Carlos Alberto de Castro Pereira

A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis.

BACKGROUND In two of three phase 3 trials, pirfenidone, an oral antifibrotic therapy, reduced disease progression, as measured by the decline in forced vital capacity (FVC) or vital capacity, in patients with idiopathic pulmonary fibrosis; in the third trial, this end point was not achieved. We sought to confirm the beneficial effect of pirfenidone on disease progression in such patients. METHODS In this phase 3 study, we randomly assigned 555 patients with idiopathic pulmonary fibrosis to receive either oral pirfenidone (2403 mg per day) or placebo for 52 weeks. The primary end point was the change in FVC or death at week 52. Secondary end points were the 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from idiopathic pulmonary fibrosis. RESULTS In the pirfenidone group, as compared with the placebo group, there was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points or more in the percentage of the predicted FVC or who died; there was also a relative increase of 132.5% in the proportion of patients with no decline in FVC (P<0.001). Pirfenidone reduced the decline in the 6-minute walk distance (P=0.04) and improved progression-free survival (P<0.001). There was no significant between-group difference in dyspnea scores (P=0.16) or in rates of death from any cause (P=0.10) or from idiopathic pulmonary fibrosis (P=0.23). However, in a prespecified pooled analysis incorporating results from two previous phase 3 trials, the between-group difference favoring pirfenidone was significant for death from any cause (P=0.01) and from idiopathic pulmonary fibrosis (P=0.006). Gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group but rarely led to treatment discontinuation. CONCLUSIONS Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable side-effect profile and fewer deaths. (Funded by InterMune; ASCEND ClinicalTrials.gov number, NCT01366209.).

Novos valores de referência para espirometria forçada em brasileiros adultos de raça branca

OBJECTIVE To describe spirometric reference equations for healthy Brazilian adults who have never smoked and to compare the predicted values with those derived in 1992. METHODS Reference equations for spirometry were derived in 270 men and 373 women living in eight cities in Brazil. Ages ranged from 20 to 85 years in women and from 26 to 86 years in men. Spirometry examinations followed the recommendations of the Brazilian Thoracic Society. Lower limits were derived by the analysis of the fifth percentiles of the residuals. RESULTS Forced vital capacity (FVC), forced expiratory volume in one second (FEV1), FEV1/FVC and FEV1/forced expiratory volume in six seconds (FEV6) were best fitted by linear regression. Flows were best fitted using log equations. For both genders, greater height resulted in lower values for FEV1/FVC, FEV1/FEV6 and flow/FVC ratios. The reference values for FEV1 and FVC in the present study were higher than those derived for Brazilian adults in 1992. CONCLUSION New predicted values for forced spirometry were obtained in a sample of white Brazilians. The values are greater than those obtained in 1992, probably due to technical factors.

Pirfenidone for idiopathic pulmonary fibrosis: Analysis of pooled data from three multinational phase 3 trials

Pirfenidone is an antifibrotic agent that has been evaluated in three multinational phase 3 trials in patients with idiopathic pulmonary fibrosis (IPF). We analysed pooled data from the multinational trials to obtain the most precise estimates of the magnitude of treatment effect on measures of disease progression. All patients randomised to pirfenidone 2403 mg·day−1 or placebo in the CAPACITY or ASCEND studies were included in the analysis. Pooled analyses of outcomes at 1 year were based on the pre-specified end-points and analytic methods described in the ASCEND study protocol. A total of 1247 patients were included in the analysis. At 1 year, pirfenidone reduced the proportion of patients with a ≥10% decline in per cent predicted forced vital capacity or death by 43.8% (95% CI 29.3–55.4%) and increased the proportion of patients with no decline by 59.3% (95% CI 29.0–96.8%). A treatment benefit was also observed for progression-free survival, 6-min walk distance and dyspnoea. Gastrointestinal and skin-related adverse events were more common in the pirfenidone group, but rarely led to discontinuation. Analysis of data from three phase 3 trials demonstrated that treatment with pirfenidone for 1 year resulted in clinically meaningful reductions in disease progression in patients with IPF. Treatment with pirfenidone for 1 year results in clinically meaningful reductions in IPF disease progression http://ow.ly/StvBk

Teste de caminhada de seis minutos: valores de referência para adultos saudáveis no Brasil

