PrecISE: Precision Medicine in Severe Asthma: An adaptive platform trial with biomarker ascertainment

Elliot Israel; Loren C. Denlinger; Leonard B. Bacharier; Lisa M. LaVange; Wendy C. Moore; Michael C. Peters; Steve N. Georas; Rosalind J. Wright; David T. Mauger; Patricia Noel; Praveen Akuthota; Julia Bach; Eugene R. Bleecker; Juan Carlos Cardet; Tara F. Carr; Mario Castro; Angeles Cinelli; Suzy A.A. Comhair; Ronina A. Covar; Laura Crotty Alexander; Emily A. DiMango; Serpil C. Erzurum; John V. Fahy; Merritt L. Fajt; Benjamin M. Gaston; Eric A. Hoffman; Fernando Holguin; Daniel J. Jackson; Sonia Jain; Nizar N. Jarjour; Yuan Ji; Nicholas J. Kenyon; Michael R. Kosorok; Monica Kraft; Jerry A. Krishnan; Rajesh Kumar; Andrew H. Liu; Mark C. Liu; Ngoc P. Ly; M. Alison Marquis; Fernando D. Martinez; James N. Moy; Wanda K. O'Neal; Victor E. Ortega; David B. Peden; Wanda Phipatanakul; Kristie Ross; Lewis J. Smith; Stanley J. Szefler; W. Gerald Teague; Abigail F. Tulchinsky; Pandurangan Vijayanand; Michael E. Wechsler; Sally E. Wenzel; Steven R. White; Amir A. Zeki; Anastasia Ivanova

doi:10.1016/j.jaci.2021.01.037

PrecISE: Precision Medicine in Severe Asthma: An adaptive platform trial with biomarker ascertainment

Elliot Israel, Loren C. Denlinger, Leonard B. Bacharier, Lisa M. LaVange, Wendy C. Moore, Michael C. Peters, Steve N. Georas, Rosalind J. Wright, David T. Mauger, Patricia Noel, Praveen Akuthota, Julia Bach, Eugene R. Bleecker, Juan Carlos Cardet, Tara F. Carr, Mario Castro, Angeles Cinelli, Suzy A.A. Comhair, Ronina A. Covar, Laura Crotty AlexanderEmily A. DiMango, Serpil C. Erzurum, John V. Fahy, Merritt L. Fajt, Benjamin M. Gaston, Eric A. Hoffman, Fernando Holguin, Daniel J. Jackson, Sonia Jain, Nizar N. Jarjour, Yuan Ji, Nicholas J. Kenyon, Michael R. Kosorok, Monica Kraft, Jerry A. Krishnan, Rajesh Kumar, Andrew H. Liu, Mark C. Liu, Ngoc P. Ly, M. Alison Marquis, Fernando D. Martinez, James N. Moy, Wanda K. O'Neal, Victor E. Ortega, David B. Peden, Wanda Phipatanakul, Kristie Ross, Lewis J. Smith, Stanley J. Szefler, W. Gerald Teague, Abigail F. Tulchinsky, Pandurangan Vijayanand, Michael E. Wechsler, Sally E. Wenzel, Steven R. White, Amir A. Zeki, Anastasia Ivanova

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	1594-1601
Number of pages	8
Journal	Journal of Allergy and Clinical Immunology
Volume	147
Issue number	5
DOIs	https://doi.org/10.1016/j.jaci.2021.01.037
State	Published - May 2021

Keywords

Severe asthma
adaptive design
biomarkers
clinical trial
master protocol
platform trial
precision medicine
therapy

ASJC Scopus subject areas

Immunology and Allergy
Immunology

Access to Document

10.1016/j.jaci.2021.01.037

Cite this

Israel, E., Denlinger, L. C., Bacharier, L. B., LaVange, L. M., Moore, W. C., Peters, M. C., Georas, S. N., Wright, R. J., Mauger, D. T., Noel, P., Akuthota, P., Bach, J., Bleecker, E. R., Cardet, J. C., Carr, T. F., Castro, M., Cinelli, A., Comhair, S. A. A., Covar, R. A., ... Ivanova, A. (2021). PrecISE: Precision Medicine in Severe Asthma: An adaptive platform trial with biomarker ascertainment. Journal of Allergy and Clinical Immunology, 147(5), 1594-1601. https://doi.org/10.1016/j.jaci.2021.01.037

