Steven A. Sahn

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.).

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

BACKGROUND Idiopathic pulmonary fibrosis is a progressive and fatal lung disease with inevitable loss of lung function. The CAPACITY programme (studies 004 and 006) was designed to confirm the results of a phase 2 study that suggested that pirfenidone, a novel antifibrotic and anti-inflammatory drug, reduces deterioration in lung function in patients with idiopathic pulmonary fibrosis. METHODS In two concurrent trials (004 and 006), patients (aged 40-80 years) with idiopathic pulmonary fibrosis were randomly assigned to oral pirfenidone or placebo for a minimum of 72 weeks in 110 centres in Australia, Europe, and North America. In study 004, patients were assigned in a 2:1:2 ratio to pirfenidone 2403 mg/day, pirfenidone 1197 mg/day, or placebo; in study 006, patients were assigned in a 1:1 ratio to pirfenidone 2403 mg/day or placebo. The randomisation code (permuted block design) was computer generated and stratified by region. All study personnel were masked to treatment group assignment until after final database lock. Treatments were administered orally, 801 mg or 399 mg three times a day. The primary endpoint was change in percentage predicted forced vital capacity (FVC) at week 72. Analysis was by intention to treat. The studies are registered with ClinicalTrials.gov, numbers NCT00287729 and NCT00287716. FINDINGS In study 004, 174 of 435 patients were assigned to pirfenidone 2403 mg/day, 87 to pirfenidone 1197 mg/day, and 174 to placebo. In study 006, 171 of 344 patients were assigned to pirfenidone 2403 mg/day, and 173 to placebo. All patients in both studies were analysed. In study 004, pirfenidone reduced decline in FVC (p=0·001). Mean FVC change at week 72 was -8·0% (SD 16·5) in the pirfenidone 2403 mg/day group and -12·4% (18·5) in the placebo group (difference 4·4%, 95% CI 0·7 to 9·1); 35 (20%) of 174 versus 60 (35%) of 174 patients, respectively, had a decline of at least 10%. A significant treatment effect was noted at all timepoints from week 24 and in an analysis over all study timepoints (p=0·0007). Mean change in percentage FVC in the pirfenidone 1197 mg/day group was intermediate to that in the pirfenidone 2403 mg/day and placebo groups. In study 006, the difference between groups in FVC change at week 72 was not significant (p=0·501). Mean change in FVC at week 72 was -9·0% (SD 19·6) in the pirfenidone group and -9·6% (19·1) in the placebo group, and the difference between groups in predicted FVC change at week 72 was not significant (0·6%, -3·5 to 4·7); however, a consistent pirfenidone effect was apparent until week 48 (p=0·005) and in an analysis of all study timepoints (p=0·007). Patients in the pirfenidone 2403 mg/day group had higher incidences of nausea (125 [36%] of 345 vs 60 [17%] of 347), dyspepsia (66 [19%] vs 26 [7%]), vomiting (47 [14%] vs 15 [4%]), anorexia (37 [11%] vs 13 [4%]), photosensitivity (42 [12%] vs 6 [2%]), rash (111 [32%] vs 40 [12%]), and dizziness (63 [18%] vs 35 [10%]) than did those in the placebo group. Fewer overall deaths (19 [6%] vs 29 [8%]) and fewer deaths related to idiopathic pulmonary fibrosis (12 [3%] vs 25 [7%]) occurred in the pirfenidone 2403 mg/day groups than in the placebo groups. INTERPRETATION The data show pirfenidone has a favourable benefit risk profile and represents an appropriate treatment option for patients with idiopathic pulmonary fibrosis. FUNDING InterMune.

Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial

BACKGROUND Idiopathic pulmonary fibrosis is a fatal disease for which no effective treatment exists. We assessed whether treatment with interferon gamma-1b improved survival compared with placebo in patients with idiopathic pulmonary fibrosis and mild-to-moderate impairment of pulmonary function. METHODS 826 patients with idiopathic pulmonary fibrosis were enrolled from 81 centres in seven European countries, the USA, and Canada. Patients were randomly assigned (double-blind) in a 2:1 ratio to receive 200 microg interferon gamma-1b (n=551) or equivalent placebo (n=275) subcutaneously, three times per week. Eligible patients were aged 40-79 years, had been diagnosed in the past 48 months, had a forced vital capacity of 55-90% of the predicted value, and a haemoglobin-corrected carbon monoxide diffusing capacity of 35-90% of the predicted value. The primary endpoint was overall survival time from randomisation measured at the second interim analysis, when the proportion of deaths had reached 75% of those expected by the study conclusion. This study is registered with ClinicalTrials.gov, number NCT00075998. FINDINGS At the second interim analysis, the hazard ratio for mortality in patients on interferon gamma-1b showed absence of minimum benefit compared with placebo (1.15, 95% CI 0.77-1.71, p=0.497), and indicated that the study should be stopped. After a median duration of 64 weeks (IQR 41-84) on treatment, 80 (15%) patients on interferon gamma-1b and 35 (13%) on placebo had died. Almost all patients reported at least one adverse event, and more patients on interferon gamma-1b group had constitutional signs and symptoms (influenza-like illness, fatigue, fever, and chills) than did those on placebo. Occurrence of serious adverse events (eg, pneumonia, respiratory failure) was similar for both treatment groups. Treatment adherence was good and few patients discontinued treatment prematurely in either group. INTERPRETATION We cannot recommend treatment with interferon gamma-1b since the drug did not improve survival for patients with idiopathic pulmonary fibrosis, which refutes previous findings from subgroup analyses of survival in studies of patients with mild-to-moderate physiological impairment of pulmonary function. FUNDING InterMune.

