The Lancet MAY 21, 2011

Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials

Paul W. Noble, Carlo Albera, Williamson Z. Bradford, Ulrich Costabel, Marilyn K. Glassberg, David Kardatzke, Talmadge E. King Jr, Lisa Lancaster, Steven A. Sahn, Javier Szwarcberg, Dominique Valeyre, Roland M. du Bois

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Bottom Line

The CAPACITY program, consisting of two concurrent phase 3 trials, evaluated the efficacy and safety of oral pirfenidone in slowing lung function decline in patients with idiopathic pulmonary fibrosis, yielding mixed results regarding the primary endpoint.

Key Findings

1. In study 004, pirfenidone 2,403 mg/day significantly reduced the decline in forced vital capacity (FVC) compared to placebo at 72 weeks, with a mean change of -8.0% (SD 16.5) versus -12.4% (18.5) (difference 4.4%, 95% CI 0.7 to 9.1; p=0.001).

2. In study 004, the proportion of patients experiencing a decline in FVC of at least 10% was 20% (35/174) in the pirfenidone group compared to 35% (60/174) in the placebo group.

3. In study 006, the primary endpoint of mean change in FVC at 72 weeks between the pirfenidone 2,403 mg/day group and placebo was not statistically significant (p=0.501).

4. Pirfenidone treatment was associated with a higher incidence of adverse events, particularly gastrointestinal issues (e.g., nausea 36% vs 17%) and skin-related events (e.g., rash 32% vs 12%) compared to placebo.

5. Across the two studies, there were numerically fewer deaths in the pirfenidone 2,403 mg/day groups (6%) compared to the placebo groups (8%).

Study Design

Design

RCT

Double-Blind

Sample

779

Patients

Duration

72 wk

Median

Setting

Multicenter, International

Population Patients aged 40-80 years with idiopathic pulmonary fibrosis

Intervention Oral pirfenidone 2,403 mg/day (or 1,197 mg/day in study 004)

Comparator Placebo

Outcome Change in percentage predicted forced vital capacity (FVC) at week 72

Study Limitations

• The primary efficacy endpoint was met in one trial (study 004) but failed to reach statistical significance in the second concurrent trial (study 006).

• The high incidence of gastrointestinal and dermatological adverse events led to increased tolerability concerns, although they rarely necessitated treatment discontinuation.

• The interpretation of the efficacy was complicated by the discrepancy between the two study outcomes, leading to subsequent pooled analyses and the initiation of the ASCEND trial to further confirm the treatment effect.

• The study population was restricted to patients aged 40-80 years, potentially limiting the generalizability to other age groups.

Clinical Significance

The CAPACITY trials provided foundational evidence for the use of pirfenidone as an antifibrotic therapy in IPF, demonstrating its ability to slow the progression of lung function decline, despite the mixed results across the two individual trials. These findings supported its eventual regulatory approval and use as a standard-of-care option to manage disease progression in IPF patients.

Historical Context

At the time of the CAPACITY trials, idiopathic pulmonary fibrosis was a progressive and fatal disease with no proven effective pharmacological treatments. These studies were designed to confirm positive phase 2 and Japanese phase 3 findings, marking a critical step in the development of targeted antifibrotic therapies for this condition.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the proposed mechanism of action of pirfenidone in the treatment of Idiopathic Pulmonary Fibrosis (IPF), and how does it relate to the pathophysiological role of TGF-beta?

Key Response

Pirfenidone is an antifibrotic and anti-inflammatory agent that inhibits the synthesis of TGF-beta, a key cytokine that drives fibroblast proliferation and collagen synthesis. Understanding this connection is foundational because IPF is characterized by aberrant myofibroblast activation and excessive extracellular matrix deposition rather than traditional inflammation.

Resident

Based on the safety profile observed in the CAPACITY trials, what specific counseling and monitoring steps are essential for a patient starting pirfenidone to ensure treatment adherence?

Key Response

The CAPACITY trials identified gastrointestinal upset (nausea, dyspepsia) and photosensitivity/rash as the most common adverse events. Residents must know to counsel patients on taking the medication with food, titrating the dose gradually, and utilizing broad-spectrum sunscreen and protective clothing to manage these common barriers to long-term therapy.

