Phase IV IPF Clinical Trials

Experimental Pharmacologic Treatments for Idiopathic Pulmonary Fibrosis: Phase 4 Trials

Nintedanib and pirfenidone are both FDA approved to treat IPF. They can slow down lung damage but cannot stop it. They do not cure IPF, and they do not seem to improve symptoms like fatigue, cough, or breathlessness. (For more information, click here). 

After approval, sometimes the FDA still asks companies to perform more studies, called Phase 4 studies. These studies keep track of thousands of patients who are using the treatment or medication. Phase 4 studies look for very rare or long-term side effects. They also look at how effective the medication or treatment is over many years and across many patients. 

Nintedanib and pirfenidone work differently from each other. Both slow down the formation of scar tissue cells (fibrotic cells) in the lungs. They do this by making it more difficult for collagen, a protein in scar tissue, to be made. They also slow down the formation of collagen tendrils, which are long strings of collagen protein. But the way that they do it is not exactly the same. Therefore, researchers have asked if taking both medications together would be more helpful to people with IPF than taking either alone. Two phase 4 studies have looked at this question.

Nintedanib First, Then Add Pirfenidone

INJOURNEY was a phase 4 trial that enrolled 104 IPF patients.¹At the start, these patients had to have a forced vital capacity (FVC) of more than 50% of what would be expected for a healthy person. FVC measures the amount of air a person can exhale with force after inhaling as deeply as possible. The level of FVC for the patients at the start of INJOURNEY is considered to be “mild-to-moderate” IPF. 

Before starting the study, the 104 patients who were enrolled had to have taken 4-5 weeks of nintedanib 150 mg twice daily. These patients had to be able to tolerate taking nintedanib. That means they could not make the dose smaller or stop it periodically because of side effects. At study start, 53 of the 104 patients were randomly chosen to keep taking nintedanib 150 mg twice daily and to also start take pirfenidone 801 mg three times daily. The other 51 were randomly chosen to keep taking nintedanib 150 mg twice daily. 

All the patients knew what they were taking, and so did the researchers. This was an “open-label” study (everyone knows what they get). The patients took either the combo treatment or the nintedanib alone for 12 weeks. 

The main thing the researchers were interested in was side effects. The concern was that taking two medications at once would cause too many side effects. In the study, gastrointestinal (digestive) side effects, like diarrhea, nausea, vomiting, or stomach pain, were reported in 37 of 53 patients (70%) treated with the combo treatment and 27 of 51 patients (53%) treated with nintedanib alone. In the combo treatment group, pirfenidone had to be stopped in 19 of 53 patients (36%) because of too many side effects. 

The researchers also looked at whether taking combo treatment was more helpful than nintedanib alone. The average change in FVC at Week 12 was −13.3 mL in the combo group and −40.9 mL in the group treated with nintedanib alone. Those numbers mean that, on average, both groups got worse from the start of the trial to the end. But, the combo treatment group did not get as bad as the nintedanib alone group. 

Pirfenidone First, Then Add Nintedanib

A second phase 4 trial looked at combo treatment, starting with pirfenidone first.²The trial enrolled 89 patients with IPF. Like the INJOURNEY trial, these patients at the start had to have an FVC of more than 50% of what would be expected for a healthy person. The patients also had to have taken pirfenidone for at least 16 weeks and tolerated a stable dose of 1602–2403 mg per day for at least 28 days. They could not have had any moderate or severe side effects during those 16 weeks of pirfenidone treatment. They also were not allowed to have stopped taking pirfenidone for more than 7 days during those 16 weeks. 

At the study start, all 89 patients added nintedanib to their pirfenidone treatment, so they were taking both medications. The dose of nintedanib was 100 mg per day during Week 1, 200 mg per day during Week 2, and 300 mg per day from Week 3 onwards (one 150-mg capsule twice a day). The trial lasted 24 weeks. This was an open-label study. There was no comparison group of patients who took pirfenidone alone.

Of the 89 patients who started the study, 73 patient scompleted 24 weeks of treatment, and 16 patients stopped treatment early. Most of the patients who stopped early (11 out of 16) did so because of too many side effects. The vast majority of patients had side effects (over 8 in 10 patients). The most common were gastrointestinal (digestive). 

The researchers looked at FVC before the study started and throughout the study. The average FVC for the enrolled patients had declined by about 0.8% in the 24 weeks before the study started. From the start of the study to week 24 of treatment, the average FVC declined by about 0.4%. That is a slower rate of decline during the study than before the study. That may mean that taking both medications together slowed down lung damage more than taking only one medication would have. However, the difference was small. 

What Do These Studies Mean?

Because these studies were small and lasted only a few months, it is hard to say if combo treatment slows down lung damage more than treatment with just one medication. Not every patient had the same results. The FVC numbers are averages for a whole group. Some patients did better, and some did worse, than others in their same group. Larger studies that last for many more months will be needed to see if combo treatment truly is more helpful than treatment with one medication only.

The two studies did show that many patients can tolerate taking the two medications together. About 20-30% (2 to 3 patients out of 10) could not tolerate taking the two medications together. Because some patients can tolerate these two mediations together, further studies will likely be done to see how helpful they are over a longer time.

References

1. Vancheri C, Kreuter M, Richeldi L, et al. Nintedanib with add-on pirfenidone in idiopathic pulmonary fibrosis. results of the INJOURNEY trial. Am J Respir Crit Care Med. 2018;197(3):356-363.
2. Flaherty KR, Fell CD, Huggins JT, et al. Safety of nintedanib added to pirfenidone treatment for idiopathic pulmonary fibrosis. Eur Respir J. 2018;52(2).