Phase 1 Study of OPT-302 Inhibition of Vascular Endothelial Growth Factors C and D for Neovascular Age-Related Macular Degeneration

OPT-302 is a novel inhibitor of vascular endothelial growth factor (VEGF)-C and VEGF-D. A phase 1 trial assessed the safety of intravitreal OPT-302 as monotherapy or combined with ranibizumab (Lucentis; Genentech, South San Francisco, CA) in patients with neovascular age-related macular degeneration...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Ophthalmology retina 2020-03, Vol.4 (3), p.250-263
Hauptverfasser: Dugel, Pravin U., Boyer, David S., Antoszyk, Andrew N., Steinle, Nathan C., Varenhorst, Michael P., Pearlman, Joel A., Gillies, Mark C., Finger, Robert P., Baldwin, Megan E., Leitch, Ian M.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 263
container_issue 3
container_start_page 250
container_title Ophthalmology retina
container_volume 4
creator Dugel, Pravin U.
Boyer, David S.
Antoszyk, Andrew N.
Steinle, Nathan C.
Varenhorst, Michael P.
Pearlman, Joel A.
Gillies, Mark C.
Finger, Robert P.
Baldwin, Megan E.
Leitch, Ian M.
description OPT-302 is a novel inhibitor of vascular endothelial growth factor (VEGF)-C and VEGF-D. A phase 1 trial assessed the safety of intravitreal OPT-302 as monotherapy or combined with ranibizumab (Lucentis; Genentech, South San Francisco, CA) in patients with neovascular age-related macular degeneration (nAMD). Open-label, dose escalation followed by a randomized dose expansion. Fifty-one patients with nAMD who were either treatment naïve (n = 25) or previously were treated with anti-VEGF A therapy (n = 26). In the dose escalation, groups of 5 patients in 4 cohorts received ascending doses of OPT-302 (0.3 mg, 1 mg, or 2 mg) in combination with ranibizumab (0.5 mg), or as monotherapy (2 mg). In the dose expansion, 31 patients were randomized (3:1) to OPT-302 (2 mg) in combination with ranibizumab (n = 23) or as monotherapy (n = 8). Participants received three intravitreal treatments of OPT-302 once every 4 weeks either with or without ranibizumab. Safety and tolerability, OPT-302 pharmacokinetics and immunogenicity, effects on best-corrected visual acuity (BCVA), and anatomic changes. Intravitreal OPT-302 with or without ranibizumab was well tolerated with low systemic exposure, no dose-limiting toxicities and no immunogenicity. In patients receiving OPT-302 monotherapy, 7 of 13 (54%) did not require rescue anti-VEGF-A therapy and the mean change in BCVA from baseline to week 12 was +5.6 letters (range, 0–18 letters). Mean BCVA gains from baseline to week 12 following combination OPT-302 with ranibizumab were +10.8 letters (95% confidence interval [CI], 4–17; n = 18) in treatment-naïve patients and +4.9 letters (95% CI, 3–7; n = 19) in previously treated patients, respectively. Corresponding reductions in mean central subfield thickness at week 12 in both groups were –119 μm (95% CI, –176 to –62 μm) and –54 μm (95% CI, –82 to –26 μm), respectively, whilst 50% of treatment-naïve patients also showed no detectable choroidal neovascularization at week 12 on fluorescein angiography. Intravitreal OPT-302 inhibition of VEGF-C and -D was well tolerated, and OPT-302 combination therapy may overcome an escape mechanism to VEGF-A suppression in the management of nAMD.
doi_str_mv 10.1016/j.oret.2019.10.008
format Article
fullrecord <record><control><sourceid>elsevier_osti_</sourceid><recordid>TN_cdi_osti_scitechconnect_1694339</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S2468653019305986</els_id><sourcerecordid>S2468653019305986</sourcerecordid><originalsourceid>FETCH-LOGICAL-c427t-1db7f5e36be2c8ce8a6a6de1eabbea14cd6e86d6755d7eaf200c4fe863bfd9d43</originalsourceid><addsrcrecordid>eNp9kEtPwzAQhC0Eggr4AxyQxT3FdhwnkbhUbXlIvMTrGjn2pnGVxpXtFnHmj5MogDhx2tVoZlb7IXRCyZgSKs6XY-sgjBmheSeMCcl20IhxkUUiicnun_0AHXu_JITQjAmRkn10ENOc8YTzEfp8rKUHTPFz2OgPbCv88PgSxYThm7Y2pQnGtr36Jr3aNNLheattqKExssFXzr6HGl9KFazzeIplq_EMV9bhe7Dbn8hkAdETNDKAxndy0GawgBac7PuP0F4lGw_H3_MQvV7OX6bX0e3D1c10chspztIQUV2mVQKxKIGpTEEmhRQaKMiyBEm50gIyoUWaJDoFWTFCFK86KS4rnWseH6Kzodf6YAqvTABVK9u2oEJBRc7jOO9MbDApZ713UBVrZ1bSfRSUFD35Yln05IuefK915LvQ6RBab8oV6N_ID-fOcDEYoPtva8D156FVoI3rr2tr_uv_AoVSlZE</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Phase 1 Study of OPT-302 Inhibition of Vascular Endothelial Growth Factors C and D for Neovascular Age-Related Macular Degeneration</title><source>MEDLINE</source><source>Alma/SFX Local Collection</source><creator>Dugel, Pravin U. ; Boyer, David S. ; Antoszyk, Andrew N. ; Steinle, Nathan C. ; Varenhorst, Michael P. ; Pearlman, Joel A. ; Gillies, Mark C. ; Finger, Robert P. ; Baldwin, Megan E. ; Leitch, Ian M.</creator><creatorcontrib>Dugel, Pravin U. ; Boyer, David S. ; Antoszyk, Andrew N. ; Steinle, Nathan C. ; Varenhorst, Michael P. ; Pearlman, Joel A. ; Gillies, Mark C. ; Finger, Robert P. ; Baldwin, Megan E. ; Leitch, Ian M.</creatorcontrib><description>OPT-302 is a novel inhibitor of vascular endothelial growth factor (VEGF)-C and VEGF-D. A phase 1 trial assessed the safety of intravitreal OPT-302 as monotherapy or combined with ranibizumab (Lucentis; Genentech, South San Francisco, CA) in patients with neovascular age-related macular degeneration (nAMD). Open-label, dose escalation followed by a randomized dose expansion. