title: Considerations for the Conduct of Clinical Trials with Antiinflammatory Agents in Cystic Fibrosis. A Cystic Fibrosis Foundation Workshop Report.
abstract: Inflammation leads to lung destruction and loss of pulmonary function in patients with cystic fibrosis (CF). Drugs that modulate the cystic fibrosis transmembrane conductance regulator (CFTR) have recently been approved. Although the impact of CFTR modulators on sweat chloride and lung function are exciting, they have not yet demonstrated an effect on inflammation. Therefore, CF antiinflammatory drug development must continue. Unfortunately, the lack of clarity with this process has left investigators and industry sponsors frustrated. The Cystic Fibrosis Foundation established a working group in early 2014 to address this issue. There are many inflammatory processes disrupted in CF, and, therefore, there are many potential targets amenable to antiinflammatory therapy. Regardless of a drug's specific mechanism of action, it must ultimately affect the neutrophil or its products to impact CF. The working group concluded that before bringing new antiinflammatory drugs to clinical trial, preclinical safety studies must be conducted in disease-relevant models to assuage safety concerns. Furthermore, although studies of antiinflammatory therapies must first establish safety in adults, subsequent studies must involve children, as they are most likely to reap the most benefit. The working group also recommended that pharmacokinetic-pharmacodynamic studies and early-phase safety studies be performed before proceeding to larger studies of longer duration. In addition, innovative study designs may improve the likelihood of adequately assessing treatment response and mitigating risk before conducting multiyear studies. Learning from past experiences and incorporating this knowledge into new drug development programs will be instrumental in bringing new antiinflammatory therapies to patients.
authors.affiliation: 1 Cystic Fibrosis Foundation, Bethesda, Maryland.
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Torphy
authors.affiliation: 2 United Kingdom Cystic Fibrosis Trust, London, United Kingdom.
authors.forename: Janet
authors.initials: J
authors.lastname: Allen
authors.affiliation: 3 Pulmonary Research Unit, Department of Anatomy and Cellular Biology, Faculty of Medicine University of Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: André M
authors.initials: AM
authors.lastname: Cantin
authors.affiliation: 4 Case Western Reserve University School of Medicine, Rainbow Babies and Children's Hospital, Cleveland, Ohio.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Konstan
authors.affiliation: 5 Department of Pediatrics, University of Colorado Denver School of Medicine, Children's Hospital Colorado, Aurora, Colorado; and.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Accurso
authors.affiliation: 1 Cystic Fibrosis Foundation, Bethesda, Maryland.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Joseloff
authors.affiliation: 6 Division of Respiratory Medicine, Department of Paediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Felix A
authors.initials: FA
authors.lastname: Ratjen
authors.affiliation: 4 Case Western Reserve University School of Medicine, Rainbow Babies and Children's Hospital, Cleveland, Ohio.
authors.forename: James F
authors.identifier: http://orcid.org/0000-0003-4495-4693
authors.initials: JF
authors.lastname: Chmiel
mesh_terms: D000293:Adolescent; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002648:Child; D002986:Clinical Trials as Topic; D003550:Cystic Fibrosis / Q000188:drug therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005260:Female; D006801:Humans; D008168:Lung / Q000503:physiopathology*; D009154:Mutation; D009504:Neutrophils
chemical_list: D000893:Anti-Inflammatory Agents; C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: airway inflammation; antiinflammatory drugs; clinical trials; cystic fibrosis; lung