Post hoc Analysis of Clinical Outcomes in Placebo- and Pirfenidone-Treated Patients with IPF Stratified by BMI and Weight Loss.

BACKGROUND: Weight loss is frequently reported in patients with idiopathic pulmonary fibrosis (IPF) and may be associated with worse outcomes in these patients. OBJECTIVE: The aim of this study was to investigate the relationships between body mass index (BMI) and weight loss, and outcomes over 1 year in patients with IPF. METHODS: Data were included from placebo patients enrolled in ASCEND (NCT01366209) and CAPACITY (NCT00287716 and NCT00287729), and all patients in INSPIRE (NCT00075998) and RIFF Cohort A (NCT01872689). An additional analysis included data from pirfenidone-treated patients. Outcomes (annualized change in percent predicted forced vital capacity [%FVC], percent predicted carbon monoxide diffusing capacity, 6-min walk distance, St. George's Respiratory Questionnaire total score, hospitalization, mortality, and serious adverse events) were analyzed by baseline BMI (<25 kg/m2, 25 kg/m2-<30 kg/m2, or ≥30 kg/m2) and annualized percent change in body weight (no loss, >0-<5% loss, or ≥5% loss). RESULTS: Placebo-treated patients with a baseline BMI <25 kg/m2 or annualized weight loss may experience worse outcomes versus those with a baseline BMI ≥25 kg/m2 or no weight loss. The proportion of placebo-treated patients who experienced a relative decline of ≥10% in %FVC or death up to 1 year post-randomization was highest in patients with a baseline BMI <25 kg/m2. Pirfenidone-treated patients with an annualized weight loss ≥5% may also experience worse outcomes versus those with no weight loss. CONCLUSIONS: Patients with a baseline BMI <25 kg/m2 or annualized weight loss of >0-<5% or ≥5% may experience worse outcomes over 1 year versus those with a baseline BMI ≥25 kg/m2 or no weight loss.

Changes in Neutrophil-Lymphocyte or Platelet-Lymphocyte Ratios and Their Associations with Clinical Outcomes in Idiopathic Pulmonary Fibrosis.

Identification of prognostic and predictive biomarkers in idiopathic pulmonary fibrosis (IPF) could aid assessment of disease severity and prediction of progression and response to treatment. This analysis examined reference ranges for neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) in IPF, and the relationship between NLR or PLR changes and clinical outcomes over 12 months. This post hoc analysis included patients with IPF from the Phase III, double-blind trials of pirfenidone, ASCEND (NCT01366209) and CAPACITY (NCT00287716 and NCT00287729). The relationship between change from baseline to Month 12 in NLR or PLR (divided into quartiles (Q1-Q4)) and outcomes (mortality, respiratory hospitalization, declines in lung function, exercise capacity and quality of life) was assessed. Estimated reference ranges at baseline for all patients analyzed (n = 1334) were 1.1-6.4 for NLR and 56.8-250.5 for PLR. Significant trends were observed across NLR and PLR quartiles for all outcomes in placebo-treated patients, with patients manifesting the greatest NLR or PLR changes experiencing the worst outcomes. These results suggest that the greatest NLR or PLR changes over 12 months were associated with worse clinical outcomes. Further research is needed to determine the utility of NLR and PLR as prognostic biomarkers in IPF.

Spectral-Domain OCT Analysis of Risk Factors for Macular Atrophy Development in the HARBOR Study for Neovascular Age-Related Macular Degeneration.

PURPOSE: To identify baseline risk factors for macular atrophy (MA) development in HARBOR via a longitudinal assessment of monthly spectral-domain (SD)-OCT scans. Previous analyses of MA in HARBOR examined data from color fundus photography (CFP) and fluorescein angiography (FA). DESIGN: Retrospective, post hoc analysis of SD-OCT images from HARBOR (ClinicalTrials.gov identifier, NCT00891735), a phase 3, multicenter, prospective, randomized, double-blind, active treatment-controlled clinical trial. PARTICIPANTS: Patients (N = 1097) with subfoveal choroidal neovascularization secondary to neovascular age-related macular degeneration (nAMD) treated with intravitreal ranibizumab 0.5 mg monthly (n = 275), 0.5 mg pro re nata (PRN) after 3 loading doses (n = 275), 2.0 mg monthly (n = 274), or 2.0 mg PRN (n = 273). METHODS: Evaluable SD-OCT macular cube scans from patients with 24 months of follow-up (N = 941) were examined monthly from baseline to month 24 by masked reading center-trained graders. Atrophy diagnosis criteria were consistent with those proposed by the Classification of Atrophy Meetings (CAM) group: hypertransmission of light into the choroid, loss of retinal pigment epithelium, and loss of outer retinal layers. Multivariable proportional hazards regression was performed for time to atrophy development. MAIN OUTCOME MEASURES: Risk factors for MA as determined by time to MA development over 24 months of treatment. RESULTS: Baseline risk factors for MA were confirmed from prior analyses that used CFP and FA data: absence of subretinal fluid, presence of intraretinal cysts, presence of Type 3 neovascularization, and presence of atrophy in the fellow eye. This analysis of SD-OCT data identified new baseline risk factors for MA: higher central drusen volume, lower choroidal thickness, presence of nascent atrophy, presence of reticular pseudodrusen, and increased central foveal thickness. Ranibizumab treatment regimen and dose level were not found to be risk factors for MA development. CONCLUSIONS: In this analysis of a major nAMD trial using CAM atrophy criteria, new baseline risk factors for MA development were identified using an SD-OCT dataset. Risk factors for MA development identified by prior analyses were confirmed. Monthly treatment with ranibizumab 0.5 mg was not found to be a risk factor for MA development over 24 months.

