Harold R Collard

University of California, San Francisco, San Francisco, California, United States

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Publications (168)1306.93 Total impact

  • Mariano E Mazzei · Luca Richeldi · Harold R Collard ·
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    ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal lung disease that occurs in older adults. The clinical course of IPF is variable and hard to predict in an individual patient. Nintedanib is a tyrosine kinase inhibitor that has recently been approved in the US and European Union for the treatment of IPF. Preclinical studies have shown that nintedanib interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation and the secretion of extracellular matrix. The safety and efficacy of nintedanib have been investigated in the phase II TOMORROW trial and in two replicate 52-week randomized, placebo-controlled phase III trials known as the INPULSIS trials. These trials demonstrated that nintedanib slowed disease progression by reducing the annual rate of decline in forced vital capacity, with a manageable side-effect profile. In this review, we summarize key data supporting nintedanib as a treatment for patients with IPF and address key questions regarding the use of nintedanib in the clinical setting. © The Author(s), 2015.
    Therapeutic Advances in Respiratory Disease 04/2015; 9(3). DOI:10.1177/1753465815579365 · 1.95 Impact Factor
  • Kerri A Johannson · John R Balmes · Harold R Collard ·
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    ABSTRACT: Air pollution exposure is a well-established risk factor for several adverse respiratory outcomes, including airways diseases and lung cancer. Few studies have investigated the relationship between air pollution and interstitial lung disease (ILD) despite many forms of ILD arising from environmental exposures. There are potential mechanisms by which air pollution could cause, exacerbate, or accelerate the progression of certain forms of ILD via pulmonary and systemic inflammation as well as oxidative stress. This article will review the current epidemiologic and translational data supporting the plausibility of this relationship and propose a new conceptual framework for characterizing novel environmental risk factors for these forms of lung disease.
    Chest 04/2015; 147(4):1161-7. DOI:10.1378/chest.14-1299 · 7.48 Impact Factor
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    ABSTRACT: Background Nintedanib, an intracellular inhibitor of tyrosine kinases, is in development for the treatment of idiopathic pulmonary fibrosis (IPF). The INPULSIS™ trials were two replicate 52-week, randomised, double-blind, placebo-controlled Phase III trials that investigated the efficacy and safety of nintedanib 150 mg twice daily in 1066 patients with IPF. Declines in forced vital capacity (FVC)% predicted of >5% and >10% in patients with IPF have been proposed as indicators of disease progression and have been associated with reduced survival. Aim To determine the effect of nintedanib on changes in FVC% predicted in the INPULSIS™ trials. Methods The proportions of patients with absolute and relative declines in FVC% predicted of >5% and >10% at week 52 in each INPULSIS™ trial were determined in a post-hoc analysis. Results In each trial, a significantly greater proportion of patients in the placebo group had an absolute decline in FVC% predicted of >5% compared with the nintedanib group. In INPULSIS™-1, a significantly greater proportion of patients in the placebo group had an absolute decline in FVC% predicted of >10% compared with the nintedanib group; the difference between groups in INPULSIS™-2 was numerically in favour of nintedanib but did not reach statistical significance. In each trial, significantly greater proportions of patients in the placebo group had relative declines in FVC% predicted of >5% and >10% compared with the nintedanib group. Conclusion In the INPULSIS™ trials, nintedanib reduced the proportion of patients with IPF who experienced disease progression as measured by categorical FVC decline.
    Pneumologie 02/2015; 69(S 01). DOI:10.1055/s-0035-1544832
  • U Costabel · L Richeldi · A Azuma · Y Inoue · HR Collard · I Tschoepe · S Stowasser · M Selman ·

    Pneumologie 02/2015; 69(S 01). DOI:10.1055/s-0035-1544828

  • Pneumologie 02/2015; 69(S 01). DOI:10.1055/s-0035-1544829
  • U Costabel · Y Inoue · L Richeldi · HR Collard · S Stowasser · I Tschoepe · A Azuma ·

    Pneumologie 02/2015; 69(S 01). DOI:10.1055/s-0035-1544867

  • Pneumologie 02/2015; 69(S 01). DOI:10.1055/s-0035-1544833

  • Pneumologie 02/2015; 69(S 01). DOI:10.1055/s-0035-1544834

  • Revue des Maladies Respiratoires 01/2015; 32. DOI:10.1016/j.rmr.2014.11.051 · 0.62 Impact Factor