Chemical Pleurodesis for Malignant Pleural Effusions

Malignant pleural effusions can be the first clinical manifestation of malignancy [1], as well as the first sign of recurrence of tumor. At the time that malignant effusion is diagnosed, three of four patients have respiratory symptoms [2]. The standard treatment of these recurrent, symptomatic pleural effusions is intrapleural instillation of a chemical agent in an attempt to produce pleurodesis [3-6]. We review the medicinal agents currently available for chemical pleurodesis but defer discussion of less considered and unavailable agents such as CalmetteGurin bacillus cell-wall skeleton [7, 8], nitrogen mustard [9], quinacrine [10, 11], and thiotepa [12]. Although not currently available for this use in the United States, tetracycline and Corynebacterium parvum are included in this review because many studies have been done on these agents. Methods Using MEDLINE (1966 to October 1992), we searched the English-language medical literature (with the addition of reference 33 translated from Japanese) that describes the treatment of malignant pleural effusions. We found reports of 1168 patients who were treated with intrapleural agents for pleurodesis. The following information was extracted from each article: pleurodesis regimen, number of patients, success rate (complete response), and adverse effects. Because criteria for success varied, we defined success as complete response only: the absence of reaccumulation of the effusion determined by clinical examination or chest radiograph. Partial response criteria differed among trials and were not included in some reports. We did not compare response duration for the various treatment regimens because of variability and inconsistency in reporting. Chemical Agents Tetracycline Hydrochloride Although it has not been approved by the Food and Drug Administration for pleurodesis, intrapleural administration of intravenous tetracycline (Achromycin, American Cyanamid; Pearl River, New York), with or without intrapleural lidocaine [13], gained acceptance in the last two decades as the pleurodesis agent of choice [4, 14]. It has been proven to be safe, effective, inexpensive, and easily administered, with reported adverse effects limited to pain (14%) and fever (10%) [3, 15] (Table 1). Intrapleural administration of the tetracyclines is usually in 30 to 50 mL of 0.9% saline, with an indwelling time of 2 to 6 hours. Its mechanism of action has been attributed to growth-factor-like activity on fibroblasts from both direct mesothelial cell activation [16] and indirect mesothelial cell activation through stimulated pleural macrophages [17]. Table 1. Success Rates and Adverse Effects in Patients Treated with Nonantineoplastic Agents for Malignant Pleural Effusions* Results of early studies [1, 18-25] using tetracycline in doses of 500 mg reported complete response in 52 (45%) of 115 patients. Subsequent studies [26-29], using doses of 1 g to 20 mg/kg body weight, reported response rates of 77%. Gravelyn and colleagues [25] treated 20 patients with 500 mg of intrapleural tetracycline and 12 patients with 1 g or more. A complete response was seen in only 5 (16%) of 32 patients, with 4 of the 5 patients receiving 1 g or more of tetracycline. Adverse effects did not differ according to dosage. In a randomized trial in 50 patients with malignant pleural effusions, 25 patients received a single dose of tetracycline, 20 mg/kg, and 25 received two doses of 20 mg/kg on consecutive days [28]. No significant difference was found in complete response between single-dose (88%) and double-dose (96%) groups. Doxycycline Intrapleural doxycycline (Vibramycin, Pfizer; Groton, Connecticut) produced a complete response in 43 (72%) of 60 patients (see Table 1). However, only 6 [10%] patients had a complete response after a single 500-mg dose of doxycycline, 6 (10%) patients after two doses, 14 (23%) patients after three doses, and 6 (10%) patients after four doses. More than four doses were required for a complete response in the remaining 11 (18%) patients [30]. Pain was reported in 40% of patients and fever occurred in 7%. Kitamura and colleagues [31] administered intrapleural doxycycline hyclate, 500 mg, to 15 patients with malignant pleural effusions twice weekly for 1 to 2 weeks. Complete response was seen in 10 (67%) patients, with a response duration of 2 to 10 months (average, 6.3 months). Mild chest pain, not requiring analgesics, was the only reported adverse effect and occurred in 5 (33%) patients. Mansson [32] reported a complete response in 11 of 18 (61%) patients with doxycycline HCl, 500 mg, for an average duration of 8.9 months (range, 1 to 27 months). Twelve patients received intravenous morphine, 10 mg, before instillation of doxycycline. Chest pain was reported in 4 (22%) patients, and 2 of the 4 patients with chest pain had received morphine. Fever occurred in 4 (22%) patients during the first 24 hours after instillation. Muir and associates [30] treated 27 patients who had malignant pleural effusions with doxycycline, 500 mg, through a chest tube; the tube was clamped for 24 hours. The procedure was repeated every 24 hours until tube drainage approximated the amount of fluid instilled; an average of 11 days was required. Complete response was reported in 22 (81%) patients. Two patients responded after a single dose of doxycycline, 1 patient after two doses, 4 (15%) patients after three doses, and 4 (15%) patients after four doses. Eight patients required 2.5 to 5.0 g of doxycycline, 6 patients required 6.0 to 9.5 g, and 2 patients required 10.5 g and 28 g. Even though larger doses of doxycycline were administered, adverse effects were similar to those in previously published studies on doxycycline. Pain occurred in 5 (19%) patients, fever in 10 (37%) patients, and an urticarial rash in 1 patient. Minocycline Intrapleural minocycline (Minocin, American Cyanamid), 300 mg with 1% lidocaine, was given to seven patients with malignant pleural effusions [33] (see Table 1). Six of the seven [86%] patients responded completely after a single dose of minocycline. However, the small number of patients, unspecified success rate criteria, and response duration make comparisons with other agents problematic. One patient reported pain. Serum minocycline concentrations were not measured and may be of concern because vestibular symptoms have occurred in 30% to 90% of patients at usual 200-mg intravenous daily doses [3, 34]. Vertigo, dizziness, ataxia, nausea, vomiting, and tinnitus have been reported in patients 1 to 3 days after receiving intravenous minocycline, 100 mg every 12 hours, with the symptoms resolving 48 hours after withdrawal of the drug. Symptoms appear to be related to the dose regimen and possibly to female sex. When receiving the same dose as men, women tend to have higher serum concentrations and are at a two to three times higher risk for developing vestibular toxicities than are men [35]. Studies with intrapleural minocycline and tetracycline in the rabbit pleural model suggest an inflammatory dose-response relation [36-40]. Extrapolating from experimental and human data on tetracycline, doses of minocycline, 300 mg or 4 to 5 mg/kg body weight, appear to be rational starting points. Bleomycin Intrapleural administration of bleomycin (Blenoxane, Bristol-Myers; Princeton, New Jersey), 1 unit/kg or 1 mg/kg [41] (15 to 240 units), produced a complete response in 108 (54%) of 199 patients with malignant pleural effusions [24, 29, 42-47] (Table 2). Pain, fever, and nausea were reported in 28%, 24%, and 11% of patients, respectively. Other adverse effects reported include hemoptysis [29], fluid accumulation and septic shock [29], rash [42], and diarrhea [45]. Forty-five percent of an intrapleural bleomycin dose is absorbed into the systemic circulation; however, alopecia and pulmonary fibrosis have rarely been reported [48]. The technique of intrapleural bleomycin administration is similar to that for tetracycline: The pleural effusion is drained by chest tube; bleomycin is instilled through the tube; and the chest tube is clamped for 2 to 6 hours and then reconnected to suction. The mechanism of action of bleomycin and the other cytotoxic antineoplastic agents is unknown. It may be caused by a combination of antineoplastic and fibrogenic effects and appears to operate differently than that of tetracycline [16]. Table 2. Success Rates and Adverse Effects in Patients Treated with Antineoplastic Agents for Malignant Pleural Effusion Ruckdeshel and colleagues [29] conducted a multicenter, randomized trial comparing intrapleural bleomycin, 60 units (37 patients), with intrapleural tetracycline, 1 g (36 patients). Ninety days after the agents were instilled, 30% of the patients in the bleomycin group and 53% in the tetracycline group had recurrent effusions (P = 0.05). Reported adverse effects were similar in the groups: 36 percent with bleomycin and 37% with tetracycline. The major disadvantage of bleomycin is its cost, approximately

