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1. Interventions to improve system-level coproduction in the Cystic Fibrosis Learning Network

Author

Rachel Gordon, Lillian O’Leary, Gregory Sawicki, Don B Sanders, David Miller, Peter J Murphy, Michael Seid, John Dickinson, Mary Lester, Catherine Hopkins, Adrienne Savant, Rebekah Brown, Preeti Sharma, Christian Merlo, Michelle Roberts, Kathryn A Sabadosa, David Hansen, Peter Michelson, Amy Filbrun, Jordan Dunitz, Christopher M Siracusa, Thida Ong, Stacy Bichl, Ahmet Uluer, Joanne Cullina, Michael Powers, Rhonda List, Lindsay Somerville, Lauren Williamson, Dana Albon, Hossein Sadeghi, Clement Ren, Thomas Keens, Nicholas Antos, Fadi Asfour, Mike Price, Kristen Nowak, Robert Balk, Erin Moore, Prigi Varghese, Cori Daines, Glenda Drake, Amy Lucero, Amanda Sharpe, Lindsey McMahon, Meghan Murray, Meghana Sathe, Traci Liberto, Rachel Linnemann, Pornchai Tirakitsoontorn, Maivy Sou, Michael Schechter, Andrea Molzhon, Karen Wunschel, Lisa A Mullen, Kyle Traver, Travis Burgett, Alex Gifford, Nicola Felicetti, Heidi Dolan, Tracey Gendreau, Danielle Beachler, Shine-Ann Pai, Stephanie Robbins, Ben McCullar, Lauren Mitchell, Andrew Scaljon, Stefanie Rushing, Golnar Raissi, Bean Corcoran, Michelle Prickett, Rachel Nelson, Stacy Allen, Lisa Greene, Sara Renschen, Betsy Price, Catherine Kier, Teresa Carney, Sandy Corr, Barbara Leyva, Jillian Salvatore, George M Solomon, Julianna Bailey, James Lawlor, Samya Z Nasr, Rebekah Raines, Catherine Enochs, Kristen Jesse, Jonathan Flath, Mackenzie Wharram, James Tolle, Susan Eastman, Nauman Chaudary, Mahsa Farsad, Kimberly Wingo, Kathryn Moffett, Erin Brozik, Paige Krack, Kevin Martin, Laura Roth, Joshua Wang, Sarah Dykes, Erin Newbill, Misty Thompson, Danielle Poulin, Breck Gamel, Srujana Bandla, David W Davison, Lindsay Silva, Raouf Amin, Maria Britto, Anna Saulitis, Kate Barnico, Cindy Murphy, Amanda Lemieux, Georgia Dangel, Melanie Lawrence, Danielle Goetz, Danielle Woerner, Megan Whelan, Katelyn Violanti, Susan Attel, Alexia Hernández Cargal, Kelly Clute, Olivia Ries, Susan Gage, Bridget Kominek, Kristin Lawrence, Megan Martin, Jessica Roach, Errin Newman, Phillip Vaden, Esther Giezendanner, Marsha Triana, Sujal Rangwalla, Meghann Weil, Randy Hunt, Emily Walker, Caroline Starnes, Kendra Adderhold, Megan Barker, Johanna Zea-Hernandez, Beth Debri, Ann Kaiser, Cindy Brown, Pi Chun Cheng, Jana Yeley, Laura Jay-Ballinger, Julian McConnie, Meghana Malapaka, Perry Aulie, Ginger Birnbaum, Cynthia Driskill, Janerisa Encarnacion, Amanda Oswald, Stephanie Fullmer, Anthony Fashoda, Laura Steinhaus, Maureen Tinley, Jame’ Vajda, Janine Cassidy, Mey Lee, Megan Akers, Susan Whitmore, Christian Santaniello, Robert Abdullah, Bryan Garcia, Cameron Crenshaw, Kandice Amos, Veronica Indihar, Lisa Shively, Anissa Hostetter, Angela Oder, Brandi Morgan, Kayla Hubley, Deborah K Froh, Holly Carroll-Owen, Lauren Miller Ahrens, Brielle Evangelista, Lucy Gettle, Tracie O'Sullivan, Autumn Bonstein, Stacey Miller, Angela Bender, Billie Jo Bennett, John Palla, Cathy O'Malley, Maria Dowell, Allison Fitch-Markham, Chladd Ford, Carolyn Heyman, Terri Laguna, Debbie Benitez, Lynn Fukushima, Martha Markovitz, Adupa Rao, Gregory Storm, Vai Jun Lam, John Mercer, Cori Muirhead, Jeff Gold, Aaron Trimble, Gopal Allada, Wendy Palmrose, Sue Sullivan, Kim Keeling, Rob Shradar, Jill Fliege, Heidi Klasna, Janelle Sorensen, Stacy Millikan, Joe Poler, Jill Rollins, Sandy Wahl, Cristy Batten, Laura Romero, Whitney Gore, Kimberly Morse, Rocio Munter, Danieli Salinas, Sylvia Sanchez, Virginia Anderson, Jami Dunn, Stephanie Gamble, Hector Gutierrez, Kelli Lachowicz, Isabel Lowell, Cathy Mims, LaShonna Stodghill, Gabriela Oates, Amanda Phillips, Linda Russo, Staci Self, Julie Desch, Ilene Hollin, Emily Kramer-Golinkoff, Pamela Mertz, Sarah Gomez, Nancy Griffin, and Drew Warmin

Subjects
Medicine (General), R5-920
Abstract

Background Coproduction is defined as patients and clinicians collaborating equally and reciprocally in healthcare and is a crucial concept for quality improvement (QI) of health services. Learning Health Networks (LHNs) provide insights to integrate coproduction with QI efforts from programmes from various health systems.Objective We describe interventions to develop and maintain patient and family partner (PFP) coproduction, measured by PFP-reported and programme-reported scales. We aim to increase percentage of programmes with PFPs reporting active QI work within their programme, while maintaining satisfaction in PFP-clinician relationships.Methods Conducted in the Cystic Fibrosis Learning Network (CFLN), an LHN comprising over 30 cystic fibrosis (CF) programmes, people with CF, caregivers and clinicians cocreated interventions in readiness awareness, inclusive PFP recruitment, onboarding process, partnership development and leadership opportunities. Interventions were adapted by CFLN programmes and summarised in a change package for existing programmes and the orientation of new ones. We collected monthly assessments for PFP and programme perceptions of coproduction and PFP self-rated competency of QI skills and satisfaction with programme QI efforts. We used control charts to analyse coproduction scales and run charts for PFP self-ratings.Results Between 2018 and 2022, the CFLN expanded to 34 programmes with 52% having ≥1 PFP reporting active QI participation. Clinicians from 76% of programmes reported PFPs were actively participating or leading QI efforts. PFPs reported increased QI skills competency (17%–32%) and consistently high satisfaction and feeling valued in their work.Conclusions Implementing system-level programmatic strategies to engage and sustain partnerships between clinicians and patients and families with CF improved perceptions of coproduction to conduct QI work. Key adaptable strategies for programmes included onboarding and QI training, supporting multiple PFPs simultaneously and developing financial recognition processes. Interventions may be applicable in other health conditions beyond CF seeking to foster the practice of coproduction.