OBJETIVO: Desenvolver equacoes de regressao para a distância caminhada no teste de caminhada de seis minutos (DTC6) em adultos saudaveis (20-80 anos de idade) no Brasil. METODOS: Foram incluidos 132 voluntarios (66 homens) sem doencas respiratorias ou cardiacas, assim como sem comorbidades que afetassem a deambulacao. Os voluntarios completaram tres testes de caminhada de seis minutos. Foram obtidos antes e ao final de cada teste: SpO2, FC maxima e escores da escala de Borg para dispneia e fadiga de pernas. Os dados incluidos na analise final foram os derivados do teste com a maior DTC6. RESULTADOS: Os valores medios de DTC6 foram de 566 ± 87 m e 538 ± 95 m em homens e mulheres, respectivamente (p = 0,08). A DTC6 aumentou com a estatura e diminuiu com a idade e com o indice de massa corporea (IMC). O melhor modelo ajustado foi o quadratico. A equacao derivada para ambos os sexos foi: DTC6 = 511 + altura2 (cm) × 0,0066 - idade2 × 0,030 - IMC2 × 0,068. Esta equacao explicou 55% da variacao na DTC6. CONCLUSOES: Valores de referencia com uma elevada variância explicada foram derivados por um modelo quadratico de regressao em adultos saudaveis com ampla variacao de idade no Brasil.

Validação de novos valores previstos brasileiros para a espirometria forçada na raça branca e comparação com os valores previstos obtidos por outras equações de referência

OBJETIVO: Comparar os novos valores previstos brasileiros de capacidade vital forcada e volume expiratorio forcado no primeiro segundo para a espirometria obtidos em 2006 com os obtidos por outras equacoes de referencia e validar os achados por meio da comparacao com uma nova amostra de brasileiros normais. METODOS: Realizou-se espirometria forcada, de acordo com as normas da Sociedade Brasileira de Pneumologia e Tisiologia, em 643 adultos brancos nao-fumantes. Os valores previstos obtidos por pesquisadores brasileiros em 1992 e os obtidos por quatro grupos de pesquisadores estrangeiros foram comparados com os novos valores previstos brasileiros obtidos em 2006. Em uma segunda fase, os valores medios obtidos em 65 mulheres e 79 homens adultos foram comparados aos valores previstos obtidos pelas diversas equacoes de referencia. RESULTADOS: O teste t para amostras pareadas revelou diferencas significativas entre os valores previstos obtidos pelas seis equacoes e os obtidos pela equacao brasileira de 2006. Na segunda fase, observou-se que os valores previstos obtidos por Crapo et al. e os obtidos por Hankinson et al. para os mexico-americanos mostraram valores medios semelhantes aos observados na nova amostra. Porem, quando os valores previstos obtidos na nova amostra foram comparados com os obtidos por esses autores, discrepâncias foram observadas, com valores previstos altos e baixos. Os valores obtidos pela equacao brasileira de 2006 mostraram as menores diferencas em comparacao com os valores medios obtidos na nova amostra. CONCLUSOES: Estes resultados sublinham a importância de se usar equacoes de predicao para espirometria que sejam apropriadas para nossa populacao.

Effect of continued treatment with pirfenidone following clinically meaningful declines in forced vital capacity: analysis of data from three phase 3 trials in patients with idiopathic pulmonary fibrosis

Background The assessment of treatment response in idiopathic pulmonary fibrosis (IPF) is complicated by the variable clinical course. We examined the variability in the rate of disease progression and evaluated the effect of continued treatment with pirfenidone in patients who experienced meaningful progression during treatment. Methods The source population included patients enrolled in the ASCEND and CAPACITY trials (N=1247). Pearsons correlation coefficients were used to characterise the relationship between changes in FVC during consecutive 6-month intervals in the placebo population. Outcomes following a ≥10% decline in FVC were evaluated by comparing the proportion of patients in the pirfenidone and placebo groups who experienced a ≥10% decline in FVC or death during the subsequent 6 months. Results A weak negative correlation was observed between FVC changes during consecutive intervals in the placebo population (coefficient, −0.146, p<0.001), indicating substantial variability. Thirty-four (5.5%) and 68 (10.9%) patients in the pirfenidone and placebo groups, respectively, experienced a ≥10% decline in FVC by month 6. During the subsequent 6 months, fewer patients in the pirfenidone group compared with placebo experienced a ≥10% decline in FVC or death (5.9% vs 27.9%; relative difference, 78.9%). There was one (2.9%) death in the pirfenidone group and 14 (20.6%) deaths in the placebo group (relative difference, 85.7%). Conclusions Longitudinal FVC data from patients with IPF showed substantial intrasubject variability, underscoring the inability to reliably assess therapeutic response using serial FVC trends. In patients who progressed during treatment, continued treatment with pirfenidone resulted in a lower risk of subsequent FVC decline or death. Trial registration numbers NCT01366209, NCT00287729, NCT00287716.