Carcinomatous involvement of the pleura: An analysis of 96 patients

1104 for a 70-unit dose [49] (Table 3). Table 3. Charges for Agents Used for Chemical Pleurodesis* Cisplatin and Cytarabine Markman and associates [50] first reported the use of intrapleural cisplatin (Platinol, Bristol-Myers) and cytarabine (Cytosar-U, Upjohn; Kalamazoo, Michigan) in seven patients with malignant pleural effusions (see Table 2). Fluid was removed from the pleural cavity by a percutaneous thoracentesis catheter. One liter of intravenous hydration was administered 1 to 2 hours before administration of intrapleural cisplatin and cytarabine. Sodium thiosulfate was given as an intravenous bolus of 4 g/m2 body surface area and followed by 12 g/m2 for a period of 6 hours beginning at the time of pleurodesis. Cisplatin, 100 mg/m2, and cytarabine, 600 mg/m2, were administered through the intrapleural catheter. Four hours after instillation, the chest cavity was drained as completely as possible and the catheter was removed. Patients with fluid

Diagnosis and Treatment of Tuberculous Pleural Effusion in 2006

Abstract To better define the prevalence, presentation, primary sites and survival of patients with Carcinomatous involvement of the pleura, we reviewed 96 cases of carcinoma of the pleura diagnosed by cytopathology or closed pleural biopsy at Colorado General Hospital from 1960 to 1975. Carcinomatous pleura) metastasis was present in 43/100,000 persons admitted to the hospital. The most common primary sites were lung in 32 of 96 (33 per cent), breast in 20 of 96 (20.9 per cent), ovary in nine of 96 (9.3 per cent) and stomach in seven of 96 (7.3 per cent). The incidence of pleural metastasis per type of carcinoma was lung in 32 of 459 (7.0 per cent), stomach in seven of 195 (3.6 per cent), breast in 20 of 645 (3.1 per cent) and ovary in nine of 303 (2.9 per cent). Chief presenting symptoms included dyspnea (57 per cent), cough (43 per cent) and chest pain (26 per cent); however, 22 of 96 subjects (23 per cent) were asymptomatic. Ninety-two per cent of the lung, breast and ovarian malignant effusions were ipsilateral to the primary lesion. The malignant pleural effusions were usually clear or serosanguineous exudates with a protein content of 3.7 ± 0.2 g/100 ml (mean ± standard error of the mean (SEM); lactic dehydrogenase 134 ± 15 lU/liter; glucose 120 ± 13 mg/100 ml, white blood cell count 2,250 ± 400/mm 3 . Mean survival was 3.1 ± 0.5 months (after diagnosis of pleural metastasis) with 54 per cent mortality within one month and 84 per cent mortality by six months. A malignant pleural effusion provided the basis for the first diagnosis of cancer in 44 of 96 patients (46 per cent). Pleural involvement, although often asymptomatic, is an ominous finding usually representing widespread metastases. Lung, breast, ovary and stomach were the most frequent primary sites, with carcinoma of the lung being the most common to involve the pleura; however, its incidence was relatively low. A malignant pleural effusion frequently represents the first evidence of cancer.

Ascertainment of Individual Risk of Mortality for Patients with Idiopathic Pulmonary Fibrosis

Tuberculous (TB) pleural effusion occurs in approximately 5% of patients with Mycobacterium tuberculosis infection. The HIV pandemic has been associated with a doubling of the incidence of extrapulmonary TB, which has resulted in increased recognition of TB pleural effusions even in developed nations. Recent studies have provided insights into the immunopathogenesis of pleural TB, including memory T-cell homing and chemokine activation. The definitive diagnosis of TB pleural effusions depends on the demonstration of acid-fast bacilli in the sputum, pleural fluid, or pleural biopsy specimens. The diagnosis can be established in a majority of patients from the clinical features, pleural fluid examination, including cytology, biochemistry, and bacteriology, and pleural biopsy. Measurement of adenosine deaminase and interferon-gamma in the pleural fluid and polymerase chain reaction for M tuberculosis has gained wide acceptance in the diagnosis of TB pleural effusions. Although promising, these tests require further evaluation before their routine use can be recommended. The treatment of TB pleural effusions in patients with HIV/AIDS is essentially similar to that in HIV-negative patients. At present, evidence regarding the use of corticosteroids in the treatment of TB pleural effusion is not clear-cut.

