article329

ASCEND (IPF)

"Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis".The New England Journal of Medicine. 2014. Published online before print.

1 Clinical Question
2 Bottom Line
3 Major Points
4 Guidelines
5 Design
6 Population
6.1 Inclusion Criteria
6.2 Exclusion Criteria
6.3 Baseline Characteristics
7 Interventions
8 Outcomes
8.1 Primary Outcomes
8.2 Secondary Outcomes
9 Criticisms
10 Funding
11 Further Reading

Clinical Question

Does pirfenidone reduce disease progression in patients with idiopathic pulmonary fibrosis compared to placebo?

Bottom Line

Pirfenidone, compared to placebo, reduced disease progression as measured by FVC change, 6-minute walk distance, and progression-free survival in patients with idiopathic pulmonary fibrosis, and had an acceptable side-effect profile with fewer deaths observed.

Major Points

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease. Previous phase 3 trials demonstrated mixed results regarding the efficacy of pirfenidone in reducing disease progression. The phase 3 ASCEND trial aimed to confirm pirfenidone's beneficial effect on disease progression in IPF patients.

Guidelines

Guideline recommendations for the use of pirfenidone in IPF were not addressed as part of this trial.

Design

- Phase 3, randomized, double-blind, placebo-controlled trial
- N=555 patients with idiopathic pulmonary fibrosis
- Randomized to receive oral pirfenidone (2403 mg per day) or placebo for 52 weeks
- Primary endpoint: change in FVC or death at week 52
- Secondary endpoints included the 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from IPF
- Conducted at 127 sites in 9 countries
- Funding: InterMune

Population

- Adults aged 40-80 years with centrally confirmed diagnosis of IPF
- Inclusion Criteria: Diagnosed with IPF, FVC 50-90% predicted, FEV1:FVC ratio ≥0.80, 6-minute walk distance ≥150m
- Exclusion Criteria: Symptomatic ventricular arrhythmias, NSVT ≥15 PVCs per hour at rate ≥120 bpm, use of investigational therapy, etc.
- Baseline Characteristics: Majority male and white, average age 65 or older, mean baseline FVC 67.8±11.2% predicted in pirfenidone group and 68.6±10.9% predicted in placebo group

Interventions

- Pirfenidone (2403 mg per day) administered with food in three divided doses, with a gradual dose increase over 2 weeks
- Placebo administered in a similar regimen

Outcomes

Primary Outcomes
- Significant relative reduction of 47.9% in patients with ≥10 percentage points decline in predicted FVC or death with pirfenidone
- Relative increase of 132.5% in patients with no decline in FVC with pirfenidone compared to placebo (P<0.001)
Secondary Outcomes
- Reduce 6-minute walk distance decline (P=0.04)
- Improved progression-free survival (P<0.001)
- No significant difference in dyspnea scores or death rates from any cause or from IPF

Criticisms

- The generalizability to patients with advanced disease and those with significant airflow limitation (FEV1:FVC <0.80) is uncertain
- Central confirmation of diagnosis may not represent the general IPF population

Funding

- The study was funded by InterMune.