a difference,” Noth said. “In this population, our goals are different. If we can increase life by two weeks, I get a patient to a lung transplantion, which is a life-altering exercise. Two weeks is actually a massive difference.”
The 6-minute walk test was chosen as the primary endpoint, based on preliminary data from a small, pilot study. Unfortunately, over the course of a larger, 24-week IPF trial, no significant difference was found between drug and placebo on walking distance: 9 of 89 sildenafil group patients improved compared to 6 of 91 placebo group patients.
But other measures of drug activity were far more encouraging. Three different surveys revealed a significant improvement in quality of life for the drug-treated patients, and several measures of pulmonary function stabilized in the sildenafil group instead of continuing to decline. Most promisingly, a mortality difference just missed significance after 28 weeks – 4 sildenafil-treated patients died compared to 11 placebo-treated patients.
“The study was not powered for sensing a mortality difference, it was too small and too short,” Noth said. “But one has to raise an eyebrow and say, wait a minute – we’re not just talking about quality of life here. When you have several secondary events all moving in concert, that’s more likely to be a true effect.”
The results were also exciting enough to inspire a follow-up trial that will try to move the mortality result from near-miss to success, Noth said. Whether the next trial is publicly funded or paid for by Pfizer – who would be delighted to find another use for one of their most successful drugs – Noth hopes that further investigation will start soon. That study would join two others currently in progress at the University of Chicago Medical Center and other sites, one testing the blood thinner Coumadin and another testing a combination of steroids and immunosuppression agents on the disease.
In the meantime, Noth said it was a relief to have some promising data at last for an unforgiving disease that doctors could do very little to treat.
“It was pretty darn good for a small, short study,” Noth said, “and certainly more than enough to indicate we should be going after a longer study to really nail this down and be definitive about it. It offers hope.”
The Idiopathic Pulmonary Fibrosis Clinical Research Network (2010). A Controlled Trial of Sildenafil in Advanced Idiopathic Pulmonary Fibrosis New England Journal of Medicine DOI: 10.1056/nejmoa1002110