Key Point:

Interferon gamma-1b did not significantly increase disease-free survival or improve lung function among patients with IPF; however, the drug showed a strong trend toward improved survival in patients with less severe IPF.

NEW HAVEN, CONN—The inflammation and widespread fibrosis underlying idiopathic pulmonary fibrosis (IPF) have proven difficult to treat. Because this condition is characterized by high levels of profibrotic cytokines and a relative lack of endogenous interferon-gamma, many experts had hypothesized that a combination of prednisone and exogenous interferon gamma-1b would improve outcomes. In Austria, a small study with 18 IPF patients reported four years ago that this combination produced significant increases in total lung capacity and arterial oxygen tension (Pao2).

However, results of a recent and much larger study of interferon gamma-1b in IPF failed to reproduce the findings of the preliminary study. When compared with placebo, this agent did not significantly alter the primary end point—progression-free survival—during the median treatment interval of 58 weeks.[1] Nor did it alter lung function, gas exchange, or quality of life. The primary endpoint was a composite of either a 10% decrease in FVC, a 5 mm Hg increase in the resting alveolar-arterial O2 difference, or death. Sixty-three percent of the failures (43/68) in the interferon gamma-1b group were due to resting alveolar-arterial O2 difference. A similar result (46/75) was observed in the placebo group. Only 8/68 failures in the treatment group and 12/75 in the placebo group were due to a 10% fall in FVC.

The study’s investigators did, however, find a trend toward increased survival in the patients given active treatment. In that group, the absolute and relative risks of death decreased by 7% and 41%; these differences nearly reached statistical significance. The differences in the absolute and relative risks of death at one year were even greater among treatment-adherent patients: 9% and 66%, respectively. Treatment adherence was a pre-specified secondary end point.

“Although we were disappointed that we did not reproduce the results in the Austrian trial, the survival difference is provocative because it suggests there is still the possibility that interferon gamma-1b modifies the natural history of IPF,” said Paul W. Noble, MD, one of the study’s principal investigators. “But we need another trial to prove that. Such a trial is under way,” added Dr. Noble, a Professor of Medicine at the Yale University School of Medicine in New Haven, Connecticut.

All 330 patients in the study had definite or probable IPF for more than one year. Their mean resting Pao2 was 74 mm Hg, mean FVC was 64% of predicted, and mean carbon monoxide diffusing capacity (Dlco) was 37% of predicted.

The patients were randomized to receive three subcutaneous injections per week of either placebo or interferon gamma-1b. Initially, 100 µg of the study drug was given, but the dose was raised to 200 µg after two weeks. Patients who were receiving prednisone (about three quarters of the participants in both groups) could continue to do so as long as the daily dose remained stable and did not exceed 15 mg. Rates of treatment adherence and premature stoppage were similar in the two study groups.

Disease progression or death occurred in 46% of the interferon group and in 52% of the placebo recipients. The median time to death or disease progression in the two groups was 439 and 344 days, respectively. Those differences were not significant.

The differences between the two groups in a number of other variables were also nonsignificant. For example, the mean decrease from baseline to week 48 in FVC was 0.20 L in the interferon group and 0.16 L in the placebo recipients. The mean increase in the difference between alveolar and arterial oxygen tension was 3.3 and 2.9 mm Hg, respectively, and the mean drop in DLCO was 1.0 and 0.7 mL/min/mm Hg, respectively. No differences between the two groups were observed in the scores for the Transition Dyspnea Index or the St. George’s Respiratory Questionnaire, which measures quality of life.

The overall incidence of adverse events was high: 99% in the interferon group and 98% in the placebo group; both groups had similar rates of mild, moderate, and life-threatening adverse events. However, pneumonia and constitutional symptoms (eg, fever, rigors, headache, and myalgia) were more common in the interferon group; nausea and vomiting were more common in the placebo recipients.

By week 48, 10% of the interferon group had died, compared with 17% of the placebo recipients. As noted, this difference did not reach significance in the overall intent to treat analysis. However, subgroup analyses suggested that statistically significant decreases in mortality were achieved in the patients with less severe baseline lung impairment, as well as in the patients who were highly compliant with treatment.

—Timothy Begany

Reference
1. Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2004;350:125-133.

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