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    ABSTRACT: The GAP (Gender-Age-Physiology) model is a validated, baseline-risk prediction model for mortality in idiopathic pulmonary fibrosis. Longitudinal variables have been shown to contribute to risk prediction in idiopathic pulmonary fibrosis and may improve the predictive performance of the baseline GAP model. Our aims were to further validate the GAP model and evaluate whether the addition of longitudinal variables improves its predictive performance. The study population was derived from a large clinical trials cohort of patients with idiopathic pulmonary fibrosis (n=1109). Model performance was determined by improvement in the C-statistic, net reclassification improvement, clinical net reclassification improvement, and a goodness-of-fit test. The GAP model had good discriminative performance with a C-statistic of 0.757 (95% CI 0.750-0.764). However, the original GAP model tended to overestimate risk in this cohort. A novel, easy to use model, consisting of the original GAP predictors plus history of respiratory hospitalisation and 24-week change in forced vital capacity (the longitudinal GAP model) improved model performance with a C-statistic of 0.785 (95% CI 0.780-0.790), net reclassification improvement of 8.5%, clinical net reclassification improvement of 25%, and a goodness-of-fit test of 0.929. The Longitudinal GAP model, along with the original GAP model, may unify baseline and longitudinal mortality risk prediction in idiopathic pulmonary fibrosis. Copyright ©ERS 2015.
    European Respiratory Journal 01/2015; 45(5). DOI:10.1183/09031936.00146314 · 7.64 Impact Factor
  • Paolo Spagnolo · Athol U Wells · Harold R Collard ·
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    ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a progressive and almost invariably lethal disease that affects primarily older adults. After a decade of negative (or inconsistent) results, two recent clinical trials have demonstrated that slowing disease progression with medication is possible. An improved understanding of disease pathogenesis, epidemiology, and diagnostic criteria has been key to this success. Yet, this is only the beginning. It is hoped that continuous efforts by dedicated scientists and clinicians, patient organizations, health authorities, and pharmaceutical companies will soon lead to the development of more effective and better-tolerated treatment strategies for this devastating disease. Copyright © 2015. Published by Elsevier Ltd.
    Drug Discovery Today 01/2015; 20(5). DOI:10.1016/j.drudis.2015.01.001 · 6.69 Impact Factor
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    ABSTRACT: Objectives Idiopathic pulmonary fibrosis (IPF) is associated with aberrant expression of signalling pathways involved in embryonic development, including the Hedgehog (Hh) pathway. Hh can promote multiple profibrotic processes including myofibroblast differentiation, expression of extracellular matrix genes, migration, and survival. Vismodegib is a small-molecule inhibitor of the Hedgehog (Hh) signalling pathway approved for the treatment of basal cell carcinoma. We sought to evaluate the activity of Hh signalling in IPF lung tissue and identify blood biomarkers of Hh pathway activity in IPF patients. Methods Gene expression in biopsies from IPF and control unused donor lungs, and in fibroblasts stimulated with Shh in vitro. CXCL14 protein was measured in plasma from IPF patients and from solid tumour patients treated with vismodegib in a phase 1b clinical trial (NCT00968981). Results We observed significantly increased expression levels of Hh pathway genes including SMO, PTCH2, GLI1, and GLI2 in IPF vs control lungs. To identify candidate systemic biomarkers of Hh pathway activity, we compared transcriptional data from IPF lung biopsies and fibroblasts stimulated in vitro with Shh. The gene most significantly upregulated in both datasets was CXCL14, which encodes a soluble secreted chemokine whose expression is inhibited in vitro by the addition of vismodegib. Circulating CXCL14 protein levels were significantly higher in plasma from IPF patients than controls. In solid tumour patients, circulating CXCL14 levels were significantly reduced upon treatment with vismodegib. Conclusions We observed strong evidence for Hedgehog pathway activity in IPF lungs. CXCL14 is a systemic biomarker that could be used to identify IPF patients with increased Hh pathway activity and monitor the pharmacodynamic effects of vismodegib in IPF. The ISLAND trial is a phase 2 randomised, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of vismodegib in IPF patients. ISLAND will enrol 129 patients with IPF, randomised 2:1 to vismodegib or placebo for 60 weeks. The primary efficacy objective is to evaluate the effect of vismodegib on mean change in forced vital capacity (FVC). Secondary outcome measures include IPF and/or Hh-associated biomarkers, progression-free survival, and change in quantitative lung fibrosis on HRCT. Enrollment is expected to start in October 2014.