Spectral-Domain OCT-Based Prevalence and Progression of Macular Atrophy in the HARBOR Study for Neovascular Age-Related Macular Degeneration.

PURPOSE: Previous studies of macular atrophy (MA) in HARBOR analyzed color fundus photography and fluorescein angiography image data. This study performed a longitudinal assessment of monthly spectral-domain (SD) OCT scans to determine MA prevalence, incidence, and progression in HARBOR. DESIGN: Post hoc analysis of SD OCT images from HARBOR (ClincalTrials.gov identifier, NCT00891735), a phase 3 multicenter, prospective, randomized, double-blind, active treatment-controlled clinical trial. PARTICIPANTS: Patients (n = 1097) with subfoveal choroidal neovascularization secondary to neovascular age-related macular degeneration (nAMD) treated with ranibizumab 0.5 mg monthly (n = 275), 0.5 mg pro re nata (PRN) after 3 loading doses (n = 275), 2.0 mg monthly (n = 274), or 2.0 mg PRN (n = 273). METHODS: Evaluable SD OCT macular cube scans from patients with 24 months of follow-up (N = 941) were examined by masked reading center-trained graders monthly from baseline to month 24. Atrophy diagnosis criteria were consistent with those proposed by the Classification of Atrophy Meetings (CAM) group: hypertransmission of light into the choroid, retinal pigment epithelium loss, and loss of outer retinal layers. Macular atrophy was considered Definite if all 3 criteria were met and Questionable if 2 were met. Study arms were compared for time to MA detection (log-rank test) and enlargement rates (time × arm interaction test). MAIN OUTCOME MEASURES: Prevalence, incidence, and enlargement rates of MA. RESULTS: At baseline, imbalance in MA rates across ranibizumab arms was evident (0.5 mg monthly, 19.1%; 0.5 mg PRN, 16.1%; 2.0 mg monthly, 10.1%; 2.0 mg PRN, 10.5%). At month 24, new MA development rates in eyes without baseline MA were similar between ranibizumab doses (0.5 mg, 25.9%; 2.0 mg, 25.4%) and treatment regimens (monthly, 26.4%; PRN, 25.0%). No significant differences in enlargement rate of new atrophy area (P = 0.479, square-root transformed) or time to detection of new MA (P = 0.997) were evident among study arms. CONCLUSIONS: In this analysis of a major nAMD trial using CAM atrophy criteria, no differences were observed in incidence or progression rates of new MA among study arms, ranibizumab doses, or treatment regimens. Monthly versus PRN treatment did not influence MA incidence or progression.

Physician characteristics associated with treatment initiation patterns in idiopathic pulmonary fibrosis.

Pirfenidone and nintedanib are oral antifibrotic agents approved for the treatment of idiopathic pulmonary fibrosis (IPF). Real-world data on factors that influence IPF treatment decisions are limited. Physician characteristics associated with antifibrotic therapy initiation following an IPF diagnosis were examined in a sample of US pulmonologists. An online, self-administered survey was fielded to pulmonologists between April 10, 2017, and May 17, 2017. Pulmonologists were included if they spent >20% of their time in direct patient care and had ≥5 patients with IPF receiving antifibrotics. Participants answered questions regarding timing and reasons for considering the initiation of antifibrotic therapy after an IPF diagnosis. A total of 169 pulmonologists participated. The majority (81.7%) considered initiating antifibrotic therapy immediately after IPF diagnosis all or most of the time (immediate group), while 18.3% considered it only some of the time or not at all (delayed group). Pulmonologists in the immediate group were more likely to work in private practice (26.1%), have a greater mean percentage of patients receiving antifibrotic therapy (60.8%), and decide to initiate treatment themselves (31.2%) versus those in the delayed group (16.1%, 30.5%, and 16.1%, respectively). Most pulmonologists consider initiating antifibrotic treatment immediately after establishing an IPF diagnosis all or most of the time versus using a "watch-and-wait" approach. Distinguishing characteristics between pulmonologists in the immediate group versus the delayed group included practice setting, percentage of patients receiving antifibrotic therapy, and the decision-making dynamics between the patient and the pulmonologist.

