Browsing by Author "Ross, Kristie"

Now showing 1 - 4 of 4
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    Geography, generalisability, and susceptibility in clinical trials
    (Elsevier, 2021) Clougherty, Jane E.; Kinnee, Ellen J.; Cardet, Juan Carlos; Mauger, David; Bacharier, Leonard; Beigelman, Avraham; Blake, Kathryn V.; Cabana, Michael D.; Castro, Mario; Chmiel, James F.; Covar, Ronina; Fitzpatrick, Anne; Gaffin, Jonathan M.; Gentile, Deborah; Israel, Elliot; Jackson, Daniel J.; Kraft, Monica; Krishnan, Jerry A.; Kumar, Harsha Vardhan; Lang, Jason E.; Lazarus, Stephen C.; Lemanske, Robert F.; Lima, John; Martinez, Fernando D.; Morgan, Wayne; Moy, James; Myers, Ross; Naureckas, Edward T.; Ortega, Victor E.; Peters, Stephen P.; Phipatanakul, Wanda; Pongracic, Jacqueline A; Ross, Kristie; Sheehan, William J.; Smith, Lewis J.; Solway, Julian; Sorkness, Christine A.; Wechsler, Michael E.; Wenzel, Sally; White, Steven R.; Holguin, Fernando; Pediatrics, School of Medicine
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    PrecISE: Precision Medicine in Severe Asthma: An adaptive platform trial with biomarker ascertainment
    (Elsevier, 2021) Israel, Elliot; Denlinger, Loren C.; Bacharier, Leonard B.; LaVange, Lisa M.; Moore, Wendy C.; Peters, Michael C.; Georas, Steve N.; Wright, Rosalind J.; Mauger, David T.; Noel, Patricia; Akuthota, Praveen; Bach, Julia; Bleecker, Eugene R.; Cardet, Juan Carlos; Carr, Tara F.; Castro, Mario; Cinelli, Angeles; Comhair, Suzy A.A.; Covar, Ronina A.; Alexander, Laura Crotty; DiMango, Emily A.; Erzurum, Serpil C.; Fahy, John V.; Fajt, Merritt L.; Gaston, Benjamin M.; Hoffman, Eric A.; Holguin, Fernando; Jackson, Daniel J.; Jain, Sonia; Jarjour, Nizar N.; Ji, Yuan; Kenyon, Nicholas J.; Kosorok, Michael R.; Kraft, Monica; Krishnan, Jerry A.; Kumar, Rajesh; Liu, Andrew H.; Liu, Mark C.; Ly, Ngoc P.; Marquis, M. Alison; Martinez, Fernando D.; Moy, James N.; O’Neal, Wanda K.; Ortega, Victor E.; Peden, David B.; Phipatanakul, Wanda; Ross, Kristie; Smith, Lewis J.; Szefler, Stanley J.; Teague, W. Gerald; Tulchinsky, Abigail F.; Vijayanand, Pandurangan; Wechsler, Michael E.; Wenzel, Sally E.; White, Steven R.; Zeki, Amir A.; Ivanova, Anastasia; Pediatrics, School of Medicine
    Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. A large proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.
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    The Precision Interventions for Severe and/or Exacerbation-Prone (PrecISE) Asthma Network: an overview of Network organization, procedures and interventions
    (Elsevier, 2022-02) Georas, Steve N.; Wright, Rosalind J.; Ivanova, Anastasia; Israel, Elliot; LaVange, Lisa M.; Akuthota, Praveen; Carr, Tara F.; Denlinger, Loren C.; Fajt, Merritt L.; Kumar, Rajesh; O’Neal, Wanda K.; Phipatanakul, Wanda; Szefler, Stanley J.; Aronica, Mark A.; Bacharier, Leonard B.; Burbank, Allison J.; Castro, Mario; Alexander, Laura Crotty; Bamdad, Julie; Cardet, Juan Carlos; Comhair, Suzy A. A.; Covar, Ronina A.; DiMango, Emily A.; Erwin, Kim; Erzurum, Serpil C.; Fahy, John V.; Gaffin, Jonathan M.; Gaston, Benjamin; Gerald, Lynn B.; Hoffman, Eric A.; Holguin, Fernando; Jackson, Daniel J.; James, John; Jarjour, Nizar N.; Kenyon, Nicholas J.; Khatri, Sumita; Kirwan, John P.; Kraft, Monica; Krishnan, Jerry A.; Liu, Andrew H.; Liu, Mark C.; Marquis, M. Alison; Martinez, Fernando; Mey, Jacob; Moore, Wendy C.; Moy, James N.; Ortega, Victor E.; Peden, David B.; Pennington, Emily; Peters, Michael C.; Ross, Kristie; Sanchez, Maria; Smith, Lewis J.; Sorkness, Ronald L.; Wechsler, Michael E.; Wenzel, Sally E.; White, Steven R.; Zein, Joe; Zeki, Amir A.; Noel, Patricia; Pediatrics, School of Medicine
    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. A current 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 U.S. The PrecISE Network was designed to conduct phase II/proof of concept clinical trials of precision interventions in the severe asthma population, 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 Network will evaluate up to six interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the 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 of severe asthma.
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    A Treatment to Eliminate SARS-CoV-2 Replication in Human Airway Epithelial Cells Is Safe for Inhalation as an Aerosol in Healthy Human Subjects
    (American Association for Respiratory Care (AARC), 2020-09-21) Davis, Michael D.; Clemente, Tatiana M.; Giddings, Olivia K.; Ross, Kristie; Cunningham, Rebekah S.; Smith, Laura; Simpson, Edward; Liu, Yunlong; Kloepfer, Kirsten; Ramsey, I. Scott; Zhao, Yi; Robinson, Christopher M.; Gilk, Stacey D.; Gaston, Benjamin; Pediatrics, School of Medicine
    Background: Low airway surface pH is associated with many airway diseases, impairs antimicrobial host defense and worsens airway inflammation. Inhaled Optate is designed to safely to raise airway surface pH and is well-tolerated in humans. Raising intracellular pH partially prevents activation of SARS-CoV-2 in primary normal human airway epithelial (NHAE) cells, decreasing viral replication by several mechanisms. Methods: Here, we grew primary normal human airway epithelial (NHAE) cells from healthy subjects, infected them with SARS-CoV-2 (isolate USA-WA1/2020), and used clinical Optate at concentrations used in humans in vivo to determine whether it would prevent viral infection and replication. Cells were pre-treated with Optate or placebo prior to infection (MOI of 0.1) and viral replication was determined by plaque assay and nucleocapsid (N) protein levels. Healthy human subjects also inhaled Optate as part of a Phase 2a safety trial. Results: Optate almost completely prevented viral replication at each time point between 24 and 120 hours, relative to placebo, both by plaque assay and by N protein expression (p < 0.001). Mechanistically, Optate inhibited expression of major endosomal trafficking genes and raised NHAE intracellular pH. Optate had no effect on NHAE cell viability at any time point. Inhaled Optate was well tolerated in 10 normal subjects, with no change in lung function, vital signs or oxygenation. Conclusions: Inhaled Optate may be well-suited for a clinical trial in patients with a pulmonary SARS-CoV-2 infection. However, it is vitally important for patient safety that formulations designed for inhalation with regards to pH, isotonicity and osmolality be used. An inhalational treatment that safely prevents SARS-CoV-2 viral replication could be helpful for treating patients with pulmonary SARS-CoV-2 infection.