Israel, E, Denlinger, LC, Bacharier, LB, LaVange, LM, Moore, WC, Peters, MC, Georas, SN, Wright, RJ, Mauger, DT, Noel, P, Akuthota, P, Bach, J, Bleecker, ER, Cardet, JC, Carr, TF, Castro, M, Cinelli, A, Comhair, SAA, Covar, RA, Alexander, LC, DiMango, EA, Erzurum, SC, Fahy, JV, Fajt, ML, Gaston, BM, Hoffman, EA, Holguin, F, Jackson, DJ, Jain, S, Jarjour, NN, Ji, Y, Kenyon, NJ, Kosorok, MR, Kraft, M, Krishnan, JA, Kumar, R, Liu, AH, Liu, MC, Ly, NP, Marquis, MA, Martinez, FD, Moy, JN, O'Neal, WK, Ortega, VE, Peden, DB, Phipatanakul, W, Ross, K, Smith, LJ, Szefler, SJ, Teague, WG, Tulchinsky, AF, Vijayanand, P, Wechsler, ME, Wenzel, SE, White, SR, Zeki, AA & Ivanova, A 2021, 'PrecISE: Precision Medicine in Severe Asthma: An adaptive platform trial with biomarker ascertainment', Journal of Allergy and Clinical Immunology, vol. 147, no. 5, pp. 1594-1601. https://doi.org/10.1016/j.jaci.2021.01.037

@article{c15d3147e4db4a1c9c42051ba3fd60f6,

title = "PrecISE: Precision Medicine in Severe Asthma: An adaptive platform trial with biomarker ascertainment",

abstract = "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.",

keywords = "Severe asthma, adaptive design, biomarkers, clinical trial, master protocol, platform trial, precision medicine, therapy",

author = "Elliot Israel and Denlinger, {Loren C.} and Bacharier, {Leonard B.} and LaVange, {Lisa M.} and Moore, {Wendy C.} and Peters, {Michael C.} and Georas, {Steve N.} and Wright, {Rosalind J.} and Mauger, {David T.} and Patricia Noel and Praveen Akuthota and Julia Bach and Bleecker, {Eugene R.} and Cardet, {Juan Carlos} and Carr, {Tara F.} and Mario Castro and Angeles Cinelli and Comhair, {Suzy A.A.} and Covar, {Ronina A.} and Alexander, {Laura Crotty} and DiMango, {Emily A.} and Erzurum, {Serpil C.} and Fahy, {John V.} and Fajt, {Merritt L.} and Gaston, {Benjamin M.} and Hoffman, {Eric A.} and Fernando Holguin and Jackson, {Daniel J.} and Sonia Jain and Jarjour, {Nizar N.} and Yuan Ji and Kenyon, {Nicholas J.} and Kosorok, {Michael R.} and Monica Kraft and Krishnan, {Jerry A.} and Rajesh Kumar and Liu, {Andrew H.} and Liu, {Mark C.} and Ly, {Ngoc P.} and Marquis, {M. Alison} and Martinez, {Fernando D.} and Moy, {James N.} and O'Neal, {Wanda K.} and Ortega, {Victor E.} and Peden, {David B.} and Wanda Phipatanakul and Kristie Ross and Smith, {Lewis J.} and Szefler, {Stanley J.} and Teague, {W. Gerald} and Tulchinsky, {Abigail F.} and Pandurangan Vijayanand and Wechsler, {Michael E.} and Wenzel, {Sally E.} and White, {Steven R.} and Zeki, {Amir A.} and Anastasia Ivanova",