Correction to: Cardiovascular Risks, Bleeding Risks, and Clinical Events from 3 Phase III Trials of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis.

In the Original Publication the colors of Figure 2 have been switched. The correct figures are given below.

Cardiovascular Risks, Bleeding Risks, and Clinical Events from 3 Phase III Trials of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis.

INTRODUCTION: This study assessed baseline cardiovascular (CV) risk factors, concomitant CV medication use, risk of major adverse cardiac events-plus (MACE-plus), and bleeding adverse events (AEs) in patients with idiopathic pulmonary fibrosis (IPF) in three randomized, placebo-controlled phase III trials of pirfenidone. METHODS: Patients in the pirfenidone phase III trials were included. Patients with unstable or deteriorating cardiac disease within 6 months before enrollment were ineligible. Medical history at baseline and concomitant CV medication use during treatment were reported. A retrospective, blinded review of AE preferred terms was conducted to identify MACE-plus and bleeding events. Subgroup analyses examined the impact of concomitant CV medication use on how pirfenidone treatment affected clinical outcomes. RESULTS: In total, 1247 patients were included [n = 623 pirfenidone (2403 mg/day) and n = 624 placebo]. The median age was 68 years, 74% were male, and 65% were current/former smokers. Commonly reported CV risk factors included hypertension (52%), obesity (44%), hypercholesterolemia (23%), and hyperlipidemia (23%). Pre-existing cardiac disorders included coronary artery disease (16%), myocardial infarction (5%), and atrial fibrillation (5%). Lipid-modifying agents (60%), antithrombotic agents (54%), and renin-angiotensin inhibitors (39%) were commonly used concomitant CV medications. The incidences of MACE-plus and bleeding events were similar between the pirfenidone and placebo groups (1.8% and 2.9% for MACE-plus events and 3.7% and 4.3% for bleeding events, respectively). Except for patients receiving heparin, pirfenidone had a beneficial effect compared with placebo on efficacy outcomes regardless of concomitant CV medications. CONCLUSIONS: CV risk factors and comorbidities and use of concomitant CV medications are common in patients with IPF. Pirfenidone did not appear to increase the risk of CV or bleeding events. Use of several concomitant CV medications, including warfarin, did not appear to adversely impact pirfenidone's beneficial effect on efficacy outcomes. TRIAL REGISTRATION: NCT00287716, NCT00287729, and NCT01366209. FUNDING: F. Hoffmann-La Roche Ltd. and Genentech, Inc.

OCT Risk Factors for Development of Late Age-Related Macular Degeneration in the Fellow Eyes of Patients Enrolled in the HARBOR Study.

PURPOSE: To evaluate the relationship between OCT features and progression to late age related-macular degeneration (AMD) in the fellow eyes of patients enrolled in the Study of Ranibizumab Administered Monthly or on an As-needed Basis in Patients With Subfoveal Neovascular AMD (HARBOR) (ClinicalTrials.gov identifier, NCT00891735). DESIGN: Post hoc analysis of a phase 3 multicenter, prospective, randomized, double-masked, active treatment-controlled clinical trial. PARTICIPANTS: Evaluable patients (n = 501) with macular neovascularization (MNV) secondary to neovascular AMD and early or intermediate AMD in the fellow eye. METHODS: Volume OCT scans from 501 fellow eyes of 501 patients with MNV were reviewed. Baseline OCT features that were assessed included intraretinal hypereflective foci (IHRF), hyporeflective foci (hRF) within drusenoid lesions (DLs), subretinal drusenoid deposits (SDDs), and drusen volume (DV) of 0.03 mm3 or more. OCT images obtained at months 6, 12, 18, and 24 were graded by masked graders for late AMD (defined as MNV, complete retinal pigment epithelium and photoreceptor atrophy [cRORA], or both). Participant demographic characteristics (age, gender, and smoke exposure) and baseline OCT features were correlated with progression to late AMD. MAIN OUTCOME MEASURES: Incidence of late AMD, hazard ratio (HR) for demographics, and OCT risk factors. RESULTS: At month 24, 33.13% of eyes (166/501) demonstrated late AMD: 20.96% (105/501) demonstrated cRORA, whereas 12.18% (61/501) demonstrated MNV. Baseline demographic factors were not associated significantly with development of late AMD, whereas significant associations were identified for all OCT features. Intraretinal hypereflective foci had an HR of 5.21 (95% confidence interval [CI], 3.29-8.26), hRF within DLs had an HR of 2.42 (95% CI, 1.74-3.38), SDD had an HR of 1.95 (95% CI, 1.34-2.82), and DV of 0.03 mm3 or more had an HR of 1.46 (95% CI, 1.03-2.07). The correlation remained significant when considering only the progression to cRORA and MNV alone, except for DV, which was not associated significantly with progression to MNV. CONCLUSIONS: We confirmed that 4 previously reported OCT risk factors were associated with progression to late AMD in the fellow eyes of patients newly diagnosed with MNV. Although outcomes of more than 2 years were not evaluated, these findings may help to identify high-risk AMD patients.