Effect of pirfenidone on mortality: pooled analyses and meta-analyses of clinical trials in idiopathic pulmonary fibrosis

BACKGROUND In clinical trials of idiopathic pulmonary fibrosis, rates of all-cause mortality are low. Thus prospective mortality trials are logistically very challenging, justifying the use of pooled analyses or meta-analyses. We did pooled analyses and meta-analyses of clinical trials of pirfenidone versus placebo to determine the effect of pirfenidone on mortality outcomes over 120 weeks. METHODS We did a pooled analysis of the combined patient populations of the three global randomised phase 3 trials of pirfenidone versus placebo-Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY 004 and 006; trial durations 72-120 weeks) and Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND 016; 52 weeks)-for all-cause mortality, treatment-emergent all-cause mortality, idiopathic-pulmonary-fibrosis-related mortality, and treatment-emergent idiopathic-pulmonary-fibrosis-related mortality at weeks 52, 72, and 120. We also did meta-analyses of these data and data from two Japanese trials of pirfenidone versus placebo-Shionogi Phase 2 (SP2) and Shionogi Phase 3 (SP3; trial durations 36-52 weeks). FINDINGS At week 52, the relative risk of death for all four mortality outcomes was significantly lower in the pirfenidone group than in the placebo group in the pooled population (all-cause mortality hazard ratio [HR] 0·52 [95% CI 0·31-0·87; p=0·0107]; treatment-emergent all-cause mortality 0·45 [0·24-0·83; 0·0094]; idiopathic-pulmonary-fibrosis-related mortality 0·35 [0·17-0·72; 0·0029]; treatment-emergent idiopathic-pulmonary-fibrosis-related mortality 0·32 [0·14-0·76; 0·0061]). Consistent with the pooled analysis, meta-analyses for all-cause mortality at week 52 also showed a clinically relevant and significant risk reduction in the pirfenidone group compared with the placebo group. Over 120 weeks, we noted significant differences in the pooled analysis favouring pirfenidone therapy compared with placebo for treatment-emergent all-cause mortality (p=0·0420), idiopathic-pulmonary-fibrosis-related mortality (0·0237), and treatment-emergent idiopathic-pulmonary-fibrosis-related (0·0132) mortality; similar results were shown by meta-analyses. INTERPRETATION Several analytic approaches demonstrated that pirfenidone therapy is associated with a reduction in the relative risk of mortality compared with placebo over 120 weeks. FUNDING F Hoffmann-La Roche/Genentech.

Safety of pirfenidone in patients with idiopathic pulmonary fibrosis: integrated analysis of cumulative data from 5 clinical trials

Background Pirfenidone is an oral antifibrotic agent that has been shown to reduce the decline in lung function in patients with idiopathic pulmonary fibrosis (IPF). We performed an integrated analysis of safety data from five clinical trials evaluating pirfenidone in patients with IPF. Methods All patients treated with pirfenidone in the three multinational Phase 3 studies (CAPACITY (studies 004 and 006), ASCEND (study 016)) and two ongoing open-label studies (study 002 and study 012 (RECAP)) were included in the analysis. Safety outcomes were assessed during the period from the first dose until 28 days after the last dose of study drug. Results A total of 1299 patients were included in the analysis. The cumulative total exposure to pirfenidone was 3160 person exposure years (PEY). The median duration of exposure was 1.7 years (range 1 week to 9.9 years), and the mean (±SD) daily dose was 2053.8 (±484.9) mg. Gastrointestinal events (nausea (37.6%), diarrhoea (28.1%), dyspepsia (18.4%), vomiting (15.9%)) and rash (25.0%) were the most common adverse events; these were generally mild to moderate in severity and without significant clinical consequence. Elevations in alanine aminotransferase or aspartate aminotransferase greater than three times the upper limit of normal occurred in 40/1299 (3.1%) patients (adjusted incidence, 2.3 per 100 PEY). Elevations were generally transient and reversible with dose modification or discontinuation. Conclusions A comprehensive analysis of safety outcomes in a large and well-defined cohort of 1299 patients with IPF who were followed prospectively for up to 9.9 years demonstrated that long-term treatment with pirfenidone is safe and generally well tolerated. Trial registration numbers NCT00287716, NCT00287729, NCT00662038, NCT01366209.