note = "Funding Information: The PrecISE study is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health (grant nos. U24 HL138998, 1UG1HL139054, 1UG1HL139098, 1UG1HL139106, 1UG1HL139117, 1UG1HL139118, 1UG1HL139119, 1UG1HL139123, 1UG1HL139124, 1UG1HL139125, and 1UG1HL139126). Support for site institutional infrastructure came from National Institute of Health Clinical & Translational Science Award grants (grant no. UL1TR002451 [Harvard], grant no. UL1TR000427 [University of Wisconsin], grant no. UL1TR002366 [University of Kansas], grant no. UL1TR002389 [University of Chicago], grant no. UL1TR002489 [University of North Carolina], grant no. UL1TR001857 [University of Pittsburgh], grant no. UL1TR001442 [University of California, San Diego], and grant no. UL1TR001872 [University of California, San Francisco]). The single institutional review bolard is supported by the Duke/Vanderbilt Trial Innovation Center (grant no. 5U24TR001608). The following endowed chair positions contributed additional support: Gloria M. and Anthony C. Simboli Distinguished Chair in Asthma Research (E.I.) and William W. and Judith H. Busse Professor of Allergy & Asthma Research (L.C.D.). The study also gratefully acknowledges receiving contributed product from Vitaeris, owned and operated by the CSL group (clazakizumab), Vitaflo (M.C.T.), Sun Pharma (imatinib), OM Pharma, a Vifor Pharma Group Company (OM-85, Broncho-Vaxom), Incyte (itacitinib), Laurel Venture (cavosonstat), and GlaxoSmithKline (Advair Diskus and Ventolin). Disclosure of potential conflict of interest: E. Israel reports grants from Gossamer Bio; grants and nonfinancial support from Circassia; grants and personal fees from Amgen, AstraZeneca, Avillion, Merck, Novartis, and Sanofi Genzyme; grants, personal fees, and nonfinancial support from Genentech, GlaxoSmithKline (GSK), and Teva; personal fees from AB Science, Biometry, Equillium, 4D Pharma, Pneuma Respiratory, PPS Health, Regeneron, and Sienna Biopharmaceutical; and other considerations from Vorso Corp, outside the submitted work. L. C. Denlinger reports grants from the National Institutes of Health (NIH)-National Heart, Lung, and Blood Institute (NHLBI), during the conduct of the study; grants and personal fees from AstraZeneca, and personal fees from Sanofi-Regeneron, outside the submitted work. L. B. Bacharier reports grants from NIH/NHLBI, during the conduct of the study; personal fees from GSK, Genentech/Novartis, DBV Technologies, AstraZeneca, WebMD/Medscape, Sanofi/Regeneron, Vectura, and Circassia, and personal fees and nonfinancial support from Merck, Teva, and Boehringer Ingelheim, outside the submitted work. L. M. LaVange reports grants from the NHLBI, during the conduct of the study. W. C. Moore reports grants from the NHLBI during the conduct of the study; grants and personal fees from AstraZeneca, GSK, and Sanofi-Regeneron, and grants from Gossamer Bio, Inc, Cumberland Pharmaceuticals, and Genentech, outside the submitted work. M. C. Peters reports grants from AstraZeneca, Boehringer Ingelheim, Genentech, GSK, Sanofi-Genzyme-Regeneron, and Teva, and personal fees from OrbiMed, outside the submitted work. R. J. Wright reports grants from the NIH, during the conduct of the study. D. T. Mauger reports grants from the NHLBI, during the conduct of the study; and grants from GSK, Teva, AstraZeneca, Genentech, NHLBI, Boehringer Ingelheim, and Sanofi-Genzyme-Regeneron, outside the submitted work. P. Akuthota reports grants from the NIH, during the conduct of the study; personal fees from WebMD/Medscape, AHK, Prime CME, UpToDate, Rockpointe, Projects in Knowledge, MJH LifeSciences, and Vindico CME, and grants and personal fees from GSK and AstraZeneca, outside the submitted work. J. Bach reports grants from the NHLBI, during the conduct of the study. E. R. Bleecker reports personal fees and other considerations from AstraZeneca, MedImmune, Boehringer Ingelheim, Regeneron, and Sanofi Genzyme; other considerations from Genentech, Johnson and Johnson (Janssen), and Novartis; and personal fees from GSK, outside the submitted work. J. C. Cardet reports personal fees from AstraZeneca, and personal fees from Genentech, outside the submitted work. T. F. Carr reports grants from the NIH/NHLBI, during the conduct of the study; grants and personal fees from AstraZeneca and Novartis, and personal fees from GSK, Regeneron, and UpToDate, outside the submitted work. M. Castro reports grants from the NIH, ALA, PCORI, Pulmatrix, and Shionogi; grants and personal fees from AstraZeneca, Novartis, GSK, and Sanofi-Aventis; and personal fees from Teva, Genentech, and Regeneron, outside the submitted work. S. A. A. Comhair reports grants from the NHLBI, during the conduct of the study, and a patent, “Capric Acid and Myristic Acid Compositions for Treatment Conditions (publication no. 20200230094),” pending. R. A. Covar reports grants from the NHLBI, during the conduct of the study; and grants from GSK, Sanofi-Regeneron, Teva, and ALA ACRC, outside the submitted work. S. C. Erzurum reports grants from the NIH, during the conduct of the study. J. V. Fahy reports personal fees from Boehringer Ingelheim, Pieris, Arrowhead Pharmaceuticals, Gossamer, Ionis Pharmaceuticals, and Suzhou Connect Biopharmaceuticals, Ltd, outside the submitted work; and a patent WO2014153009A2, “Thiosaccharide mucolytic agents,” issued, and a patent WO2017197360, “CT Mucus Score - A new scoring system that quantifies airway mucus impaction using CT lung scans,” pending. M. L. Fajt reports personal fees from the American Academy of Allergy, Asthma & Immunology, and grants from Breathe PA Organization, outside the submitted work. B. M. Gaston reports grants from the NIH during the conduct of the study, and personal fees from Laurel and Respiratory Research, Inc, outside the submitted work. E. A. Hoffman is a founder and shareholder of VIDA Diagnostics, a company commercializing lung image analysis software developed, in part, at the University of Iowa. D. J. Jackson