Pirfenidone in patients with idiopathic pulmonary fibrosis and more advanced lung function impairment.

BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) demonstrate a range of lung function impairment. However, the efficacy of antifibrotics compared with placebo has not been assessed in patients with more advanced disease. This post-hoc analysis investigated the efficacy and safety of pirfenidone versus placebo in patients with IPF and more advanced lung function impairment, defined as percent predicted forced vital capacity (%FVC) < 50% and/or percent predicted carbon monoxide diffusing capacity <35%. METHODS: Patients randomised to pirfenidone 2,403 mg/day or placebo in the ASCEND (NCT01366209) and CAPACITY (NCT00287716; NCT00287729) trials with more advanced baseline lung function impairment (pirfenidone, n = 90; placebo, n = 80) were included. Mortality, lung function, hospitalisation, exercise capacity and dyspnoea were investigated over 52 weeks. RESULTS: At Week 52 versus placebo, pirfenidone was associated with significantly lower risks of all-cause mortality (hazard ratio [HR] 0.28; 95% confidence interval [CI] 0.09-0.86; p=0.0180), ≥10% absolute %FVC decline or all-cause mortality (HR 0.40; 95% CI 0.23-0.69; p=0.0006) and ≥10% absolute %FVC decline or respiratory-related hospitalisation or all-cause mortality (HR 0.46; 95% CI 0.28-0.76; p=0.0018). At Week 52, median treatment differences favouring pirfenidone were 36.7 m for 6-min walk distance and -8.0 points for the University of California-San Diego Shortness of Breath Questionnaire total score. Treatment-emergent adverse events (TEAEs) led to discontinuation in 14.4% and 21.3% of patients with pirfenidone and placebo, respectively. CONCLUSION: Pirfenidone demonstrated clinically relevant benefits across multiple domains in patients with IPF and more advanced disease without an increased risk of discontinuation due to TEAEs. CLINICAL TRIALS REGISTRATION: clinicaltrials. gov (ASCEND: NCT01366209; CAPACITY: NCT00287716; NCT00287729).

Efficacy of Pirfenidone in the Context of Multiple Disease Progression Events in Patients With Idiopathic Pulmonary Fibrosis.

BACKGROUND: Declines in percent predicted FVC (% predicted FVC), declines in 6-min walk distance (6MWD), and respiratory hospitalizations are events associated with disease progression and mortality in idiopathic pulmonary fibrosis. The incidence of multiple events in the same patient over 12 months of pirfenidone treatment is unknown. METHODS: Patients who received pirfenidone 2,403 mg/d (n = 623) or placebo (n = 624) in the ASCEND (study 016; NCT01366209) and CAPACITY (studies 004 and 006; NCT00287716 and NCT00287729) phase III trials were included in this post hoc analysis. Disease progression events were defined as relative decline in % predicted FVC ≥ 10%, absolute decline in 6MWD ≥ 50 m, respiratory hospitalization, or death from any cause. The incidence of disease progression events over 12 months was assessed. RESULTS: The most frequent disease progression events were declines in % predicted FVC (pirfenidone vs placebo; 202 vs 304 events) and declines in 6MWD (pirfenidone vs placebo; 265 vs 348 events). Fewer patients who received pirfenidone had more than one progression event compared with placebo (17.0% vs 30.1%; P < .0001). Death following one or more progression event occurred less frequently in the pirfenidone group than in the placebo group (2.1% vs 6.3%; P = .0002). CONCLUSIONS: Pirfenidone significantly reduced the incidence of multiple progression events and death after a progression event over 12 months of treatment compared with placebo. These findings suggest that continued treatment with pirfenidone confers a benefit despite the occurrence of any single disease progression event. TRIAL REGISTRY: ClinicalTrials.gov; Nos. NCT01366209, NCT00287716, and NCT00287729; URL: www.clinicaltrials.gov.