Pulmonary manifestations of systemic lupus erythematosus: review of twelve cases of acute lupus pneumonitis.

RATIONALE Several predictors of mortality in patients with idiopathic pulmonary fibrosis have been described; however, there is a need for a practical and accurate method of quantifying the prognosis of individual patients. OBJECTIVES Develop a practical mortality risk scoring system for patients with idiopathic pulmonary fibrosis. METHODS We used a Cox proportional hazards model and data from two clinical trials (n = 1,099) to identify independent predictors of 1-year mortality among patients with idiopathic pulmonary fibrosis. From the comprehensive model, an abbreviated clinical model comprised of only those predictors that are readily and reliably ascertained by clinicians was derived. Beta coefficients for each predictor were then used to develop a practical mortality risk scoring system. MEASUREMENTS AND MAIN RESULTS Independent predictors of mortality included age, respiratory hospitalization, percent predicted FVC, 24-week change in FVC, percent predicted carbon monoxide diffusing capacity, 24-week change in percent predicted carbon monoxide diffusing capacity, and 24-week change in health-related quality of life. An abbreviated clinical model comprising only four predictors (age, respiratory hospitalization, percent predicted FVC, and 24-wk change in FVC), and the corresponding risk scoring system produced estimates of 1-year mortality risk consistent with observed data (9.9% vs. 9.7%; C statistic = 0.75; 95% confidence interval, 0.71–0.79). CONCLUSIONS The prognosis for patients with idiopathic pulmonary fibrosis may be accurately determined using four readily ascertainable predictors. Our simplified scoring system may be a valuable tool for determining prognosis and guiding clinical management. Additional research is needed to validate the applicability and accuracy of the scoring system.

Six-minute-walk test in idiopathic pulmonary fibrosis: test validation and minimal clinically important difference.

Acute lupus pneumonitis was the presenting manifestation of systemic lupus erythematosus in six of 12 cases in this series. The clinical picture was characterized by severe dyspnea, tachypnea, fever and arterial hypoxemia. Radiographic findings included an acinar filling pattern which was invariably found in the lower lobes and was bilateral in 10 of the cases. Studies failed to reveal evidence of infection as a cause of the acute pulmonary infiltrates. All patients were treated with oxygen and corticosteroids; seven received azathioprine. Six patients survived and are clinically well 14 months to four years following their acute illness. Three of these patients have residual interstitial infiltrates with persistent pulmonary function test abnormalities indicating progression to chronic interstitial pneumonitis. Histologic sections of the lungs available from four patients revealed hyaline membranes and interstitial edema (four cases), acute alveolitis (two cases), arteriolar thrombosis (one case) and a prominent lymphocytic interstitial pneumonitis with organizing bronchiolitis (one case).

Forced vital capacity in patients with idiopathic pulmonary fibrosis: test properties and minimal clinically important difference.

RATIONALE The 6-minute-walk test (6MWT) is a practical and clinically meaningful measure of exercise tolerance with favorable performance characteristics in various cardiac and pulmonary diseases. Performance characteristics in patients with idiopathic pulmonary fibrosis (IPF) have not been systematically evaluated. OBJECTIVES To assess the reliability, validity, and responsiveness of the 6MWT and estimate the minimal clinically important difference (MCID) in patients with IPF. METHODS The study population included all subjects completing a 6MWT in a clinical trial evaluating interferon gamma-1b (n = 822). Six-minute walk distance (6MWD) and other parameters were measured at baseline and at 24-week intervals using a standardized protocol. Parametric and distribution-independent correlation coefficients were used to assess the strength of the relationships between 6MWD and measures of pulmonary function, dyspnea, and health-related quality of life. Both distribution-based and anchor-based methods were used to estimate the MCID. MEASUREMENTS AND MAIN RESULTS Comparison of two proximal measures of 6MWD (mean interval, 24 d) demonstrated good reliability (coefficient = 0.83; P < 0.001). 6MWD was weakly correlated with measures of physiologic function and health-related quality of life; however, values were consistently and significantly lower for patients with the poorest functional status, suggesting good construct validity. Importantly, change in 6MWD was highly predictive of mortality; a 24-week decline of greater than 50 m was associated with a fourfold increase in risk of death at 1 year (hazard ratio, 4.27; 95% confidence interval, 2.57- 7.10; P < 0.001). The estimated MCID was 24-45 m. CONCLUSIONS The 6MWT is a reliable, valid, and responsive measure of disease status and a valid endpoint for clinical trials in IPF.