reports grants from the NIH-ECHO/CREW, the NHLBI, and the National Institute of Allergy and Infectious Diseases (NIAID), during the conduct of the study; personal fees from Sanofi-Regeneron, Pfizer, AstraZeneca, Novartis, and Vifor Pharma, and grants and personal fees from GSK, outside the submitted work. S. Jain reports grants from the NIH, during the conduct of the study. N. N. Jarjour reports grants from the NIH-NHLBI during the conduct of the study; grants and personal fees from AstraZeneca, and personal fees from GSK and Boehringer Ingelheim for consultations outside the submitted work. Y. Ji reports personal fees and other considerations from Bayesoft, other considerations from Laiya Consulting, and personal fees from Astella, outside the submitted work. M. Kraft reports grants from the NIH, Sanofi, the ALA, Chiesi, and AstraZeneca, and other considerations from Elsevier, Sanofi, and AstraZeneca, outside the submitted work. J. A. Krishnan reports grants from the NIH-NHLBI during the conduct of the study, and grants from PCORI, Regeneron, and Sergey Brin Family Foundation outside the submitted work. R. Kumar reports grants from the NHLBI, during the conduct of the study; and personal fees from Regeneron outside the submitted work. A. H. Liu reports grants from the NIH, during the conduct of the study; and other considerations from Propeller Health, outside the submitted work. M. C. Liu reports grants from the NIH, during the conduct of the study; personal fees from AstraZeneca, grants and personal fees from Gossamer Bio, and grants from GSK, Boehringer Ingelheim, Mereo BioPharma, and MedImmune, outside the submitted work. N. P. Ly reports grants from Vertex and Gilead, outside the submitted work. M. A. Marquis reports grants from the NHLBI, during the conduct of the study. F. D. Martinez reports grants from the NIH/NHLBI, the NIH/National Institute of Environmental Health Sciences, the NIH/NIAID, and the NIH/Office of Director, and personal fees from Copeval, outside the submitted work. W. K. O'Neal reports grants from the NHLBI, during the conduct of the study. V. E. Ortega reports personal fees from Regeneron and Sanofi, outside the submitted work. W. Phipatanakul reports grants from the NIH, and other considerations from CSL Behring, Vitaflo, AstraZeneca, Merck, GSK, Sun Pharma, Vifor, and Circassia, during the conduct of the study; grants, personal fees, and other considerations from Genentech/Novartis and Regeneron/Sanofi, and other considerations from Thermo Fisher, Lincoln Diagnostics, and Kaleo, outside the submitted work. K. Ross reports grants from the NIH, during the conduct of the study; grants and nonfinancial support from Teva, grants from AstraZeneca, Boehringer Ingelheim, and Novartis, and nonfinancial support from GlaxoSmithKline and Merck, outside the submitted work. L. J. Smith reports grants from the NHLBI, during the conduct of the study; and personal fees from GSK, outside the submitted work. S. J. Szefler reports grants from Propeller Health, and other considerations from Boehringer Ingelheim, GSK, AstraZeneca, Sanofi, and Regeneron, outside the submitted work. W. G. Teague reports grants from the NIH/NHLBI, during the conduct of the study; and grants from the NIH/NHLBI R21, outside the submitted work. M. E. Wechsler reports grants, personal fees, and nonfinancial support from Teva; grants and personal fees from Novartis, Sanofi, and GSK; personal fees from Regeneron, Mylan, Genentech, Sentien, Restorbio, Equillium, GALA Therapeutics, Pulmatrix, and Cohero Health; personal fees and nonfinancial support from Boehringer Ingelheim and AstraZeneca, and nonfinancial support from Merck, outside the submitted work. S. E. Wenzel reports grants from Boehringer Ingelheim and Teva; and grants and personal fees from AstraZeneca, GSK, Sanofi Genzyme, and Novartis, outside the submitted work. S. R. White reports grants from the NHLBI, during the conduct of the study; and personal fees from Regeneron, AstraZeneca, the CHEST Foundation, and Sanofi, outside the submitted work. A. A. Zeki reports other considerations from InStatin, Inc, outside the submitted work; and a patent PCT/US2020/025543 pending (no sponsor). A. Ivanova reports other considerations from CSL Behring, outside the submitted work. The rest of the authors declare that they have no relevant conflicts of interest. Funding Information: The PrecISE study is funded by the National Heart, Lung, and Blood Institute , National Institutes of Health (grant nos. U24 HL138998, 1UG1HL139054, 1UG1HL139098, 1UG1HL139106, 1UG1HL139117, 1UG1HL139118, 1UG1HL139119, 1UG1HL139123, 1UG1HL139124, 1UG1HL139125 , and 1UG1HL139126 ). Support for site institutional infrastructure came from National Institute of Health Clinical & Translational Science Award grants (grant no. UL1TR002451 [Harvard], grant no. UL1TR000427 [University of Wisconsin], grant no. UL1TR002366 [University of Kansas], grant no. UL1TR002389 [University of Chicago], grant no. UL1TR002489 [University of North Carolina], grant no. UL1TR001857 [University of Pittsburgh], grant no. UL1TR001442 [University of California, San Diego], and grant no. UL1TR001872 [University of California, San Francisco]). The single institutional review bolard is supported by the Duke/Vanderbilt Trial Innovation Center (grant no. 5U24TR001608 ). The following endowed chair positions contributed additional support: Gloria M. and Anthony C. Simboli Distinguished Chair in Asthma Research (E.I.) and William W. and Judith H. Busse Professor of Allergy & Asthma Research (L.C.D.). The study also gratefully acknowledges receiving contributed product from Vitaeris, owned and operated by the CSL group (clazakizumab), Vitaflo (M.C.T.), Sun Pharma (imatinib), OM Pharma, a Vifor Pharma Group Company (OM-85, Broncho-Vaxom), Incyte (itacitinib), Laurel Venture (cavosonstat), and GlaxoSmithKline (Advair Diskus and Ventolin). Publisher Copyright: {\textcopyright} 2021 American Academy of Allergy, Asthma & Immunology",

