Pulmonary Fibrosis Treatment Trickier Than Drug Trials Imply

Jim Kling

October 02, 2015

AMSTERDAM — The annual mortality rate is higher in real-world idiopathic pulmonary fibrosis (IPF) patients than in clinical trial participants, and disease is more severe, according to an analysis of an ongoing German registry.

Until now, clinical drug trials have been the main source of information about the natural course, severity, and clinical burden of the disease.

"This study is about seeing the whole picture," Jürgen Behr, MD, from the Ludwig Maximilians University in Munich, told Medscape Medical News. "In this cohort, the disease is much more severe, and patients have a huge variety of comorbidities, which reduce quality of life and increase mortality."

Dr Behr presented the results here at the European Respiratory Society International Congress 2015.

His team analyzed data on 547 patients from the INSIGHTS-IPF registry, and followed them for a median 1.2 years. Mean age of the patients was 69 years, and 77% were men.

In the study cohort, median 6-minute walk distance was 271 m, the mean percent of predicted forced vital capacity was 72%, and the percent of predicted diffusion capacity for carbon dioxide was 35%.

During the follow-up period, 30.6% of the patients were admitted to the hospital and 4.9% underwent lung transplantation.

Overall, the annual mortality rate in the cohort was 14.2%. And the mortality rate was higher in patients who experienced a greater decline in forced vital capacity.

Table. Data From the INSIGHTS-IPF Registry

Variable Percent
Drug Use  
   Pirfenidone 41.0
   N-acetylcysteine 30.6
   Oral steroids 25.2
   Others 5.4
   None 19.9
Forced vital capacity at 1 year  
   Decline of at least 5% 36.1
   Decline of at least 10% 16.1

 

Dr Behr was asked whether these results change his view of the results of the pirfenidone and nintedanib clinical trials. "It's too early to say," he replied. "We have data on the cohorts taking different drugs and we will see how they behave, how quality of life is affected, and how different treatments do in real life."

The phase 3 randomized controlled ASCEND trial evaluated pirfenidone in patients with idiopathic pulmonary fibrosis (N Engl J Med. 2014;370:2083-2092). The double-blind, placebo-controlled PANTHER-IPF trial evaluated N-acetylcysteine (N Engl J Med. 2014;370:2093-2101). The phase 3 INPULSIS-1 and INPULSIS-2 trials evaluated nintedanib (N Engl J Med. 2014;370:2071-2082).

Dr Behr's team plans to look at potential adverse effects, dropout rates, switching rates, and combination rates. "All this will be captured in the future," he explained. "We are just at the beginning of that; we have only had data on nintedanib since March."

Treatment responses are another consideration. In Germany, pirfenidone is only approved for mild to moderate idiopathic pulmonary fibrosis. As individuals progress to more severe disease, "we can see the effect of pirfenidone in those patients," said Dr Behr. "All those questions can be answered, and that is the real motivation to do this."

This is "a terrific cohort to be studying," said Athol Wells, MD, head of the interstitial lung disease unit at the Royal Brompton Hospital in London, United Kingdom.

 
This is a terrific cohort to be studying.
 

He said he would like to see more detail in the analysis, especially which specific patient types are not represented in clinical trials for pirfenidone and nintedanib.

This could be important because the annual mortality rate in the clinical trials was lower in the placebo group — at 7% to 8% — than in the drug groups, Dr Wells explained.

"That immediately tells you that there's major selection at work," he told Medscape Medical News. "If you're going to actually be able to use the trial results in the real world, it's critical to establish real-world populations."

"We think we know what the biases are, but instead of speculating, you can actually find out and you might get some surprises," he pointed out.

The degree of disease severity could be a confounder. In the United Kingdom, for example, pirfenidone is only approved for mild to moderate disease and nintedanib is not available. So patients with advanced disease likely don't qualify for trial enrollment. This analysis of the Germany registry indicates that such patients might be more common than clinical trials suggest.

"It would make sense to consider reducing the threshold for treatment, or at least doing a trial focused on patients with more severe disease," session moderator Elisabetta Renzoni, PhD, a consultant chest physician at the Royal Brompton Hospital, told Medscape Medical News.

The INSIGHTS-IPF registry is financed by an unrestricted educational grant from Boehringer Ingelheim. Dr Behr reports receiving speaking fees and travel funding from Boehringer Ingelheim. Dr Wells reports consulting for Boehringer Ingelheim and other pharmaceutical companies. Dr Renzoni has disclosed no relevant financial relationships.

European Respiratory Society (ERS) International Congress 2015: Abstract OA4965. Presented September 30, 2015.

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