Phase 2, randomised placebo-controlled trial to evaluate the efficacy and safety of an anti-GM-CSF antibody (KB003) in patients with inadequately controlled asthma

ObjectivesWe wished to evaluate the effects of an antigranulocyte-macrophage colony-stimulating factor monoclonal antibody (KB003) on forced expiratory volume in 1 s (FEV1), asthma control and asthma exacerbations in adult asthmatics inadequately controlled by long-acting bronchodilators and inhaled...

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Published in:BMJ open 2016-01, Vol.6 (1), p.e007709-e007709
Main Authors: Molfino, Nestor A, Kuna, Piotr, Leff, Jonathan A, Oh, Chad K, Singh, Dave, Chernow, Marlene, Sutton, Brian, Yarranton, Geoffrey
Format: Article
Language:English
Subjects:
Adrenal Cortex Hormones - therapeutic use
Adult
Airway management
Anti-Asthmatic Agents - adverse effects
Anti-Asthmatic Agents - pharmacology
Anti-Asthmatic Agents - therapeutic use
Antibodies, Monoclonal - therapeutic use
Asthma
Asthma - drug therapy
Asthma - immunology
Asthma - physiopathology
Bronchodilator Agents - therapeutic use
Cytokines
Drug dosages
Eosinophils - metabolism
Female
Forced Expiratory Volume
Genotype & phenotype
Granulocyte-Macrophage Colony-Stimulating Factor - metabolism
Humans
Infusions, Intravenous
Male
Middle Aged
Monoclonal antibodies
Neutrophils
Phenotype
Respiratory Medicine
School dropout programs
Spirometry
Steroids
Trends
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cited_by cdi_FETCH-LOGICAL-b472t-1e374b2ff555d38093f781284b7d66195496e8aea41cbfcd29c2fde89e90fef73
cites cdi_FETCH-LOGICAL-b472t-1e374b2ff555d38093f781284b7d66195496e8aea41cbfcd29c2fde89e90fef73
container_end_page e007709
container_issue 1
container_start_page e007709
container_title BMJ open
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creator Molfino, Nestor A
Kuna, Piotr
Leff, Jonathan A
Oh, Chad K
Singh, Dave
Chernow, Marlene
Sutton, Brian
Yarranton, Geoffrey
description ObjectivesWe wished to evaluate the effects of an antigranulocyte-macrophage colony-stimulating factor monoclonal antibody (KB003) on forced expiratory volume in 1 s (FEV1), asthma control and asthma exacerbations in adult asthmatics inadequately controlled by long-acting bronchodilators and inhaled/oral corticosteroids.Settings47 ambulatory asthma care centres globally.Primary outcome measuresChange in FEV1 at week 24.Participants311 were screened, 160 were randomised and 129 completed the study.Interventions7 intravenous infusions of either 400 mg KB003 or placebo at baseline and weeks 2, 4, 8, 12, 16 and 20.Primary and secondary outcome measuresFEV1 at week 24, asthma control, exacerbation rates and safety in all participants as well as prespecified subgroups.Main resultsIn the KB003 treated group, FEV1 at week 24 improved to 118 mL compared with 54 mL in the placebo group (p=0.224). However, FEV1 improved to 253 vs 26 mL at week 24 (p=0.02) in eosinophilic asthmatics (defined as >300 peripheral blood eosinophils/mL at baseline) and comparable improvements were seen at weeks 20 (p=0.034) and 24 (p=0.077) in patients with FEV1 reversibility ≥20% at baseline and at weeks 4 (p=0.029), 16 (p=0.018) and 20 (p=0.006) in patients with prebronchodilator FEV1 ≤50% predicted at baseline. There were no effects on asthma control or exacerbation rates. The most frequent adverse events in the KB003 group were rhinosinusitis and headache. There was no significant difference in antidrug antibody response between placebo and treated groups. There were no excess infections or changes in biomarkers known to be associated with the development of pulmonary alveolar proteinosis.ConclusionsHigher doses and/or further asthma phenotyping may be required in future studies with KB003.Trial registration numberNCT01603277; Results.