year = "2021",

month = may,

doi = "10.1016/j.jaci.2021.01.037",

language = "English (US)",

volume = "147",

pages = "1594--1601",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

number = "5",

}

TY - JOUR

T1 - PrecISE

T2 - Precision Medicine in Severe Asthma: An adaptive platform trial with biomarker ascertainment

AU - Israel, Elliot

AU - Denlinger, Loren C.

AU - Bacharier, Leonard B.

AU - LaVange, Lisa M.

AU - Moore, Wendy C.

AU - Peters, Michael C.

AU - Georas, Steve N.

AU - Wright, Rosalind J.

AU - Mauger, David T.

AU - Noel, Patricia

AU - Akuthota, Praveen

AU - Bach, Julia

AU - Bleecker, Eugene R.

AU - Cardet, Juan Carlos

AU - Carr, Tara F.

AU - Castro, Mario

AU - Cinelli, Angeles

AU - Comhair, Suzy A.A.

AU - Covar, Ronina A.

AU - Alexander, Laura Crotty

AU - DiMango, Emily A.

AU - Erzurum, Serpil C.

AU - Fahy, John V.

AU - Fajt, Merritt L.

AU - Gaston, Benjamin M.

AU - Hoffman, Eric A.

AU - Holguin, Fernando

AU - Jackson, Daniel J.

AU - Jain, Sonia

AU - Jarjour, Nizar N.

AU - Ji, Yuan

AU - Kenyon, Nicholas J.

AU - Kosorok, Michael R.

AU - Kraft, Monica

AU - Krishnan, Jerry A.

AU - Kumar, Rajesh

AU - Liu, Andrew H.

AU - Liu, Mark C.

AU - Ly, Ngoc P.

AU - Marquis, M. Alison

AU - Martinez, Fernando D.

AU - Moy, James N.

AU - O'Neal, Wanda K.

AU - Ortega, Victor E.

AU - Peden, David B.

AU - Phipatanakul, Wanda

AU - Ross, Kristie

AU - Smith, Lewis J.