Published
2024
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2. Cystic fibrosis learning network telehealth innovation lab during the COVID-19 pandemic: a success QI story for interdisciplinary care and agenda setting

Author

Rachel Gordon, Lucinda Murphy, Gregory Sawicki, Michael Seid, Rebekah Brown, Preeti Sharma, Maria T Britto, Christian Merlo, Peter Michelson, Jordan Dunitz, Christopher M Siracusa, Raouf S Amin, Thida Ong, Ahmet Uluer, Joanne Cullina, Sydney Schiff, Rhonda List, Lindsay Somerville, Lauren Williamson, Dana Albon, Hossein Sadeghi, Nicholas Antos, Fadi Asfour, Mike Price, Lacrecia Thomas, Lindsay Hoberg, Sophia Stamper, Prigi Varghese, Ella Balasa, Matthew Roman, Melanie Miner, Emily Gehring, Clifford Gammon, Mike Powers, Cori Daines, Glenda Drake, Amy Lucero, Lilly Mees, Amanda Sharpe, Lindsey McMahon, Melanie Abdelnour, Meghan Murray, Meghana Sathe, Traci Liberto, Rachel Linnemann, Alexia Hernandez Cargal, Heather Tucker, Pornchai Tirakitsoontorn, Maivy Sou, Alicia Maciel, Michael Schechter, Andrea Molzhon, Nicole Brueck, Karen Wunschel, Lisa A Mullen, Kyle Traver, Travis Burgett, Alex Gifford, Nicola Felicetti, Heidi Dolan, Tracey Gendreau, Danielle Beachler, Shine-Ann Pai, Stephanie Robbins, Zoe Orcutt, Ben McCullar, Lindsaey Deveaux, Lauren Mitchell, Andrew Scaljon, Stefanie Rushing, Virginia Birnbaum, Golnar Raissi, Bean Corcoran, Michelle Prickett, Rachel Nelson, Anne Snuggerud, Stacy Allen, Sabrina Gorry, Lisa Greene, Sara Renschen, Betsy Price, Catherine Kier, Teresa Carney, Sandy Corr, Barbara Leyva, Jillian Salvatore, George M Solomon, Julianna Bailey, James Lawlor, Samya Z Nasr, Rebekah Raines, Catherine Enochs, Kristen Jesse, Kayla Warner, Jonathan Flath, Mackenzie Wharram, Deborah Froh, Holly Carroll-Owens, James Tolle, Susan Eastman, Marrisa Benchea, Nauman Chaudary, Mahsa Farsad, Kimberly Wingo, Kathryn Moffett, Erin Brozik, and Jillian Huffman

Subjects
Medicine (General), R5-920
Published
2022
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3. Diagnostic Accuracy of Nasopharyngeal Swab Cultures in Children Less Than Five Years with Chronic Wet Cough

Author

Ali A. Asseri, Nasim Khattab, Dima Ezmigna, Nabil J. Awadalla, Cori Daines, and Wayne Morgan

Subjects
bacterial pathogens, bronchoalveolar lavage (BAL), chronic wet cough, nasopharyngeal swab, persistent bacterial bronchitis (PBB), Pediatrics, RJ1-570
Abstract

Background: It is necessary to find a non-invasive and accurate procedure to predict persistent bacterial bronchitis (PBB) causative organisms and guide antibiotic therapy. The study objective was to compare the diagnostic accuracy of nasopharyngeal swab cultures with bronchoalveolar lavage (BAL) cultures in children with PBB. Methods: Nasopharyngeal swab and BAL fluid specimens were collected and cultured for bacterial pathogens prospectively from less than five-year-old children undergoing flexible bronchoscopy for chronic wet cough. Results: Of the 59 children included in the study, 26 (44.1%) patients had a positive BAL bacterial culture with neutrophilic inflammation. Prevalence of positive cultures for any of the four common respiratory pathogens implicated in PBB (Moraxella catarrhalis, Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae) was significantly higher (p = 0.001) in NP swabs compared to BAL fluids (86.4% and 44.1% of PBB cases, respectively). NP swab cultures for any of the four main bacterial pathogens had 85% (95% CI: 65–96%) and 48% (95% CI: 31–66%) sensitivity and specificity of detecting PBB, respectively. Positive and negative predictive values were 56% (95% CI: 47–65%) and 80% (95% CI: 60–91%), respectively. In conclusion, in children less than 5 years of age with chronic wet cough (PBB-clinical), a negative NP swab result reduces the likelihood of lower airway infection; however, a positive NP swab does not accurately predict the presence of lower airway pathogens. Flexible bronchoscopy should be considered in those with recurrent PBB-clinical or with clinical pointers of central airway anomalies.

Published
2021
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4. Discontinuation versus continuation of hypertonic saline or dornase alfa in modulator treated people with cystic fibrosis (SIMPLIFY): results from two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials

Author

Nicole Mayer-Hamblett, Felix Ratjen, Renee Russell, Scott H Donaldson, Kristin A Riekert, Gregory S Sawicki, Katherine Odem-Davis, Julia K Young, Daniel Rosenbluth, Jennifer L Taylor-Cousar, Christopher H Goss, George Retsch-Bogart, John Paul Clancy, Alan Genatossio, Brian P O'Sullivan, Ariel Berlinski, Susan L Millard, Gregory Omlor, Colby A Wyatt, Kathryn Moffett, David P Nichols, Alex H Gifford, Margaret Kloster, Katie Weaver, Claire Chapdu, Jing Xie, Michelle Skalland, Melita Romasco, Sonya Heltshe, Noah Simon, Jill VanDalfsen, Anna Mead, Rachael Buckingham, Kathy Seidel, Nikita Midamba, Laurel Couture, Brooke Zappone Case, Wendy Au, Elsie Rockers, Diane Cooke, Amber Olander, Irene Bondick, Miya Johnson, Lisya VanHousen, Boris Nicholson, Michelle Parrish, Dion Roberts, Jillian Head, Jessica Carey, Lindsay Caverly, Joy Dangerfield, Rachel Linnemann, Jason Fullmer, Chelsea Roman, Peter Mogayzel, Deanne Reyes, Amy Harmala, Jerimiah Lysinger, Jonathan Bergeron, Isabel Virella-Lowell, Perry Brown, Lejla Godusevic, Alicia Casey, Lauren Paquette, Thomas Lahiri, Julie Sweet, Scott Donaldson, Joshua Harris, Shelia Parnell, Sylvia Szentpetery, Deborah Froh, Erica Tharrington, Manu Jain, Rachel Nelson, Sharon Kadon, Gary McPhail, Kimberly McBennett, Tia Rone, Elliott Dasenbrook, Dave Weaver, Terri Johnson, Karen McCoy, Raksha Jain, Maria Mcleod, Mary Klosterman, Preeti Sharma, Amy Jones, Gary Mueller, Rachel Janney, Jennifer Taylor-Cousar, Mary Cross, Jordana Hoppe, James Cahill, Zubin Mukadam, Jill Finto, Karen Schultz, Silvia Delgado Villalta, Alexa Smith, Susan Millard, Thomas Symington, Gavin Graff, Diane Kitch, Don Sanders, Misty Thompson, Tahuanty Pena, Mary Teresi, Jennifer Gafford, David Schaeffer, Joel Mermis, Lawrence Scott, Hugo Escobar, Kristen Williams, Dana Dorman, Brian O'Sullivan, Ryan Bethay, Zoran Danov, Kat Turbeville, Jimmy Johannes, Angelica Rodriguez, Bridget Marra, Robert Zanni, Ronald Morton, Terri Simeon, Andrew Braun, Nicole Dondlinger, Julie Biller, Erin Hubertz, Nicholas Antos, Laura Roth, Joanne Billings, Catherine Larson, Priya Balaji, John McNamara, Tammy Clark, Rebecca Griffith, Nancy Martinez, Sabiha Hussain, Halina Malveaux, Marie Egan, Catalina Guzman, Joan DeCelie-Germana, Susan Galvin, Adrienne Savant, Nicole Falgout, Patricia Walker, Teresa Demarco, Emily DiMango, Maria Ycaza, Julie Ballo, Pornchai Tirakitsoontorn, Daniel Layish, Desiree Serr, Floyd Livingston, Sherry Wooldridge, Carlos Milla, Jacquelyn Spano, Rebecca Davis, Okan Elidemir, Subramanyam Chittivelu, Ashley Scott, Sarah Alam, Daniel Dorgan, Matt Butoryak, Daniel Weiner, Harmony Renna, Colby Wyatt, Brendan Klein, Anne Stone, Meg Lessard, Michael S. Schechter, Barbara Johnson, Steven Scofield, Theodore Liou, Jane Vroom, Kathryn Akong, Marissa Gil, Legna Betancourt, Jonathan Singer, Ngoc Ly, Courtney Moreno, Moira Aitken, Teresa Gambol, Ronald Gibson, Allison Lambert, Joan Milton, Sarah Smith, Deanna Green, Diana Hodge, Christopher Fortner, Mary Forell, Rachel Karlnoski, Kapil Patel, Cori Daines, Elizabeth Ryan, Rodolfo Amaro-Galvez, Elizabeth Dohanich, Alison Lennox, Zachary Messer, Holly Hanes, Kay Powell, and Deepika Polineni

Subjects
Pulmonary and Respiratory Medicine
Abstract

Reducing treatment burden is a priority for people with cystic fibrosis, whose health has benefited from using new modulators that substantially increase CFTR protein function. The SIMPLIFY study aimed to assess the effects of discontinuing nebulised hypertonic saline or dornase alfa in individuals using the CFTR modulator elexacaftor plus tezacaftor plus ivacaftor (ETI).The SIMPLIFY study included two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials at 80 participating clinics across the USA in the Cystic Fibrosis Therapeutics Development Network. We included individuals with cystic fibrosis aged 12-17 years with percent predicted FEVFrom Aug 25, 2020, to May 25, 2022, a total of 672 unique participants were screened for eligibility for one or both trials, resulting in 847 total random assignments across both trials with 594 unique participants. 370 participants were randomly assigned in the hypertonic saline trial and 477 in the dornase alfa trial. Participants across both trials had an average ppFEVIn individuals with cystic fibrosis on ETI with relatively well preserved pulmonary function, discontinuing daily hypertonic saline or dornase alfa for 6 weeks did not result in clinically meaningful differences in pulmonary function when compared with continuing treatment.