doi_str_mv 10.1136/bmjopen-2015-007709
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However, FEV1 improved to 253 vs 26 mL at week 24 (p=0.02) in eosinophilic asthmatics (defined as &gt;300 peripheral blood eosinophils/mL at baseline) and comparable improvements were seen at weeks 20 (p=0.034) and 24 (p=0.077) in patients with FEV1 reversibility ≥20% at baseline and at weeks 4 (p=0.029), 16 (p=0.018) and 20 (p=0.006) in patients with prebronchodilator FEV1 ≤50% predicted at baseline. There were no effects on asthma control or exacerbation rates. The most frequent adverse events in the KB003 group were rhinosinusitis and headache. There was no significant difference in antidrug antibody response between placebo and treated groups. There were no excess infections or changes in biomarkers known to be associated with the development of pulmonary alveolar proteinosis.ConclusionsHigher doses and/or further asthma phenotyping may be required in future studies with KB003.Trial registration numberNCT01603277; Results.</description><identifier>ISSN: 2044-6055</identifier><identifier>EISSN: 2044-6055</identifier><identifier>DOI: 10.1136/bmjopen-2015-007709</identifier><identifier>PMID: 26739717</identifier><language>eng</language><publisher>England: BMJ Publishing Group LTD</publisher><subject>Adrenal Cortex Hormones - therapeutic use ; Adult ; Airway management ; Anti-Asthmatic Agents - adverse effects ; Anti-Asthmatic Agents - pharmacology ; Anti-Asthmatic Agents - therapeutic use ; Antibodies, Monoclonal - therapeutic use ; Asthma ; Asthma - drug therapy ; Asthma - immunology ; Asthma - physiopathology ; Bronchodilator Agents - therapeutic use ; Cytokines ; Drug dosages ; Eosinophils - metabolism ; Female ; Forced Expiratory Volume ; Genotype &amp; phenotype ; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism ; Humans ; Infusions, Intravenous ; Male ; Middle Aged ; Monoclonal antibodies ; Neutrophils ; Phenotype ; Respiratory Medicine ; School dropout programs ; Spirometry ; Steroids ; Trends</subject><ispartof>BMJ open, 2016-01, Vol.6 (1), p.e007709-e007709</ispartof><rights>Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing</rights><rights>Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ 2016 This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b472t-1e374b2ff555d38093f781284b7d66195496e8aea41cbfcd29c2fde89e90fef73</citedby><cites>FETCH-LOGICAL-b472t-1e374b2ff555d38093f781284b7d66195496e8aea41cbfcd29c2fde89e90fef73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1860805692/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1860805692?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>112,113,230,315,733,786,790,891,3213,25783,27582,27583,27957,27958,37047,37048,44625,53827,53829,75483</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26739717$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Molfino, Nestor A</creatorcontrib><creatorcontrib>Kuna, Piotr</creatorcontrib><creatorcontrib>Leff, Jonathan A</creatorcontrib><creatorcontrib>Oh, Chad K</creatorcontrib><creatorcontrib>Singh, Dave</creatorcontrib><creatorcontrib>Chernow, Marlene</creatorcontrib><creatorcontrib>Sutton, Brian</creatorcontrib><creatorcontrib>Yarranton, Geoffrey</creatorcontrib><title>Phase 2, randomised placebo-controlled trial to evaluate the efficacy and safety of an anti-GM-CSF antibody (KB003) in patients with inadequately controlled asthma</title><title>BMJ open</title><addtitle>BMJ Open</addtitle><description>ObjectivesWe wished to evaluate the effects of an antigranulocyte-macrophage colony-stimulating factor monoclonal antibody (KB003) on forced expiratory volume in 1 s (FEV1), asthma control and asthma exacerbations in adult asthmatics inadequately controlled by long-acting bronchodilators and inhaled/oral corticosteroids.Settings47 ambulatory asthma care centres globally.Primary outcome measuresChange in FEV1 at week 24.Participants311 were screened, 160 were randomised and 129 completed the study.Interventions7 intravenous infusions of either 400 mg KB003 or placebo at baseline and weeks 2, 4, 8, 12, 16 and 20.Primary and secondary outcome measuresFEV1 at week 24, asthma control, exacerbation rates and safety in all participants as well as prespecified subgroups.Main resultsIn the KB003 treated group, FEV1 at week 24 improved to 118 mL compared with 54 mL in the placebo group (p=0.224). However, FEV1 improved to 253 vs 26 mL at week 24 (p=0.02) in eosinophilic asthmatics (defined as &gt;300 peripheral blood eosinophils/mL at baseline) and comparable improvements were seen at weeks 20 (p=0.034) and 24 (p=0.077) in patients with FEV1 reversibility ≥20% at baseline and at weeks 4 (p=0.029), 16 (p=0.018) and 20 (p=0.006) in patients with prebronchodilator FEV1 ≤50% predicted at baseline. There were no effects on asthma control or exacerbation rates. The most frequent adverse events in the KB003 group were rhinosinusitis and headache. There was no significant difference in antidrug antibody response between placebo and treated groups. 