AU - Szefler, Stanley J.

AU - Teague, W. Gerald

AU - Tulchinsky, Abigail F.

AU - Vijayanand, Pandurangan

AU - Wechsler, Michael E.

AU - Wenzel, Sally E.

AU - White, Steven R.

AU - Zeki, Amir A.

AU - Ivanova, Anastasia

N1 - Funding Information: The PrecISE study is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health (grant nos. U24 HL138998, 1UG1HL139054, 1UG1HL139098, 1UG1HL139106, 1UG1HL139117, 1UG1HL139118, 1UG1HL139119, 1UG1HL139123, 1UG1HL139124, 1UG1HL139125, and 1UG1HL139126). Support for site institutional infrastructure came from National Institute of Health Clinical & Translational Science Award grants (grant no. UL1TR002451 [Harvard], grant no. UL1TR000427 [University of Wisconsin], grant no. UL1TR002366 [University of Kansas], grant no. UL1TR002389 [University of Chicago], grant no. UL1TR002489 [University of North Carolina], grant no. UL1TR001857 [University of Pittsburgh], grant no. UL1TR001442 [University of California, San Diego], and grant no. UL1TR001872 [University of California, San Francisco]). The single institutional review bolard is supported by the Duke/Vanderbilt Trial Innovation Center (grant no. 5U24TR001608). The following endowed chair positions contributed additional support: Gloria M. and Anthony C. Simboli Distinguished Chair in Asthma Research (E.I.) and William W. and Judith H. Busse Professor of Allergy & Asthma Research (L.C.D.). The study also gratefully acknowledges receiving contributed product from Vitaeris, owned and operated by the CSL group (clazakizumab), Vitaflo (M.C.T.), Sun Pharma (imatinib), OM Pharma, a Vifor Pharma Group Company (OM-85, Broncho-Vaxom), Incyte (itacitinib), Laurel Venture (cavosonstat), and GlaxoSmithKline (Advair Diskus and Ventolin). Disclosure of potential conflict of interest: E. Israel reports grants from Gossamer Bio; grants and nonfinancial support from Circassia; grants and personal fees from Amgen, AstraZeneca, Avillion, Merck, Novartis, and Sanofi Genzyme; grants, personal fees, and nonfinancial support from Genentech, GlaxoSmithKline (GSK), and Teva; personal fees from AB Science, Biometry, Equillium, 4D Pharma, Pneuma Respiratory, PPS Health, Regeneron, and Sienna Biopharmaceutical; and other considerations from Vorso Corp, outside the submitted work. L. C. Denlinger reports grants from the National Institutes of Health (NIH)-National Heart, Lung, and Blood Institute (NHLBI), during the conduct of the study; grants and personal fees from AstraZeneca, and personal fees from Sanofi-Regeneron, outside the submitted work. L. B. Bacharier reports grants from NIH/NHLBI, during the conduct of the study; personal fees from GSK, Genentech/Novartis, DBV Technologies, AstraZeneca, WebMD/Medscape, Sanofi/Regeneron, Vectura, and Circassia, and personal fees and nonfinancial support from Merck, Teva, and Boehringer Ingelheim, outside the submitted work. L. M. LaVange reports grants from the NHLBI, during the conduct of the study. W. C. Moore reports grants from the NHLBI during the conduct of the study; grants and personal fees from AstraZeneca, GSK, and Sanofi-Regeneron, and grants from Gossamer Bio, Inc, Cumberland Pharmaceuticals, and Genentech, outside the submitted work. M. C. Peters reports grants from AstraZeneca, Boehringer Ingelheim, Genentech, GSK, Sanofi-Genzyme-Regeneron, and Teva, and personal fees from OrbiMed, outside the submitted work. R. J. Wright reports grants from the NIH, during the conduct of the study. D. T. Mauger reports grants from the NHLBI, during the conduct of the study; and grants from GSK, Teva, AstraZeneca, Genentech, NHLBI, Boehringer Ingelheim, and Sanofi-Genzyme-Regeneron, outside the submitted work. P. Akuthota reports grants from the NIH, during the conduct of the study; personal fees from WebMD/Medscape, AHK, Prime CME, UpToDate, Rockpointe, Projects in Knowledge, MJH LifeSciences, and Vindico CME, and grants and personal fees from GSK and AstraZeneca, outside the submitted work. J. Bach reports grants from the NHLBI, during the conduct of the study. E. R. Bleecker reports personal fees and other considerations from AstraZeneca, MedImmune, Boehringer Ingelheim, Regeneron, and Sanofi Genzyme; other considerations from Genentech, Johnson and Johnson (Janssen), and Novartis; and personal fees from GSK, outside the submitted work. J. C. Cardet reports personal fees from