Published
2023

5. Non-respiratory health-related quality of life in people with cystic fibrosis receiving elexacaftor/tezacaftor/ivacaftor

Author

Isabelle Fajac, Cori Daines, Isabelle Durieu, Jennifer L. Goralski, Harry Heijerman, Christiane Knoop, Christof Majoor, Bote G. Bruinsma, Samuel Moskowitz, Valentin Prieto-Centurion, Kate Van Brunt, Yaohua Zhang, Alexandra Quittner, and Pulmonary medicine

Subjects
Pulmonary and Respiratory Medicine, Pediatrics, Perinatology and Child Health
Abstract

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in people with cystic fibrosis (CF) heterozygous for F508del and a minimal function mutation (F/MF) or homozygous for F508del (F/F) in two pivotal Phase 3 trials, significantly improving percentage predicted forced expiratory volume in 1 second, Cystic Fibrosis Questionnaire-Revised, Respiratory Domain (CFQ-R RD) scores, and sweat chloride concentration. Here, we analyzed the 11 non-respiratory domains (non-RDs) of the CFQ-R, which assess general health-related quality of life (i.e., Physical Functioning, Role Functioning, Vitality, Health Perceptions, Emotional Functioning, and Social Functioning) and quality of life impacted by CF (i.e., Body Image, Eating Problems, Treatment Burden, Weight, and Digestive Symptoms), for participants in these two Phase 3 trials. ELX/TEZ/IVA treatment led to higher scores in all CFQ-R non-RDs, with improvements in most domains compared with control treatments. These findings demonstrate that ELX/TEZ/IVA improves a range of CF-specific symptoms and general functioning and well-being.

Published
2023

6. A Randomized Clinical Trial of Antimicrobial Duration for Cystic Fibrosis Pulmonary Exacerbation Treatment

Author

Christopher H. Goss, Sonya L. Heltshe, Natalie E. West, Michelle Skalland, Don B. Sanders, Raksha Jain, Tara L. Barto, Barbra Fogarty, Bruce C. Marshall, Donald R. VanDevanter, Patrick A. Flume, Gregory Omlor, Brenda Bourne, Dion Roberts, Vicki Roberts, Samya Nasr, Dawn Kruse, Rachel Linnemann, Tsion Hailemichael, Caralee Forseen, Heidi Stapp, Natalie West, S. Patel, A. Claudio, Jerimiah Lysinger, Amy Harmala, George Solomon, Latona Kersh, Karen Miller, Dixie Durham, Ahmet Uluer, Robert Fowler, Carla Frederick, Nadine Caci, Charlotte Teneback, Julie Sweet, Michael Parkins, Clare Smith, Jennifer Goralski, Kelsey Haywood, Patrick Flume, Caroline Brailsford, Dana Albon, Christie Aderholt, Kimberly McBennett, Cindy Schaefer, Alpa Patel, April Hunt, Lauren Schumacher, Hari Polenakovik, Linda Clark, Jerry Nick, Katie Poch, Dana Kissner, James Cahill, Jorge Lascano, Erin Silverman, John McArdle, Alison Champagne, Robert Vender, Lisa Allwein, Lance Cohen, Norma (Jean) Barton, Tara Barto, Ami Patel, Cynthia Brown, Nia Vorhees, Michael Crosser, Lawrence Scott, Alix Ashare, Barbara Rodgers, Robert Zanni, Lisa Koval, Andrew Braun, Sophia Chiron Stevens, Maria Tupayachi Ortiz, Patricia Graham, Julie Biller, Erin Hubertz, Kathryn Moffett, Tammy Clark, Rebecca Griffith, Nancy Martinez, Sabiha Hussain, Fei Chen, Marie Egan, Catalina Guzman, Janice Wang, Aileen Espinal, Patricia Walker, Anne Kukral, Emily DiMango, Sarah Fracasso Francis, Carlos Milla, Colleen Dunn, Subramanyam Chittivelu, Ashley Scott, Daniel Dorgan, Sharon Ng, Joseph Pilewski, Rose Lanzo, Nauman Chaudary, Ryan Hayden, Steven Scofield, Barb Johnson, Brian Morrissey, Brandt Robinson, Douglas Conrad, Jenna Mielke, Moira Aitken, Chami Sanlors, Ravi Nayak, Freda Branch, Daniel Rosenbluth, Molly Siegel, Anil Ghimire, Mary Forell, Cori Daines, Monica Varela, Leslie Couch, Rebekah Hibbard, Allen Dozor, Armando Ramirez, Victor Ortega, Kathryn Kennedy, David Fish, and Karen Longtine

Subjects
Adult, Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Time Factors, Cystic Fibrosis, Exacerbation, Critical Care and Intensive Care Medicine, Cystic fibrosis, law.invention, Randomized controlled trial, law, Internal medicine, medicine, Humans, Pseudomonas Infections, Respiratory system, Respiratory Tract Infections, business.industry, Cystic Fibrosis Pulmonary Exacerbation, Editorials, Respiratory infection, Original Articles, Middle Aged, medicine.disease, Antimicrobial, Anti-Bacterial Agents, Respiratory Function Tests, Clinical trial, Pseudomonas aeruginosa, Disease Progression, Female, business
Abstract

RATIONALE: People with cystic fibrosis (CF) experience acute worsening of respiratory symptoms and lung function known as pulmonary exacerbations. Treatment with intravenous antimicrobials is common; however, there is scant evidence to support a standard treatment duration. OBJECTIVES: To test differing durations of intravenous antimicrobials for CF exacerbations. METHODS: STOP2 (Standardized Treatment of Pulmonary Exacerbations 2) was a multicenter, randomized, controlled clinical trial in exacerbations among adults with CF. After 7–10 days of treatment, participants exhibiting predefined lung function and symptom improvements were randomized to 10 or 14 days’ total antimicrobial duration; all others were randomized to 14 or 21 days’ duration. MEASUREMENTS AND MAIN RESULTS: The primary outcome was percent predicted FEV(1) (ppFEV(1)) change from treatment initiation to 2 weeks after cessation. Among early responders, noninferiority of 10 days to 14 days was tested; superiority of 21 days compared with 14 days was compared for the others. Symptoms, weight, and adverse events were secondary. Among 982 randomized people, 277 met improvement criteria and were randomized to 10 or 14 days of treatment; the remaining 705 received 21 or 14 days of treatment. Mean ppFEV(1) change was 12.8 and 13.4 for 10 and 14 days, respectively, a ‒0.65 difference (95% CI [‒3.3 to 2.0]), excluding the predefined noninferiority margin. The 21- and 14-day arms experienced 3.3 and 3.4 mean ppFEV(1) changes, a difference of ‒0.10 (‒1.3 to 1.1). Secondary endpoints and sensitivity analyses were supportive. CONCLUSIONS: Among adults with CF with early treatment improvement during exacerbation, ppFEV(1) after 10 days of intravenous antimicrobials is not inferior to 14 days. For those with less improvement after one week, 21 days is not superior to 14 days. Clinical trial registered with www.clinicaltrials.gov (NCT02781610).