Dispneia em DPOC: além da escala modified Medical Research Council

OBJECTIVE To determine the correlations among various dyspnea scales, spirometric data, exercise tolerance data, and the Body mass index, airway Obstruction, Dyspnea, and Exercise capacity (BODE) index in patients with COPD. METHODS Between March of 2008 and July of 2009, 79 patients with COPD were recruited, and 50 of those patients were included in the study. After being regularly treated with formoterol for one month, the patients completed the modified Medical Research Council (mMRC, dyspnea scale), Baseline Dyspnea Index (BDI), Oxygen Cost Diagram (OCD), and Shortness Of Breath Questionnaire (SOBQ). Subsequently, the patients underwent spirometry and six-minute walk tests (6MWTs), with determination of the six-minute walk distance (6MWD), as well as initial and final SpO2. All patients also completed the Visual Analogue Scale (VAS) and the Borg scale. RESULTS The best correlations were between the Borg scale and the VAS (r s = 0.79) and between the BDI and the SOBQ (r s = -0.73). Among the one-dimensional scales (the VAS, mMRC, OCD, and Borg scale), only the VAS correlated with the spirometric parameters, whereas the multidimensional scales BDI and SOBQ did correlate, but poorly. The MRC, BDI, and SOBQ correlated well with 6MWD. Among the spirometric data, inspiratory capacity (IC) and FVC had the strongest correlations with 6MWD. In the multivariate analysis, BDI and IC were selected as the best predictors of 6MWD. CONCLUSIONS Multidimensional dyspnea scales should be applied in the evaluation of COPD patients.

P13 Safety of pirfenidone in patients with idiopathic pulmonary fibrosis (IPF): Integrated analysis of cumulative data from 5 clinical trials

Introduction and objectives IPF is a chronic, progressive and irreversible disease that requires long-term clinical management. To further evaluate the clinical safety of pirfenidone in patients with IPF, we performed a comprehensive integrated analysis of safety data from 5 clinical trials. Methods All patients assigned to receive pirfenidone (2403 mg/d) in the Phase 3 ASCEND (016) and CAPACITY (004/006) studies and all patients receiving ≥1 dose of pirfenidone in either of two ongoing open-label studies (studies 002 and 012) comprised the integrated population. EAP (002) is a compassionate use study in the U.S.; RECAP (012) is evaluating pirfenidone in patients who completed one of the Phase 3 studies. Analyses were based on the January 15, 2014 interim data cut. Results 1299 patients were included in the integrated population. The cumulative total exposure to pirfenidone was 3160 person exposure years (PEY). The median duration of exposure was 1.7 years (range, 1 week–9.9 years); 545 (42%) patients received pirfenidone for ≥2 years and 325 (25%) patients received pirfenidone for ≥4 years. The majority of patients (75.8%) received a mean daily dose of ≥1800 mg. Consistent with prior observations, gastrointestinal and skin-related events were among the most common treatment emergent adverse events (Table 1); these were almost always mild to moderate in severity, reversible with dose modification and rarely led to treatment discontinuation. Cough, dyspnoea and IPF were the most common respiratory adverse events in the integrated population—a finding that is consistent with expectations in patients with a chronic progressive respiratory disease followed over a long period of observation. Aminotransferase (ALT or AST) elevations (>3 × ULN) occurred in 40/1299 (3.0%) patients in the integrated population.Abstract P13 Table 1 Treatment emergent adverse events in the integrated population compared with the pooled pirfenidone 2403 mg/d and placebo groups in the Phase 3 trials* Integrated population (N = 1299)† OE = treatment emergent adverse event ment emergent adverse events d sun exposure during treatment with pirfenidone. the skin du Median (range) duration of exposure, yr 1.7 (>0, 9.9) Treatment emergent adverse event,% Nausea 37.6 Cough 35.1 Dyspnea 30.9 Upper respiratory tract infection 30.6 Idiopathic pulmonary fibrosis 29.3 Fatigue 28.2 Diarrhoea 28.1 Rash 25.0 Bronchitis 23.8 Headache 21.6 Nasopharyngitis 21.3 Dizziness 21.2 Dyspepsia 18.4 Vomiting 15.9 Weight decreased 15.6 Back pain 15.4 Anorexia 15.2 *Occurring in ≥15% of patients in the cumulative clinical database. †Includes 2 patients in Study 002 with a diagnosis of “pulmonary fibrosis.” Conclusions A comprehensive integrated analysis of safety outcomes in a large, well–defined cohort of 1299 patients with IPF who were treated with pirfenidone for up to 9.9 years demonstrated that treatment with pirfenidone is safe and generally well tolerated. These observations provide further evidence to support the long-term clinical safety of pirfenidone in patients with IPF.