AstraZeneca, and personal fees from Genentech, outside the submitted work. T. F. Carr reports grants from the NIH/NHLBI, during the conduct of the study; grants and personal fees from AstraZeneca and Novartis, and personal fees from GSK, Regeneron, and UpToDate, outside the submitted work. M. Castro reports grants from the NIH, ALA, PCORI, Pulmatrix, and Shionogi; grants and personal fees from AstraZeneca, Novartis, GSK, and Sanofi-Aventis; and personal fees from Teva, Genentech, and Regeneron, outside the submitted work. S. A. A. Comhair reports grants from the NHLBI, during the conduct of the study, and a patent, “Capric Acid and Myristic Acid Compositions for Treatment Conditions (publication no. 20200230094),” pending. R. A. Covar reports grants from the NHLBI, during the conduct of the study; and grants from GSK, Sanofi-Regeneron, Teva, and ALA ACRC, outside the submitted work. S. C. Erzurum reports grants from the NIH, during the conduct of the study. J. V. Fahy reports personal fees from Boehringer Ingelheim, Pieris, Arrowhead Pharmaceuticals, Gossamer, Ionis Pharmaceuticals, and Suzhou Connect Biopharmaceuticals, Ltd, outside the submitted work; and a patent WO2014153009A2, “Thiosaccharide mucolytic agents,” issued, and a patent WO2017197360, “CT Mucus Score - A new scoring system that quantifies airway mucus impaction using CT lung scans,” pending. M. L. Fajt reports personal fees from the American Academy of Allergy, Asthma & Immunology, and grants from Breathe PA Organization, outside the submitted work. B. M. Gaston reports grants from the NIH during the conduct of the study, and personal fees from Laurel and Respiratory Research, Inc, outside the submitted work. E. A. Hoffman is a founder and shareholder of VIDA Diagnostics, a company commercializing lung image analysis software developed, in part, at the University of Iowa. D. J. Jackson reports grants from the NIH-ECHO/CREW, the NHLBI, and the National Institute of Allergy and Infectious Diseases (NIAID), during the conduct of the study; personal fees from Sanofi-Regeneron, Pfizer, AstraZeneca, Novartis, and Vifor Pharma, and grants and personal fees from GSK, outside the submitted work. S. Jain reports grants from the NIH, during the conduct of the study. N. N. Jarjour reports grants from the NIH-NHLBI during the conduct of the study; grants and personal fees from AstraZeneca, and personal fees from GSK and Boehringer Ingelheim for consultations outside the submitted work. Y. Ji reports personal fees and other considerations from Bayesoft, other considerations from Laiya Consulting, and personal fees from Astella, outside the submitted work. M. Kraft reports grants from the NIH, Sanofi, the ALA, Chiesi, and AstraZeneca, and other considerations from Elsevier, Sanofi, and AstraZeneca, outside the submitted work. J. A. Krishnan reports grants from the NIH-NHLBI during the conduct of the study, and grants from PCORI, Regeneron, and Sergey Brin Family Foundation outside the submitted work. R. Kumar reports grants from the NHLBI, during the conduct of the study; and personal fees from Regeneron outside the submitted work. A. H. Liu reports grants from the NIH, during the conduct of the study; and other considerations from Propeller Health, outside the submitted work. M. C. Liu reports grants from the NIH, during the conduct of the study; personal fees from AstraZeneca, grants and personal fees from Gossamer Bio, and grants from GSK, Boehringer Ingelheim, Mereo BioPharma, and MedImmune, outside the submitted work. N. P. Ly reports grants from Vertex and Gilead, outside the submitted work. M. A. Marquis reports grants from the NHLBI, during the conduct of the study. F. D. Martinez reports grants from the NIH/NHLBI, the NIH/National Institute of Environmental Health Sciences, the NIH/NIAID, and the NIH/Office of Director, and personal fees from Copeval, outside the submitted work. W. K. O'Neal reports grants from the NHLBI, during the conduct of the study. V. E. Ortega reports personal fees from Regeneron and Sanofi, outside the submitted work. W. Phipatanakul reports grants from the NIH, and other considerations from CSL Behring, Vitaflo, AstraZeneca, Merck, GSK, Sun Pharma, Vifor, and Circassia, during the conduct of the study; grants, personal fees, and other considerations from Genentech/Novartis and Regeneron/Sanofi, and other