Published
2021

7. Childhood Respiratory Conditions: Nonasthma Chronic Lung Disease

Author

Cori, Daines

Subjects
Cystic Fibrosis, Child, Preschool, Quality of Life, Humans, Child, Lung
Abstract

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that results from impaired lung development or lung injury from ventilatory support. It primarily is seen in infants born prematurely. Approximately 95% of infants with BPD had a low birth weight (ie, less than 1,500 g). This condition affects pulmonary function throughout the life span. Many children with BPD develop asthmalike symptoms with recurrent wheezing beginning in the preschool-aged years. Complications include pulmonary hypertension, tracheomalacia, glottic damage, sleep apnea, and more frequent and/or severe respiratory infections. Measures should be taken to prevent respiratory infections in these patients. Cystic fibrosis (CF) is caused by an autosomal recessive sequence variation in the CF transmembrane conductance regulator (

Published
2022

8. The Precision Interventions for Severe and/or Exacerbation-Prone (PrecISE) Asthma Network: An overview of Network organization, procedures, and interventions

Author

Steve N. Georas, Rosalind J. Wright, Anastasia Ivanova, Elliot Israel, Lisa M. LaVange, Praveen Akuthota, Tara F. Carr, Loren C. Denlinger, Merritt L. Fajt, Rajesh Kumar, Wanda K. O’Neal, Wanda Phipatanakul, Stanley J. Szefler, Mark A. Aronica, Leonard B. Bacharier, Allison J. Burbank, Mario Castro, Laura Crotty Alexander, Julie Bamdad, Juan Carlos Cardet, Suzy A.A. Comhair, Ronina A. Covar, Emily A. DiMango, Kim Erwin, Serpil C. Erzurum, John V. Fahy, Jonathan M. Gaffin, Benjamin Gaston, Lynn B. Gerald, Eric A. Hoffman, Fernando Holguin, Daniel J. Jackson, John James, Nizar N. Jarjour, Nicholas J. Kenyon, Sumita Khatri, John P. Kirwan, Monica Kraft, Jerry A. Krishnan, Andrew H. Liu, Mark C. Liu, M. Alison Marquis, Fernando Martinez, Jacob Mey, Wendy C. Moore, James N. Moy, Victor E. Ortega, David B. Peden, Emily Pennington, Michael C. Peters, Kristie Ross, Maria Sanchez, Lewis J. Smith, Ronald L. Sorkness, Michael E. Wechsler, Sally E. Wenzel, Steven R. White, Joe Zein, Amir A. Zeki, Patricia Noel, Dean Billheimer, Eugene R. Bleecker, Emily Branch, Michelle Conway, Cori Daines, Isaac Deaton, Alexandria Evans, Paige Field, Dave Francisco, Annette T. Hastie, Bob Hmieleski, Jeffrey O. Krings, Yanqin Liu, Janell L. Merchen, Deborah A. Meyers, Nirushan Narendran, Stephen P. Peters, Anna Pippins, Matthew A. Rank, Ronald Schunk, Raymond Skeps, Benjamin Wright, Tina M. Banzon, Lisa M. Bartnikas, Sachin N. Baxi, Vishwanath Betapudi, Isabelle Brick, Conor Brockway, Thomas B. Casale, Kathleen Castillo-Ruano, Maria Angeles Cinelli, Elena Crestani, Amparito Cunningham, Megan Day-Lewis, Natalie Diaz-Cabrera, Angela DiMango, Brittany Esty, Eva Fandozzi, Jesse Fernandez, Elizabeth Fitzpatrick, Victoria E. Forth, Katarina Gentile, David Gubernick, Seyni Gueye-Ndiaye, Sigfus Gunnlaagsson, Marissa Hauptmann, Stephanie N. Hudey, Donya S. Imanirad, Tiffani Kaage, Nicholas Kolinsky, Brenna LaBere, Peggy Sue Lai, Meghan Le, Dennis K. Ledford, Richard Lockey, Margee Louisias, Andrew J. Macginnitie, Michelle C. Maciag, Allison O’Neill, Amber N. Pepper, Perdita Permaul, Mya Pugh, Dianna Queheillalt, Tarnjot Saroya, William Sheehan, Catherine Smith, Carmela Socolovsky, Else Treffeisen, Lorenzo Trippa, Abigail Tulchinsky, Christina Yee, Tina Carter, Jun Fu, Vanessa Garcia, Jenny Hixon, Carly Jackson, Yuan Ji, Ravi Kalhan, Opinderjit Kaur, Grace Li, Melanie M. Makhija, Spring Maleckar, Edward T. Naureckas, Anju T. Peters, Valerie Press, Mehreen Qureshi, Paul A. Reyfman, Sharon R. Rosenberg, Dominika Ryba, Jianrong Sheng, Ben Xu, Rafeul Alam, Darci Anderson, Sonya Belimezova, Jennifer Bitzan, Geoffrey Chupp, Brian J. Clark, Lauren Cohn, Margaret Hope Cruse, Jean Estrom, Leah Freid, Jose Gomez Villalobos, Nicole Grant, Vamsi P. Guntur, Carole Holm, Christena Kolakowski, Laurie A. Manka, Naomi Miyazawa, Juno Pak, Diana M. Pruitt, Sunita Sharma, Allen D. Stevens, Kisori Thomas, Brooke Tippin, Karissa Valente, Cynthia L. Wainscoat, Michael P. White, Daniel Winnica, Shuyu Ye, Pamela L. Zeitlin, Julia Bach, Joshua Brownell, Lauren Castro, Julie DeLisa, Sean B. Fain, Paul S. Fichtinger, Heather Floerke, James E. Gern, Vinay Goswamy, Jenelle Grogan, Wendy Hasse, Rick L. Kelley, Danika Klaus, Stephanie LaBedz, Paige Lowell, Andrew Maddox, Sameer K. Mathur, Amanda McIntyre, Lourdes M. Norwick, Sharmilee M. Nyenhuis, Matthew J. O’Brien, Tina Palas, Andrea A. Pappalardo, Mark Potter, Sima K. Ramratnam, Daniel L. Rosenberg, Eric M. Schauberger, Mark L. Schiebler, Angela Schraml, Mohamed Taki, Matthew C. Tattersall, Jissell Torres, Lori Wollet, Simon Abi-Saleh, Lisa Bendy, Larry Borish, James F. Chmiel, Aska Dix, Lisa France, Rebecca Gammell, Adam Gluvna, Brittany Hirth, Bo Hu, Elise Hyser, Kirsten M. Kloepfer, Michelle Koo, Nadia L. Krupp, Monica Labadia, Joy Lawrence, Laurie Logan, Angela Marko, Brittany Matuska, Deborah Murphy, Rachel Owensby, Erica A. Roesch, Don B. Sanders, Jackie Sharp, W. Gerald Teague, Laura Veri, Kristin Wavell Shifflett, Matt Camiolo, Sarah Collins, Jessa Demas, Courtney Elvin, Marc C. Gauthier, Melissa Ilnicki, Jenn Ingram, Lisa Lane, Seyed Mehdi Nouraie, John B. Trudeau, Michael Zhang, Jeffrey Barry, Howard Brickner, Janelle Celso, Matejka Cernelc-Kohan, Damaris Diaz, Ashley Du, Sonia Jain, Neiman Liu, Yusife Nazir, Julie Ryu, Pandurangan Vijayanand, Rogelio Almario, Ariana Baum, Kellen Brown, Marilynn H. Chan, Barbara Gale, Angela Haczku, Richart W. Harper, Raymond Heromin, Celeste Kivler, Brooks T. Kuhn, Ngoc P. Ly, Paula McCourt, Xavier Orain, Audrey Plough, Karla Ramirez, Ellese Roberts, Michael Schivo, Amisha Singapuri, Tina Tham, Daniel Tompkins, Patricia Michelle Twitmyer, Jade Vi, Jarron Atha, Jennifer Bedard, Jonathan S. Boomer, Andrew Chung, Vanessa Curtis, Chase S. Hall, Emily Hart, Fatima Jackson, Pamela Kemp, Sharli Maxwell, Maggie Messplay, Crystal Ramirez, Brynne Thompson, Ashley Britt, Hope Bryan, Nathan M. Gotman, Yue Jiang, Michael R. Kosorok, David T. Mauger, Kelsey Meekins, Jeanette K. Mollenhauer, Sarah Moody, Cheyanne Ritz, Stefanie Schwartz, Chalmer Thomlinson, and Nicole Wilson