Fellow

The CAPACITY program consisted of two identical trials (004 and 006) where 004 met its primary endpoint for FVC change while 006 did not. How should a subspecialist interpret this discrepancy when evaluating the efficacy of antifibrotics in mild-to-moderate disease?

Key Response

The discrepancy underscores the clinical heterogeneity of IPF and the sensitivity of the FVC endpoint to the specific population enrolled. While 006 failed to reach significance, the pooled analysis and the magnitude of effect in 004 suggest a clinically meaningful benefit, highlighting why fellows must look at the totality of evidence rather than isolated trial failures in rare lung diseases.

Attending

How do the mixed results of the CAPACITY trials influence the 'shared decision-making' conversation regarding the trade-off between the drug's cost/side effects and its primary benefit of slowing functional decline rather than improving lung function?

Key Response

Attendings must emphasize that pirfenidone does not reverse fibrosis or improve symptoms; it merely slows the rate of decline. In light of the CAPACITY results, clinicians must manage expectations, teaching trainees that 'success' in IPF is the stabilization of a surrogate marker (FVC) rather than a symptomatic cure, which is a difficult concept for many patients to accept.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

In the CAPACITY trials, the primary endpoint was the mean change in percent-predicted FVC at week 72. What are the statistical implications of using a continuous mean change versus a categorical decline (e.g., >10% FVC loss) in a disease with high inter-patient variability like IPF?

Key Response

While mean change provides more statistical power, it can be skewed by outliers. Categorical decline is often considered more clinically relevant because a 10% drop in FVC is a validated predictor of mortality. Researchers must balance the sensitivity of continuous data against the clinical 'hard' endpoints required for regulatory approval and clinical utility.

Journal Editor

If you were the editor reviewing the CAPACITY manuscript, what specific concerns would you have regarding the robustness of the data given the discordant results between Study 004 and 006, and how does the inclusion of a 'pooled analysis' affect the editorial significance?

Key Response

A tough reviewer would flag that Study 006's failure might suggest the treatment effect is marginal or population-dependent. However, the pooled analysis is significant for an editor because it increases the sample size to detect a signal in a rare disease. The editorial challenge is ensuring the 'failed' trial is not minimized while acknowledging the weight of the collective data.

Guideline Committee

How did the mixed primary endpoint results of the CAPACITY trials initially impact the ATS/ERS/JRS/ALAT clinical practice guidelines, and how does this compare to the 'strong' recommendation eventually given after the subsequent ASCEND trial?

Key Response

Initially, the CAPACITY results led to a conditional recommendation for pirfenidone because of the inconsistent findings between the two trials. It wasn't until the ASCEND trial provided a 'tie-breaker' with a more definitive benefit that guidelines moved toward a stronger recommendation. This reflects how committees weigh the quality of evidence (GRADE) based on consistency across multiple phase 3 trials.

Clinical Landscape

Noteworthy Related Trials

2012

PANTHER-IPF Trial

n = 341 · NEJM

Tested

Prednisone, azathioprine, and N-acetylcysteine

Population

Patients with idiopathic pulmonary fibrosis

Comparator

Placebo

Endpoint

Death or hospitalization

Key result: Triple therapy was associated with an increased risk of death and hospitalization compared to placebo, leading to early termination of this treatment arm.

2014

ASCEND Trial

n = 555 · NEJM

Tested

Pirfenidone 2403 mg/day

Population

Patients with idiopathic pulmonary fibrosis

Comparator

Placebo

Endpoint

Change in percent predicted forced vital capacity (FVC) at week 52

Key result: Pirfenidone significantly reduced the decline in FVC and reduced the proportion of patients with a decline in FVC of 10% or more.

2014

INPULSIS-1 and INPULSIS-2 Trials

n = 1066 · NEJM

Tested

Nintedanib 150 mg twice daily

Population

Patients with idiopathic pulmonary fibrosis

Comparator

Placebo

Endpoint

Annual rate of decline in forced vital capacity (FVC)

Key result: Nintedanib significantly slowed the progression of IPF as measured by the annual rate of decline in FVC.

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