considerations from Thermo Fisher, Lincoln Diagnostics, and Kaleo, outside the submitted work. K. Ross reports grants from the NIH, during the conduct of the study; grants and nonfinancial support from Teva, grants from AstraZeneca, Boehringer Ingelheim, and Novartis, and nonfinancial support from GlaxoSmithKline and Merck, outside the submitted work. L. J. Smith reports grants from the NHLBI, during the conduct of the study; and personal fees from GSK, outside the submitted work. S. J. Szefler reports grants from Propeller Health, and other considerations from Boehringer Ingelheim, GSK, AstraZeneca, Sanofi, and Regeneron, outside the submitted work. W. G. Teague reports grants from the NIH/NHLBI, during the conduct of the study; and grants from the NIH/NHLBI R21, outside the submitted work. M. E. Wechsler reports grants, personal fees, and nonfinancial support from Teva; grants and personal fees from Novartis, Sanofi, and GSK; personal fees from Regeneron, Mylan, Genentech, Sentien, Restorbio, Equillium, GALA Therapeutics, Pulmatrix, and Cohero Health; personal fees and nonfinancial support from Boehringer Ingelheim and AstraZeneca, and nonfinancial support from Merck, outside the submitted work. S. E. Wenzel reports grants from Boehringer Ingelheim and Teva; and grants and personal fees from AstraZeneca, GSK, Sanofi Genzyme, and Novartis, outside the submitted work. S. R. White reports grants from the NHLBI, during the conduct of the study; and personal fees from Regeneron, AstraZeneca, the CHEST Foundation, and Sanofi, outside the submitted work. A. A. Zeki reports other considerations from InStatin, Inc, outside the submitted work; and a patent PCT/US2020/025543 pending (no sponsor). A. Ivanova reports other considerations from CSL Behring, outside the submitted work. The rest of the authors declare that they have no relevant conflicts of interest. Funding Information: The PrecISE study is funded by the National Heart, Lung, and Blood Institute , National Institutes of Health (grant nos. U24 HL138998, 1UG1HL139054, 1UG1HL139098, 1UG1HL139106, 1UG1HL139117, 1UG1HL139118, 1UG1HL139119, 1UG1HL139123, 1UG1HL139124, 1UG1HL139125 , and 1UG1HL139126 ). Support for site institutional infrastructure came from National Institute of Health Clinical & Translational Science Award grants (grant no. UL1TR002451 [Harvard], grant no. UL1TR000427 [University of Wisconsin], grant no. UL1TR002366 [University of Kansas], grant no. UL1TR002389 [University of Chicago], grant no. UL1TR002489 [University of North Carolina], grant no. UL1TR001857 [University of Pittsburgh], grant no. UL1TR001442 [University of California, San Diego], and grant no. UL1TR001872 [University of California, San Francisco]). The single institutional review bolard is supported by the Duke/Vanderbilt Trial Innovation Center (grant no. 5U24TR001608 ). The following endowed chair positions contributed additional support: Gloria M. and Anthony C. Simboli Distinguished Chair in Asthma Research (E.I.) and William W. and Judith H. Busse Professor of Allergy & Asthma Research (L.C.D.). The study also gratefully acknowledges receiving contributed product from Vitaeris, owned and operated by the CSL group (clazakizumab), Vitaflo (M.C.T.), Sun Pharma (imatinib), OM Pharma, a Vifor Pharma Group Company (OM-85, Broncho-Vaxom), Incyte (itacitinib), Laurel Venture (cavosonstat), and GlaxoSmithKline (Advair Diskus and Ventolin). Publisher Copyright: © 2021 American Academy of Allergy, Asthma & Immunology

PY - 2021/5

Y1 - 2021/5

N2 - 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.

AB - 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.

KW - Severe asthma

KW - adaptive design

KW - biomarkers

KW - clinical trial

KW - master protocol

KW - platform trial

KW - precision medicine

KW - therapy

UR - http://www.scopus.com/inward/record.url?scp=85106538421&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85106538421&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2021.01.037

DO - 10.1016/j.jaci.2021.01.037

M3 - Article

C2 - 33667479

AN - SCOPUS:85106538421

SN - 0091-6749

VL - 147

SP - 1594

EP - 1601

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 5

ER -

PrecISE: Precision Medicine in Severe Asthma: An adaptive platform trial with biomarker ascertainment

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this