Subjects
Severe asthma, Exacerbation, Allergy, Disease, non-type 2 asthma, Severity of Illness Index, asthma exacerbation, Clinical Protocols, Immunology and Allergy, Precision Medicine, Tomography, Lung, education.field_of_study, X-Ray Computed, Asthma Control Questionnaire, Research Design, Respiratory, biomarker, medicine.medical_specialty, precision medicine, Population, Advisory Committees, Clinical Trials and Supportive Activities, Immunology, patient advisory committee, Natural history of disease, Article, Clinical Trials, Phase II as Topic, Clinical Research, medicine, Humans, type 2 asthma, Clinical Trials, Intensive care medicine, education, PrecISE Study Team, Disease burden, Asthma, adaptive clinical trial design, non–type 2 asthma, business.industry, Phase II as Topic, medicine.disease, Precision medicine, respiratory tract diseases, Good Health and Well Being, business, Tomography, X-Ray Computed, Biomarkers
Abstract

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. Acurrent challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

Published
2022

9. Long-term safety and efficacy of tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years or older who are homozygous or heterozygous for Phe508del CFTR (EXTEND): an open-label extension study

Author

Patrick A Flume, Reta Fischer Biner, Damian G Downey, Cynthia Brown, Manu Jain, Rainald Fischer, Kris De Boeck, Gregory S Sawicki, Philip Chang, Hildegarde Paz-Diaz, Jaime L Rubin, Yoojung Yang, Xingdi Hu, David J Pasta, Stefanie J Millar, Daniel Campbell, Xin Wang, Neil Ahluwalia, Caroline A Owen, Claire E Wainwright, Ronald L. Gibson, Steven M. Rowe, Noah Lechtzin, Richard C. Ahrens, Karen S. McCoy, Moira Aitken, Scott H. Donaldson, Kimberly Ann McBennett, Joseph M. Pilewski, Joanne Billings, Carlos Milla, Ronald Rubenstein, Daniel Brian Rosenbluth, Rachel Linnemann, Michael R. Powers, Christopher Fortner, Carla Anne Frederick, Theodore G. Liou, Philip Black, Janice Wang, John L. Colombo, Maria Berdella, Maria Veronica Indihar, Cynthia D. Brown, Michael Anstead, Lara Bilodeau, Leonard Sicilian, James Jerome Tolle, Kathryn Moffett, Samya Nasr, Jennifer Taylor-Cousar, Tara Lynn Barto, Nicholas Antos, John S. Rogers, Bryon Quick, Henry R. Thompson, Gregory Sawicki, Bruce Barnett, Robert L. Zanni, Thomas C. Smith, Karen D. Schultz, Claire Keating, Patrick Flume, Gregory J. Omlor, Alix Ashare, Karen Voter, Nighat Mehdi, Maria Gabriela Tupayachi Ortiz, Tonia E. Gardner, Steven R. Boas, Barbara Messore, Edith Zemanick, Raksha Jain, Michael McCarthy, Dana G. Kissner, Kapilkumar Patel, John McNamara, Julie Philley, Ariel Berlinski, Francisco J. Calimano, Terry Chin, Douglas Conrad, Cori Daines, Hengameh H. Raissy, Thomas G. Keens, Jorge E. Lascano, Bennie McWilliams, Brian Morrissey, Santiago Reyes, Subramanyam Chittivelu, Sabiha Hussain, Arvey Stone, James Wallace, Ross Klingsberg, Julie A. Biller, Stephanie Bui, Olaf Sommerburg, Elisabetta Bignamini, Mirella Collura, Alexander Moller, Donatello Salvatore, Chantal Belleguic, Lea Bentur, Ori Efrati, Eitan Kerem, Dario Prais, Esther Quintana Gallego, Peter Barry, Galit Livnat-Levanon, Jose Ramon Villa Asensi, David Stuart Armstrong, Oscar Asensio de la Cruz, Francis Gilchrist, Diana Elizabeth Tullis, Bradley Quon, Larry C. Lands, Nancy Morrison, Annick Lavoie, Barry Linnane, Okan Elidemir, Felix Ringshausen, Matthias Kappler, Helge Hebestreit, Jochen Mainz, Alexander Kiefer, Cordula Koerner-Rettberg, Doris Staab, Wolfgang Gleiber, Tacjana Pressler, Florian Stehling, Andreas Hector, Sivagurunathan Sutharsan, Lutz Naehrlich, Damian Downey, Jane Carolyn Davies, Robert Ian Ketchell, Mary Patricia Carroll, Simon Doe, Gordon MacGregor, Edward Fairbairn Nash, Nicholas Withers, Daniel Gavin Peckham, Martin James Ledson, Sonal Kansra, Timothy William Rayner Lee, Bertrand Delaisi, Gilles Rault, Jean Le Bihan, Dominique Hubert, Isabelle Fajac, Isabelle Sermet-Gaudelus, Marleen Bakker, Bert Arets, Christiane De Boeck, Raphael Chiron, Philippe Reix, Catherine Mainguy, Eva van Braeckel, Anne Malfroot, Isabelle Durieu, Nadine Desmazes Dufeu, Anne Prevotat, Renske van der Meer, Petrus Merkus, E.J.M. Weersink, Isabel Barrio Gomez-Aguero, Silvia Gartner, Amparo Sole Jover, Antonio Alvarez Fernandez, Desmond William Cox, Edward F. McKone, Barry James Plant, Hiranjan Selvadurai, Simon David Bowler, Claire Elizabeth Wainwright, Daniel Smith, Peter Gordon Middleton, John William Wilson, Sonia Volpi, Carla Colombo, Benedetta Fabrizzi, Vincenzina Lucidi, Federico Cresta, Salvatore Cucchiara, Ernst Eber, Helmut Ellemunter, Isidor Huttegger, Lena Hjelte, Christina Krantz, Marita Gilljam, and Pulmonology

Subjects
Adult, Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Indoles, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Quinolones, Aminophenols, Cystic fibrosis, Time, Ivacaftor, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Internal medicine, medicine, Clinical endpoint, Humans, Benzodioxoles, 030212 general & internal medicine, Israel, biology, business.industry, Australia, medicine.disease, Cystic fibrosis transmembrane conductance regulator, Discontinuation, Europe, Drug Combinations, Treatment Outcome, Clinical research, 030228 respiratory system, Tolerability, Mutation, North America, biology.protein, Female, business, medicine.drug
Abstract

Summary Background Tezacaftor–ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8–24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor–ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor–ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. Methods Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor–ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor–ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov ( NCT02565914 ). Findings Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor–ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor–ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor–ivacaftor-treated F/F participants versus untreated matched historical controls. Interpretation Tezacaftor–ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor–ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor–ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes. Funding Vertex Pharmaceuticals Incorporated.

Published
2021

10. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation

Author

Harry G M Heijerman, Edward F McKone, Damian G Downey, Eva Van Braeckel, Steven M Rowe, Elizabeth Tullis, Marcus A Mall, John J Welter, Bonnie W Ramsey, Charlotte M McKee, Gautham Marigowda, Samuel M Moskowitz, David Waltz, Patrick R Sosnay, Christopher Simard, Neil Ahluwalia, Fengjuan Xuan, Yaohua Zhang, Jennifer L Taylor-Cousar, Karen S McCoy, Karen McCoy, Scott Donaldson, Seth Walker, James Chmiel, Ronald Rubenstein, Deborah K. Froh, Isabel Neuringer, Manu Jain, Kathryn Moffett, Jennifer L. Taylor-Cousar, Bruce Barnett, Gary Mueller, Patrick Flume, Floyd Livingston, Nighat Mehdi, Charlotte Teneback, John Welter, Raksha Jain, Dana Kissner, Kapilkumar Patel, Francisco J. Calimano, Jimmy Johannes, Cori Daines, Thomas Keens, Herschel Scher, Subramanyam Chittivelu, Sudhakar Reddivalam, Ross Carl Klingsberg, Larry G. Johnson, Stijn Verhulst, Patricia Macedo, Damien Downey, Gary Connett, Edward Nash, Nicholas Withers, Timothy Lee, Marleen Bakker, Harry Heijerman, Francois Vermeulen, Christiane Knoop, Elke De Wachter, Renske van der Meer, Petrus Merkus, Christof Majoor, Pulmonology, AII - Inflammatory diseases, Clinical sciences, Physiotherapy, Human Physiology and Anatomy, and Pediatrics