    Thorax 12/2014; 69(Suppl 2):A87-A87. DOI:10.1136/thoraxjnl-2014-206260.173 · 8.29 Impact Factor
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    ABSTRACT: Background Nintedanib, an intracellular inhibitor of tyrosine kinases, is in development for the treatment of idiopathic pulmonary fibrosis (IPF). The INPULSIS™ trials were two replicate randomised, double-blind, placebo-controlled, 52-week Phase III trials that assessed the efficacy and safety of nintedanib 150 mg twice daily in patients with IPF. The primary endpoint was the annual rate of decline in forced vital capacity (FVC), which was significantly reduced in the nintedanib group compared with placebo in both trials. Aim To assess the impact of baseline FVC on the effect of nintedanib on rate of decline in FVC. Methods A pre-specified subgroup analysis of patients with baseline FVC >70% versus ≤70% of predicted value was undertaken using pooled data from both trials. Results 700 patients (nintedanib 431, placebo 269) had baseline FVC >70% predicted and 361 patients (nintedanib 207, placebo 154) had baseline FVC ≤70% predicted. For patients with a baseline FVC >70% predicted, mean age was 67.4 years, 76.9% were male, 55.7% were White and mean carbon monoxide diffusion capacity (DLCO) was 4.0 mmol/min/kPa. For patients with a baseline FVC ≤70% predicted, mean age was 65.5 years, 83.9% were male, 60.4% were White and mean DLCO was 3.6 mmol/min/kPa. There was no significant treatment by subgroup interaction: the difference in adjusted annual rate of decline in FVC between the nintedanib and placebo groups was comparable in both subgroups. Conclusion A subgroup analysis of pooled data from the INPULSIS™ trials showed that nintedanib 150 mg twice daily slowed the decline in lung function in patients with IPF, independent of severity of lung function impairment at baseline.
    Thorax 12/2014; 69(Suppl 2):A9-A9. DOI:10.1136/thoraxjnl-2014-206260.18 · 8.29 Impact Factor
  • Brett Ley · Kevin K Brown · Harold R Collard ·
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    ABSTRACT: Molecular biomarkers are highly desired in idiopathic pulmonary fibrosis (IPF) where they hold the potential to elucidate underlying disease mechanisms, accelerated drug development, and advance clinical management. Currently, there are no molecular biomarkers in widespread clinical use for IPF, and the search for potential markers remains in its infancy. Proposed core mechanisms in the pathogenesis of IPF for which candidate markers have been offered include alveolar epithelial cell dysfunction, immune dysregulation, and fibrogenesis. Useful markers reflect important pathologic pathways, are practically and accurately measured, have undergone extensive validation, and are an improvement upon the current approach for their intended use. The successful development of useful molecular biomarkers is a central challenge for the future of translational research in IPF and will require collaborative efforts among those parties invested in advancing the care of patients with IPF.
    AJP Lung Cellular and Molecular Physiology 09/2014; 307(9). DOI:10.1152/ajplung.00014.2014 · 4.08 Impact Factor
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    ABSTRACT: Background There is microscopic spatial and temporal heterogeneity of pathological changes in idiopathic pulmonary fibrosis (IPF) lung tissue, which may relate to heterogeneity in pathophysiological mediators of disease and clinical progression. We assessed relationships between gene expression patterns, pathological features, and systemic biomarkers to identify biomarkers that reflect the aggregate disease burden in patients with IPF. Methods Gene expression microarrays (N=40 IPF; 8 controls) and immunohistochemical analyses (N=22 IPF; 8 controls) of lung biopsies. Clinical characterisation and blood biomarker levels of MMP3 and CXCL13 in a separate cohort of patients with IPF (N=80). Results 2940 genes were significantly differentially expressed between IPF and control samples (|fold change| >1.5, p<0.05). Two clusters of co-regulated genes related to bronchiolar epithelium or lymphoid aggregates exhibited substantial heterogeneity within the IPF population. Gene expression in bronchiolar and lymphoid clusters corresponded to the extent of bronchiolisation