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phenotype</subject><subject>Granulocyte-Macrophage Colony-Stimulating Factor - metabolism</subject><subject>Humans</subject><subject>Infusions, Intravenous</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Monoclonal antibodies</subject><subject>Neutrophils</subject><subject>Phenotype</subject><subject>Respiratory Medicine</subject><subject>School dropout programs</subject><subject>Spirometry</subject><subject>Steroids</subject><subject>Trends</subject><issn>2044-6055</issn><issn>2044-6055</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>9YT</sourceid><sourceid>ACMMV</sourceid><sourceid>PIMPY</sourceid><recordid>eNqNUlFr1TAULqK4MfcLBAn4MmGdSZo0zYswL26KEwX1OaTpic2lbbomnfT37I-aeq_j6pMhkJOT7_tyTvJl2XOCLwgpytd1v_UjDDnFhOcYC4Hlo-yYYsbyEnP--CA-yk5D2OI0GJec06fZES1FIQURx9n9l1YHQPQcTXpofO8CNGjstIHa58YPcfJdl1JxcrpD0SO4092sI6DYAgJrndFmQYmLgrYQF-Rt2qUZXX79Kd98vfod175Z0NnHtxgXr5Ab0KijgyEG9NPFNiV0A7erbLegg1t1iG2vn2VPrO4CnO7Xk-z71btvm_f5zefrD5vLm7xmgsacQCFYTa3lnDdFhWVhRUVoxWrRlCWRnMkSKg2aEVNb01BpqG2gkiCxBSuKk-zNTnec6x4ak-qbdKfGyfV6WpTXTv19MrhW_fB3igmS9FeBs73A5G9nCFGl9zTQdXoAPwdFRIkrWbGSJujLf6BbP09Dak-RKqEwL-WKKnYoM_kQJrAPxRCsVh-ovQ_U6gO180FivTjs44Hz59cT4GIHSOz_UvwFsNnA1A</recordid><startdate>20160101</startdate><enddate>20160101</enddate><creator>Molfino, Nestor A</creator><creator>Kuna, Piotr</creator><creator>Leff, Jonathan A</creator><creator>Oh, Chad K</creator><creator>Singh, Dave</creator><creator>Chernow, Marlene</creator><creator>Sutton, Brian</creator><creator>Yarranton, Geoffrey</creator><general>BMJ Publishing Group LTD</general><general>BMJ Publishing Group</general><scope>9YT</scope><scope>ACMMV</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88G</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>BTHHO</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>K9-</scope><scope>K9.</scope><scope>KB0</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>NAPCQ</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PSYQQ</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20160101</creationdate><title>Phase 2, randomised placebo-controlled trial to evaluate the efficacy and safety of an anti-GM-CSF antibody (KB003) in patients with inadequately controlled asthma</title><author>Molfino, Nestor A ; Kuna, Piotr ; Leff, Jonathan A ; Oh, Chad K ; Singh, Dave ; Chernow, Marlene ; Sutton, Brian ; Yarranton, Geoffrey</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b472t-1e374b2ff555d38093f781284b7d66195496e8aea41cbfcd29c2fde89e90fef73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adrenal Cortex Hormones - therapeutic use</topic><topic>Adult</topic><topic>Airway management</topic><topic>Anti-Asthmatic Agents - adverse effects</topic><topic>Anti-Asthmatic Agents - pharmacology</topic><topic>Anti-Asthmatic Agents - therapeutic use</topic><topic>Antibodies, Monoclonal - therapeutic use</topic><topic>Asthma</topic><topic>Asthma - drug therapy</topic><topic>Asthma - immunology</topic><topic>Asthma - physiopathology</topic><topic>Bronchodilator Agents - therapeutic use</topic><topic>Cytokines</topic><topic>Drug dosages</topic><topic>Eosinophils - metabolism</topic><topic>Female</topic><topic>Forced Expiratory Volume</topic><topic>Genotype &amp; phenotype</topic><topic>Granulocyte-Macrophage Colony-Stimulating Factor - metabolism</topic><topic>Humans</topic><topic>Infusions, Intravenous</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Monoclonal antibodies</topic><topic>Neutrophils</topic><topic>Phenotype</topic><topic>Respiratory Medicine</topic><topic>School dropout programs</topic><topic>Spirometry</topic><topic>Steroids</topic><topic>Trends</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Molfino, Nestor A</creatorcontrib><creatorcontrib>Kuna, Piotr</creatorcontrib><creatorcontrib>Leff, Jonathan A</creatorcontrib><creatorcontrib>Oh, Chad