Subjects
Male, Indoles, Pyrrolidines, Cystic Fibrosis, Pyridines, Clinical Trial, Phase III, Phases of clinical research, Cystic Fibrosis Transmembrane Conductance Regulator, 030204 cardiovascular system & hematology, Quinolones, Aminophenols, Cystic fibrosis, law.invention, Ivacaftor, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, 030212 general & internal medicine, Pyridines/administration & dosage, Non-U.S. Gov't, Chloride Channel Agonists, Sweat, Child, Chloride Channel Agonists/administration & dosage, Medicine(all), biology, Research Support, Non-U.S. Gov't, Lumacaftor, General Medicine, Indoles/administration & dosage, Clinical Trial, Cystic fibrosis transmembrane conductance regulator, Pyrrolidines/administration & dosage, Quinolones/administration & dosage, Randomized Controlled Trial, Combination, Drug Therapy, Combination, Female, medicine.drug, medicine.medical_specialty, Adolescent, Research Support, Article, Benzodioxoles/administration & dosage, Sweat/chemistry, N.I.H, 03 medical and health sciences, Phase III, Research Support, N.I.H., Extramural, Double-Blind Method, Drug Therapy, Internal medicine, Journal Article, medicine, Aminophenols/administration & dosage, Humans, Benzodioxoles, business.industry, Extramural, medicine.disease, Pyrazoles/administration & dosage, Clinical trial, Regimen, chemistry, biology.protein, Pyrazoles, Cystic Fibrosis Transmembrane Conductance Regulator/genetics, sense organs, Cystic Fibrosis/drug therapy, business
Abstract

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation.METHODS: This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV1) of 40-90%, inclusive. After a 4-week tezacaftor plus ivacaftor run-in period, participants were randomly assigned (1:1) to 4 weeks of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h versus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h alone. The primary outcome was the absolute change from baseline (measured at the end of the tezacaftor plus ivacaftor run-in) in ppFEV1 at week 4. Key secondary outcomes were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548.FINDINGS: Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus ivacaftor group and 52 in the tezacaftor plus ivacaftor group) and completed the 4-week treatment period. The elexacaftor plus tezacaftor plus ivacaftor group had improvements in the primary outcome of ppFEV1 (least squares mean [LSM] treatment difference of 10·0 percentage points [95% CI 7·4 to 12·6], pINTERPRETATION: Elexacaftor plus tezacaftor plus ivacaftor provided clinically robust benefit compared with tezacaftor plus ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation.FUNDING: Vertex Pharmaceuticals.

Published
2019

11. Azithromycin for Early Pseudomonas Infection in Cystic Fibrosis. The OPTIMIZE Randomized Trial

Author

Nicole Mayer-Hamblett, George Retsch-Bogart, Margaret Kloster, Frank Accurso, Margaret Rosenfeld, Gary Albers, Philip Black, Perry Brown, AnneMarie Cairns, Stephanie D. Davis, Gavin R. Graff, Gwendolyn S. Kerby, David Orenstein, Rachael Buckingham, Bonnie W. Ramsey, Frank J. Accurso, Michelle Howenstine, Susan Jacob, Richard Kronmal, Robert Kuhn, Karen McCoy, David Nichols, Scott Sagel, Lisa Saiman, John Sheridan, Benjamin Wilfond, Edith Zemanick, Irene Bondick, Lauren Braam, Margaret Brassil, Missy Cianciola, Sonya Heltshe, Miya Johnson, Jean Kirihara, Ada Kong, Shelly Ma, Sharon McNamara, Lindsey Mann, Kelly Moormann, Matthew Myers, Kathy Seidel, Michelle Skalland, Carmen Ufret-Vincenty, Jill VanDalfsen, Christopher H. Goss, David J. Horne, Erin K. Kross, Peter J. Leary, Kathleen J. Ramos, Patricia Roush, Jack C. Salerno, Gregory Omlor, Deborah Ouellette, Deanna Green, Kathy Hosler, Adrienne Savant, Zainub Ashrafi, Ariel Berlinski, Andrea Ross, Gregory Sawicki, Robert Fowler, Monica Ulles, Freda Branch, Kevin Kirchner, Kerry DiBenardo, Gwendolyn Kerby, Meg Anthony, Thomas Keens, Alejandra Franquez, Carmen Reyes, Ibrahim Abdulhamid, Catherine Van Wagnen, Elizabeth Hartigan, Carley Mihlo, Ronald Williams, Margaret Lessard, Laura Sass, Erin McAndrews, Jennifer Parrott, Julie Noe, Patricia Hastings, Theresa Kump, John Clancy, Stacey Niehaus, Juyan Zhou, Gary Mueller, Sandy Bartosik, Jason Fullmer, Colleen Millian, Arlene Stecenko, Joy Dangerfield, Gavin Graff, Diane Kitch, Carrie Milliard, Robert Zanni, Bridget Marra, Patsy Guittar, Melinda Smith, David Schaeffer, Elizabeth DeLuca, John Welter, Meighan Gallagher, Armando Ramirez, Alexandra Cornell, Erika Simeon, Dion Roberts, Katherine Nelson, James Chmiel, Cindy Schaefer, Lori Shively, James Wallace, Allisa Richter, Bonnie Ramsey, Jessica Pittman, Tina Hicks, Dixie Durham, Carlos Milla, Jacquelyn Zirbes, Christopher Fortner, Valoree Suttmore, Rose Thompson, Cori Daines, Monica Varela, Timothy Starner, Mary Teresi, Samya Nasr, Dawn Kruse, Heather Thomas, Lisa Houdesheldt, Carol Barlow, Rose Cunnion, Saumini Srinivasan, Catherine Horobetz, Fadi Asfour, Jessica Francis, Michael Rock, Linda Makholm, Marie Egan, and Catalina Guzman

Subjects
Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Time Factors, Adolescent, Cystic Fibrosis, medicine.drug_class, Antibiotics, Azithromycin, Critical Care and Intensive Care Medicine, medicine.disease_cause, Cystic fibrosis, law.invention, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, Recurrence, law, Pseudomonas infection, Internal medicine, Administration, Inhalation, medicine, Tobramycin, Humans, Pseudomonas Infections, 030212 general & internal medicine, Child, Original Research, Inhalation, Pseudomonas aeruginosa, business.industry, Infant, medicine.disease, Anti-Bacterial Agents, Treatment Outcome, 030228 respiratory system, Child, Preschool, Drug Therapy, Combination, Female, Erratum, business, medicine.drug
Abstract

Rationale: New isolation of Pseudomonas aeruginosa (Pa) is generally treated with inhaled antipseudomonal antibiotics such as tobramycin inhalation solution (TIS). A therapeutic approach that complements traditional antimicrobial therapy by reducing the risk of pulmonary exacerbation and inflammation may ultimately prolong the time to Pa recurrence. Objectives: To test the hypothesis that the addition of azithromycin to TIS in children with cystic fibrosis and early Pa decreases the risk of pulmonary exacerbation and prolongs the time to Pa recurrence. Methods: The OPTIMIZE (Optimizing Treatment for Early Pseudomonas aeruginosa Infection in Cystic Fibrosis) trial was a multicenter, double-blind, randomized, placebo-controlled, 18-month trial in children with CF, 6 months to 18 years of age, with early Pa. Azithromycin or placebo was given 3× weekly with standardized TIS. Measurements and Main Results: The primary endpoint was the time to pulmonary exacerbation requiring antibiotics and the secondary endpoint was the time to Pa recurrence, in addition to other clinical and safety outcomes. A total of 221 participants (111 placebo, 110 azithromycin) out of a planned 274 were enrolled. Enrollment was stopped early by the NHLBI because the trial had reached the prespecified interim boundary for efficacy. The risk of pulmonary exacerbation was reduced by 44% in the azithromycin group as compared with the placebo group (hazard ratio, 0.56; 95% confidence interval, 0.37–0.83; P = 0.004). Weight increased by 1.27 kg in the azithromycin group compared with the placebo group (95% confidence interval, 0.01–2.52; P = 0.046). No significant differences were seen in microbiological or other clinical or safety endpoints. Conclusions: Azithromycin was associated with a significant reduction in the risk of pulmonary exacerbation and a sustained improvement in weight, but had no impact on microbiological outcomes in children with early Pa. Clinical trial registered with clinicaltrials.gov (NCT02054156).