and lymphoid aggregates determined by immunohistochemistry in adjacent tissue sections. Elevated serum levels of MMP3, encoded in the bronchiolar cluster, and CXCL13, encoded in the lymphoid cluster, corresponded to disease severity and shortened survival time (p<10−7 for MMP3 and p<10−5 for CXCL13; Cox proportional hazards model). Conclusions Microscopic pathological heterogeneity in IPF lung tissue corresponds to specific gene expression patterns related to bronchiolisation and lymphoid aggregates. MMP3 and CXCL13 are systemic biomarkers that reflect the aggregate burden of these pathological features across total lung tissue. These biomarkers may have clinical utility as prognostic and/or surrogate biomarkers of disease activity in interventional studies in IPF.
    Thorax 09/2014; 70(1). DOI:10.1136/thoraxjnl-2013-204596 · 8.29 Impact Factor
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    ABSTRACT: While widespread use of animal modeling has transformed pulmonary research, the overarching goal of biomedical research is to enhance our understanding of human physiology and pathology. Thus, we believe that future gains in understanding human lung disease will be enhanced when studying patient-derived samples becomes an integral part of the investigational process. For idiopathic pulmonary fibrosis (IPF), investigators need quality human specimens, collected in a standardized fashion, along with carefully annotated, long-term clinical and outcomes data to address current knowledge gaps. Access to human lung tissues through commercial entities or the Lung Tissue Resource Consortium, an NHLBI-funded consortium, has demonstrated the feasibility of this approach. However, these samples are not always well-annotated or collected uniformly, and are limited in their breadth to address future IPF research needs. Therefore, we propose leveraging ongoing and future studies in IPF to establish a biorepository which will meet current and future needs of IPF investigations. Specifically, we propose that blood, cell, and lung samples, linked to robust longitudinal clinical phenotyping generated from future industry, federally-sponsored, and investigator-initiated clinical studies be prospectively and uniformly collected and stored in a biorepository and linked registry. Here we outline standardized methodologies that would allow specimens and clinical data collected from different studies to be integrated and accessible to the IPF research community for investigations which will inform future basic and translational research in IPF. Such a biorepository needs the combined efforts of all stakeholders, to be driven by projected future scientific needs and to be available to all qualified researchers. We believe this infrastructure is crucial, is feasible, and would accelerate research in IPF.
    08/2014; 11(8). DOI:10.1513/AnnalsATS.201406-289OI
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    ABSTRACT: Background: The feasibility of an interventional clinical trial in idiopathic pulmonary fibrosis (IPF) using death and hospitalization as primary end points is an area of uncertainty. Using data from a large well-characterized clinical trial population, this article aims to illustrate the impact of cohort enrichment and study duration on sample size requirements for IPF clinical trials in which death alone or death plus hospitalization serve as the primary end point. Methods: Event rate estimates for death and hospitalization were determined from patients enrolled in National Institutes of Health-sponsored IPF Clinical Research Network clinical trials. Standard equations were applied to estimate the total sample size required for varying gender, age, and pulmonary function (GAP) stage-based cohorts. Results: Risk estimates for death and hospitalization in the clinical trial cohort were substantially lower than those published. An IPF trial with death as its primary end point enrolling subjects designated as GAP stage 1 and 2 over 1 year with a minimum follow-up of 1 year would require an estimated 7,986 subjects to achieve 90% power for a hazard ratio of 0.70. Alternatively, an IPF trial with death plus hospitalization as its primary end point enrolling subjects with GAP stage 2 and 3 over 2 years with a minimum follow-up of 1 year would require an estimated 794 subjects for the same power and hazard ratio. Conclusions: Study design decisions, in particular cohort enrichment strategies, have a substantial impact on sample size requirements for IPF clinical trials using time-to-event primary end points such as death and death plus hospitalization.
    Chest 08/2014; 146(5). DOI:10.1378/chest.14-0492 · 7.48 Impact Factor