K</creatorcontrib><creatorcontrib>Singh, Dave</creatorcontrib><creatorcontrib>Chernow, Marlene</creatorcontrib><creatorcontrib>Sutton, Brian</creatorcontrib><creatorcontrib>Yarranton, Geoffrey</creatorcontrib><collection>BMJ Journals (Open Access)</collection><collection>BMJ Journals:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Proquest Nursing &amp; 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Medical Complete (Alumni)</collection><collection>Nursing &amp; Allied Health Database (Alumni Edition)</collection><collection>ProQuest Consumer Health Database</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Psychology Database (ProQuest)</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest One Psychology</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>BMJ open</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Molfino, Nestor A</au><au>Kuna, Piotr</au><au>Leff, Jonathan A</au><au>Oh, Chad K</au><au>Singh, Dave</au><au>Chernow, Marlene</au><au>Sutton, Brian</au><au>Yarranton, Geoffrey</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Phase 2, randomised placebo-controlled trial to evaluate the efficacy and safety of an anti-GM-CSF antibody (KB003) in patients with inadequately controlled asthma</atitle><jtitle>BMJ open</jtitle><addtitle>BMJ Open</addtitle><date>2016-01-01</date><risdate>2016</risdate><volume>6</volume><issue>1</issue><spage>e007709</spage><epage>e007709</epage><pages>e007709-e007709</pages><issn>2044-6055</issn><eissn>2044-6055</eissn><notes>ObjectType-Article-2</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-1</notes><notes>ObjectType-News-3</notes><notes>content type line 23</notes><abstract>ObjectivesWe wished to evaluate the effects of an antigranulocyte-macrophage colony-stimulating factor monoclonal antibody (KB003) on forced expiratory volume in 1 s (FEV1), asthma control and asthma exacerbations in adult asthmatics inadequately controlled by long-acting bronchodilators and inhaled/oral corticosteroids.Settings47 ambulatory asthma care centres globally.Primary outcome measuresChange in FEV1 at week 24.Participants311 were screened, 160 were randomised and 129 completed the study.Interventions7 intravenous infusions of either 400 mg KB003 or placebo at baseline and weeks 2, 4, 8, 12, 16 and 20.Primary and secondary outcome measuresFEV1 at week 24, asthma control, exacerbation rates and safety in all participants as well as prespecified subgroups.Main resultsIn the KB003 treated group, FEV1 at week 24 improved to 118 mL compared with 54 mL in the placebo group (p=0.224). However, FEV1 improved to 253 vs 26 mL at week 24 (p=0.02) in eosinophilic asthmatics (defined as &gt;300 peripheral blood eosinophils/mL at baseline) and comparable improvements were seen at weeks 20 (p=0.034) and 24 (p=0.077) in patients with FEV1 reversibility ≥20% at baseline and at weeks 4 (p=0.029), 16 (p=0.018) and 20 (p=0.006) in patients with prebronchodilator FEV1 ≤50% predicted at baseline. There were no effects on asthma control or exacerbation rates. The most frequent adverse events in the KB003 group were rhinosinusitis and headache. There was no significant difference in antidrug antibody response between placebo and treated groups. There were no excess infections or changes in biomarkers known to be associated with the development of pulmonary alveolar proteinosis.ConclusionsHigher doses and/or further asthma phenotyping may be required in future studies with KB003.Trial registration numberNCT01603277; Results.</abstract><cop>England</cop><pub>BMJ Publishing Group LTD</pub><pmid>26739717</pmid><doi>10.1136/bmjopen-2015-007709</doi><oa>free_for_read</oa></addata></record>
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subjects Adrenal Cortex Hormones - therapeutic use
Adult
Airway management
Anti-Asthmatic Agents - adverse effects
Anti-Asthmatic Agents - pharmacology
Anti-Asthmatic Agents - therapeutic use
Antibodies, Monoclonal - therapeutic use
Asthma
Asthma - drug therapy
Asthma - immunology
Asthma - physiopathology
Bronchodilator Agents - therapeutic use
Cytokines
Drug dosages
Eosinophils - metabolism
Female
Forced Expiratory Volume
Genotype & phenotype
Granulocyte-Macrophage Colony-Stimulating Factor - metabolism
Humans
Infusions, Intravenous
Male
Middle Aged
Monoclonal antibodies
Neutrophils
Phenotype
Respiratory Medicine
School dropout programs
Spirometry
Steroids
Trends
title Phase 2, randomised placebo-controlled trial to evaluate the efficacy and safety of an anti-GM-CSF antibody (KB003) in patients with inadequately controlled asthma
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