Published
2018

12. Outcome measures for pediatric laryngotracheal reconstruction: International consensus statement

Author

Karthik, Balakrishnan, Douglas R, Sidell, Nancy M, Bauman, Gaston F, Bellia-Munzon, R Paul, Boesch, Matthew, Bromwich, Shelagh A, Cofer, Cori, Daines, Alessandro, de Alarcon, Nöel, Garabedian, Catherine K, Hart, Jonathan B, Ida, Nicolas, Leboulanger, Peter B, Manning, Deepak K, Mehta, Philippe, Monnier, Charles M, Myer, Jeremy D, Prager, Diego, Preciado, Evan J, Propst, Reza, Rahbar, John, Russell, Michael J, Rutter, Briac, Thierry, Dana M, Thompson, Michele, Torre, Patricio, Varela, Shyan, Vijayasekaran, David R, White, Andre M, Wineland, Robert E, Wood, Christopher T, Wootten, Karen, Zur, and Robin T, Cotton

Subjects
Reoperation, Trachea, Laryngoplasty, Delphi Technique, Outcome Assessment, Health Care, Practice Guidelines as Topic, Humans, Larynx, Plastic Surgery Procedures, Child, Pediatrics, Otorhinolaryngologic Surgical Procedures
Abstract

Develop multidisciplinary and international consensus on patient, disease, procedural, and perioperative factors, as well as key outcome measures and complications, to be reported for pediatric airway reconstruction studies.Standard Delphi methods were applied. Participants proposed items in three categories: 1) patient/disease characteristics, 2) procedural/intraoperative/perioperative factors, and 3) outcome measures and complications. Both general and anatomic site-specific measures were elicited. Participants also suggested specific operations to be encompassed by this project. We then used iterative ranking and review to develop consensus lists via a priori Delphi consensus criteria.Thirty-three pediatric airway experts from eight countries in North and South America, Europe, and Australia participated, representing otolaryngology (including International Pediatric Otolaryngology Group members), pulmonology, general surgery, and cardiothoracic surgery. Consensus led to inclusion of 19 operations comprising open expansion, resection, and slide procedures of the larynx, trachea, and bronchi as well as three endoscopic procedures. Consensus was achieved on multiple patient/comorbidity (10), disease/stenosis (7), perioperative-/intraoperative-/procedure-related (16) factors. Consensus was reached on multiple outcome and complication measures, both general and site-specific (8 general, 13 supraglottic, 15 glottic, 17 subglottic, 8 cervical tracheal, 12 thoracic tracheal). The group was able to clarify how each outcome should be measured, with specific instruments defined where applicable.This consensus statement provides a framework to communicate results consistently and reproducibly, facilitating meta-analyses, quality improvement, transfer of information, and surgeon self-assessment. It also clarifies expert opinion on which patient, disease, procedural, and outcome measures may be important to consider in any pediatric airway reconstruction patient.5 Laryngoscope, 129:244-255, 2019.

Published
2018

13. Glutathione and arginine levels: Predictors for acetaminophen-associated asthma exacerbation?

Author

Claudia R. Morris, David T. Mauger, Jung H. Suh, Wanda Phipatanakul, William J. Sheehan, James N. Moy, Ian M. Paul, Stanley J. Szefler, Daniel J. Jackson, Anne M. Fitzpatrick, Deborah Gentile, Erica Butler, Jennifer Maiolo, Sara Misplay, David Skoner, Glennys Smith, Jacqueline Pongracic, Rachel Robison, Iliana Flexas, Rajesh Kumar, Melanie Makhija, Nashmia Qamar, Christine Szychlinski, Fernando Martinez, Wayne Morgan, Cori Daines, Michael Daines, Valerie Bloss, Mark Brown, Katherine Chee, Sarah David, Clara S. Ehrman, Dima Ezmigna, Jamie Goodwin, Roni Grad, Anunya Hiranratta, Silvia Lopez, Andrea Paco, Janette Priefert, Natalie S. Provencio, Elizabeth Ryan, Monica Varela, Monica Vasquez, Rosemary Weese, Jesus Wences, Mindy Benson, Claudia Morris, Jung Suh, Jyothi Marbin, Jason Decker, Keonna Harrison, Dayna Long, Kelley Meade, Robert Mok, Cindy Nelson-Purdy, Dennis Ren, Hollie Stessel, William Sheehan, Jonathan Gaffin, Sachin Baxi, Lisa Bartnikas, Alisha Bouzaher, Christopher Burke, Matthew Cavanaugh, Julia Chen, Elizabeth Cunningham, Amparito Cunningham, James Friedlander, Enal Hindi, David Kantor, Lianne Kopel, Perdita Permaul, Deviko Rao, Melinda Rossi, Doris Schierembergg, Lynda Schneider, Jennifer Troung, Dale Umetsu, Joseph Zhou, Elliot Israel, Stanley Szefler, Fernando Holguin, Shean Aujla, John Broyles, Hey Chong, Patricia Dubin, Jonathan Finder, Todd Green, Lori Holt, Adam Kufen, Geoffrey Kurland, Rose Lanzo, David Nash, Julianne Parente, Catherine Smith, Jonathan Spahr, Daniel Weiner, Anne Fitzpatrick, Timothy Beaty, Shanae Wakefield Brown, Alice Bruce, Jennifer Dodds, Shaneka Douglas, Karen Freedle, Dawn Simon, Denise Whitlock, Ronina Covar, Tod Olin, Melanie Gleason, Gayle Spears, D. Sundstrom, Michael White, Kathryn Blake, John Lima, Jenny Batalla, Michelle Littlefield, Burnese Rutledge, Deanna Seymour, Jason Lang, Shanae Brown, Omar OquendoFlores, David Mauger, Ian Paul, Sue Boehmer, Loretta Doty, Beth Gern, Aimee Merchlinski, Jonathan Nelson, James Schmidt, Lindsay Texter, Angela Updegrave, Jennifer Zeller, Ronald Zimmerman, James Chmiel, Ross Myers, Kristie Ross, Daniel Craven, Amy DiMarino, Meeghan Hart, Leigh Kerns, Laurie Logan, Laura Veri, James Moy, Christopher Codispoti, Jun Fu, Grace Li, Diana Munoz-Mendoza, Shannon Stevens, Benjamin Thompson, Samantha Zitzer, Michaal Cabana, Stephen Lazarus, Ngoc Ly, Shannon Thyne, Jessica Bowman, Vicky Bowyer, Judy Gonzales-Vargas, Michelle McKean, Nancy Tran, Harsha Vardhan Kumar, Hengameh Raissy, Christina Batson, Lea Davies, Franceska Kelly, Esmeralda Morales, Abby Redway, Mary Spicher, Robert Lemanske, Daniel Jackson, Christine Sorkness, Lauren Kaminski, Megan Knutson, Shelly Olson, Sheila Turcsanyi, Tanya Watson, Stephen Peters, Adam Gower, Cheryl Wilmoth, Leonard Bacharier, Avraham Beigelman, Wanda Caldwell, Courtney Dula, Alysa Ellis, Caroline Horner, Lila Kertz, Tina Norris, Katherine Rivera-Spoljaric, Oscar Rodriguez, and Robert Strunk

Subjects
Male, Ornithine, medicine.medical_specialty, Arginine, Immunology, MEDLINE, Gastroenterology, Article, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Text mining, Randomized controlled trial, law, 030225 pediatrics, Internal medicine, Immunology and Allergy, Medicine, Humans, 030212 general & internal medicine, Anti-Asthmatic Agents, Acetaminophen, Lung, Asthma exacerbations, business.industry, Infant, Glutathione, Analgesics, Non-Narcotic, Asthma, medicine.anatomical_structure, chemistry, Child, Preschool, Fluticasone, Female, business, Biomarkers, medicine.drug
Published
2017