Real-World Practice Patterns for Prevention and Management of Potential Adverse Events with Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis.

INTRODUCTION: Pirfenidone is an oral antifibrotic agent approved for idiopathic pulmonary fibrosis (IPF). Real-world data on adverse event (AE) management for pirfenidone are limited. Strategies for managing potential antifibrotic therapy AEs were examined in a sample of US pulmonologists. METHODS: An online, self-administered survey was fielded to pulmonologists between April 10 and May 17, 2017. Pulmonologists were included if they spent > 20% of their time in direct patient care and had ≥ 5 patients with IPF on antifibrotic therapy. Participants answered questions regarding initiation of pirfenidone, dose titration, and management of potential AEs. RESULTS: A total of 169 pulmonologists participated. Gastrointestinal (GI) intolerance was the most important factor in implementing alternative titration schedules for pirfenidone. Approximately three-quarters of pulmonologists recommended the standard titration scheme for starting treatment; however, a range of titration schedules up to 8 weeks were described, with a 4-week schedule being most common. Pulmonologists reported that most patients treated with alternative titration schedules could achieve the full dose of pirfenidone. Pulmonologists who were most effective at mitigating pirfenidone-related GI AEs by advising dosing at mealtimes more frequently recommended taking pirfenidone during a substantial meal than pulmonologists who were less effective. For photosensitivity AEs, pulmonologists recommended sunscreen use, sun avoidance, wearing a hat, and ultraviolet protection factor clothing. CONCLUSIONS: Pulmonologists reported that alternative titration schedules for initiating pirfenidone were common and can aid in maintaining the full dose. Proposed strategies to ameliorate pirfenidone-related GI and photosensitivity AEs included taking pirfenidone during a substantial meal and minimizing sun exposure, respectively. FUNDING: F. Hoffmann-La Roche Ltd./Genentech, Inc. Plain language summary available for this article.

Nonparametric confidence intervals for Tmax in sequence-stratified crossover studies.

Tmax is the time associated with the maximum serum or plasma drug concentration achieved following a dose. While Tmax is continuous in theory, it is usually discrete in practice because it is equated to a nominal sampling time in the noncompartmental pharmacokinetics approach. For a 2-treatment crossover design, a Hodges-Lehmann method exists for a confidence interval on treatment differences. For appropriately designed crossover studies with more than two treatments, a new median-scaling method is proposed to obtain estimates and confidence intervals for treatment effects. A simulation study was done comparing this new method with two previously described rank-based nonparametric methods, a stratified ranks method and a signed ranks method due to Ohrvik. The Normal theory, a nonparametric confidence interval approach without adjustment for periods, and a nonparametric bootstrap method were also compared. Results show that less dense sampling and period effects cause increases in confidence interval length. The Normal theory method can be liberal (i.e. less than nominal coverage) if there is a true treatment effect. The nonparametric methods tend to be conservative with regard to coverage probability and among them the median-scaling method is least conservative and has shortest confidence intervals. The stratified ranks method was the most conservative and had very long confidence intervals. The bootstrap method was generally less conservative than the median-scaling method, but it tended to have longer confidence intervals. Overall, the median-scaling method had the best combination of coverage and confidence interval length. All methods performed adequately with respect to bias.

Comparison of models for average bioequivalence in replicated crossover designs.

Average bioequivalence (ABE) has been the regulatory standard for bioequivalence (BE) since the 1990s. BE studies are commonly two-period crossovers, but may also use replicated designs. The replicated crossover will provide greater power for the ABE assessment. FDA has recommended that ABE analysis of replicated crossovers use a model which includes terms for separate within- and between-subject components for each formulation and which allows for a subject x formulation interaction component. Our simulation study compares the performance of four alternative mixed effects models: the FDA model, a three variance component model proposed by Ekbohm and Melander (EM), a random intercepts and slopes model (RIS) proposed by Patterson and Jones, and a simple model that contains only two variance components. The simple model fails (when not 'true') to provide adequate coverage and it accepts the hypothesis of equivalence too often. FDA and EM models are frequently indistinguishable and often provide the best performance with respect to coverage and probability of concluding BE. The RIS model concludes equivalence too often when both the within- and between-subject variance components differ between formulations. The FDA analysis model is recommended because it provides the most detail regarding components of variability and has a slight advantage over the EM model in confidence interval length.