Suspected acute exacerbation of idiopathic pulmonary fibrosis as an outcome measure in clinical trials

Abstract

Background: Acute exacerbation of idiopathic pulmonary fibrosis has become an important outcome measure in clinical trials. This study aimed to explore the concept of suspected acute exacerbation as an outcome measure.

Methods: Three investigators retrospectively reviewed subjects enrolled in the Sildenafil Trial of Exercise Performance in IPF who experienced a respiratory serious adverse event during the course of the study. Events were classified as definite acute exacerbation, suspected acute exacerbation, or other, according to established criteria.

Results: Thirty-five events were identified. Four were classified as definite acute exacerbation, fourteen as suspected acute exacerbation, and seventeen as other. Definite and suspected acute exacerbations were clinically indistinguishable. Both were most common in the winter and spring months and were associated with a high risk of disease progression and short-term mortality.

Conclusions: In this study one half of respiratory serious adverse events were attributed to definite or suspected acute exacerbations. Suspected acute exacerbations are clinically indistinguishable from definite acute exacerbations and represent clinically meaningful events. Clinical trialists should consider capturing both definite and suspected acute exacerbations as outcome measures.

Figures

Figure 1

Incidence of acute respiratory worsening by cause. The adjudicated cause of the 35 acute respiratory worsening events in the STEP-IPF cohort are represented. Four definite acute exacerbations (black bar) and fourteen suspected acute exacerbations (striped bar) were identified. Cases of other acute worsenings are listed by cause (grey bars). Abbreviations: AEX = acute exacerbation; LTR = lower respiratory tract.

Figure 2

Seasonal variation in risk of definite and suspected acute exacerbation and acute worsening. The number of acute worsening events (definite acute exacerbation = black; suspected acute exacerbation = striped; other acute worsening = grey) are demonstrated by calendar month. The number of acute exacerbation events (definite and suspected) per month normalized to the number of patients at risk were significantly higher from December to May than from June to November, with an odds ratio of 8.06 (95% CI 1.76, 36.89, p = 0.007).

Figure 3

Association of acute exacerbation and other acute worsenings with disease progression. Disease progression was variably defined by ≥10% relative decline in forced vital capacity (FVC), ≥ 15% relative decline in diffusion capacity for carbon monoxide (DLCO), ≥ 30 meter decline in 6 minute walk distance (6MWD), ≥ 5 point increase in the University of California San Diego (UCSD) shortness of breath questionnaire, and ≥ 5 point increase in the St. George’s Respiratory Questionnaire (SGRQ).

Figure 4

Acute worsening and survival. Cases adjudicated as definite or suspected acute exacerbation (AEX) of IPF (solid line) and other acute worsening (dashed line) were associated with similar short-term risk of death.