14. Phenotypes of Recurrent Wheezing in Preschool Children: Identification by Latent Class Analysis and Utility in Prediction of Future Exacerbation

Author

Anne M. Fitzpatrick, Leonard B. Bacharier, Theresa W. Guilbert, Daniel J. Jackson, Stanley J. Szefler, Avraham Beigelman, Michael D. Cabana, Ronina Covar, Fernando Holguin, Robert F. Lemanske, Fernando D. Martinez, Wayne Morgan, Wanda Phipatanakul, Jacqueline A. Pongracic, Robert S. Zeiger, David T. Mauger, Sachin Baxi, Mindy Benson, Kathryn Blake, Susan Boehmer, Carey-Ann Burnham, Michael Cabana, Mario Castro, James Chmiel, Cori Daines, Michael Daines, Anne Fitzpatrick, Jonathan Gaffin, Deborah Ann Gentile, W. Adam Gower, Theresa Guilbert, Elliot Israel, Daniel Jackson, H. William Kelly, Harsha Vardhan Kumar, null Jason Lang, Stephen Lazarus, John Lima, Robert Lemanske, Ngoc Ly, Fernando Martinez, Jyothi Marbin, David Mauger, Kelley Meade, James Moy, Ross Myers, Tod Olin, Ian Paul, Stephen Peters, Jacqueline Pongracic, Hengameh Raissy, Rachel Robison, Kristie Ross, null Christine Sorkness, William Sheehan, Stanley Szefler, W. Gerald Teague, and Shannon Thyne

Subjects
Male, Pediatrics, medicine.medical_specialty, Treatment response, Exacerbation, medicine.drug_class, Article, Allergic sensitization, Adrenal Cortex Hormones, Wheeze, Hypersensitivity, medicine, Humans, Immunology and Allergy, Sensitization, Respiratory Sounds, Cross-Over Studies, business.industry, Infant, Latent class model, Clinical trial, Phenotype, medicine.anatomical_structure, Latent Class Analysis, Child, Preschool, Disease Progression, Corticosteroid, Female, medicine.symptom, business
Abstract

BACKGROUND: Recurrent preschool wheezing is a heterogeneous disorder with significant morbidity, yet little is known about phenotypic determinants and their impact on clinical outcomes. OBJECTIVE: Latent class analysis (LCA) was used to identify latent classes of recurrent preschool wheeze and their association with future exacerbations and inhaled corticosteroid (ICS) treatment response. METHODS: Data from five clinical trials of 1,708 children age 12–71 months with recurrent wheezing were merged. LCA was performed on 10 demographic, exposure and sensitization variables to determine the optimal number of latent classes. The primary outcome was the annualized rate of wheezing exacerbations requiring systemic corticosteroids during the study intervention period; the secondary outcome was the time to first exacerbation. Exploratory analyses examined the effect of daily ICS treatment on exacerbation outcomes. RESULTS: Four latent classes of recurrent wheezing were identified; these were not distinguished by current symptoms or historical exacerbations but differed with regard to allergen sensitization and/or exposures. Annualized exacerbation rates (mean ± SEM/year) were 0.65 ± 0.06 for class 1 (“minimal sensitization”), 0.93 ± 0.10 for class 2 (“sensitization with indoor pet exposure”), 0.60 ± 0.07 for class 3 (“sensitization with tobacco smoke exposure”), and 0.81 ± 0.10 for class 4 (“multiple sensitization and eczema”) (p < 0.001). In a research setting of high adherence, daily ICS treatment improved exacerbation rates in classes 2 and 4 but not the other groups. CONCLUSION: Sensitization and exposure assessments are useful in the prediction of future exacerbation and may identify children most likely to respond favorably to daily ICS treatment.

Published
2019

15. Contributors

Author

Robin Michael Abel, Steven H. Abman, Mutasim N. Abu-Hasan, Najma N. Ahmed, Daniel R. Ambruso, Raouf S. Amin, Robert J. Arceci, M. Innes Asher, Ian M. Balfour-Lynn, Peter J. Barnes, Robyn J. Barst, Leslie L. Barton, Pierre-Yves Berclaz, Thomas F. Boat, Itzhak Brook, James W. Brooks, Andrew Bush, Michael R. Bye, Emmanuel Canet, Todd C. Carpenter, Robert G. Castile, Anne B. Chang, Victor Chernick, Lyn S. Chitty, Allan L. Coates, Giuseppe N. Colasurdo, Misty Colvin, Dan M. Cooper, Jonathan Corren, Robin T. Cotton, James E. Crowe, Garry R. Cutting, Cori Daines, Jane C. Davies, Jonathan M. Davis, Pamela B. Davis, Robert Dinwiddie, Emily L. Dobyns, Michelle Duggan, Peter R. Durie, Anthony G. Durmowicz, Joanne Embree, Leland L. Fan, Philip M. Farrell, David Gozal, Cameron Grant, Anne Greenough, Jürg Hammer, Jonny Harcourt, Ulrich Heininger, Marianna M. Henry, Peter W. Heymann, Ellis K.L. Hon, Alan H. Jobe, Richard B. Johnston, Sebastian L. Johnston, Meyer Kattan, Brian P. Kavanagh, James S. Kemp, Carolyn M. Kercsmar, Leila Kheirandish, Jennifer Knight-Madden, Alan P. Knutsen, Thomas M. Krummel, Claire Langston, Ada S. Lee, Margaret W. Leigh, Ann Marie LeVine, Albert Martin Li, Gerald M. Loughlin, Anna M. Mandalakas, Paulo J.C. Marostica, Robert B. Mellins, Mark Montgomery, Samira Mubareka, Thomas M. Murphy, Joseph J. Nania, Christopher J.L. Newth, Andrew G. Nicholson, Terry L. Noah, Lawrence M. Nogee, Blakeslee E. Noyes, Andrew H. Numa, Hugh O'Brodovich, Christopher O'Callaghan, Øystein E. Olsen, Catherine M. Owens, Nikolaos G. Papadopoulos, Hans Pasterkamp, Thomas A.E. Platts-Mills, Arnold C.G. Platzker, Jean-Paul Praud, Stelios Psarras, Mobeen H. Rathore, Gregory J. Redding, Michael J. Rock, Erika Berman Rosenzweig, Michael J. Rutter, L. Barry Seltz, Amir H. Shahlaee, David Sigalet, Samatha Sonnappa, Chaim Springer, James M. Stark, Jeffrey R. Starke, Renato T. Stein, Kurt R. Stenmark, Janet Stocks, Dennis C. Stokes, James Temprano, Bradley T. Thach, Bruce C. Trapnell, Colin Wallis, Miles Weinberger, Susan E. Wert, John B. West, Jeffrey A. Whitsett, Robert W. Wilmott, Mary Ellen B. Wohl, Robert E. Wood, Peter F. Wright, and Pamela L. Zeitlin

Published
2006

18. Microbiology, safety, and pharmacokinetics of aztreonam lysinate for inhalation in patients with cystic fibrosisSome of the results of this study were previously reported at the North American Cystic Fibrosis Conference in October 2004.

Author

Ronald L. Gibson, George Z. Retsch‐Bogart, Christopher Oermann, Carlos Milla, Joseph Pilewski, Cori Daines, Richard Ahrens, Kevin Leon, Morty Cohen, Sharon McNamara, Tracy L. Callahan, Richard Markus, and Jane L. Burns

Published
2006
Full Text
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20. Randomized, Double-Blind, Placebo-Controlled, Dose-Escalating Study of Aerosolized Interferon Gamma-1b in Patients With Mild to Moderate Cystic Fibrosis Lung DiseaseOur results were presented in part at the American Thoracic Society 2003 Annual Meeting (Moss et al., Am J Respir Crit Care Med 2003;167:923).Conflict of interest statement: Karen Starko, M.D., is an employee of Intermune, Inc., which partly sponsored this study, provided study agents, and participated in data analysis.

Author

Richard B. Moss, Nicole Mayer-Hamblett, Jeffrey Wagener, Cori Daines, Kathryn Hale, Richard Ahrens, Ronald L. Gibson, Paula Anderson, George Retsch-Bogart, Samya Z. Nasr, Imre Noth, David Waltz, Pamela Zeitlin, Bonnie Ramsey, and Karen Starko

Published
2005
Full Text
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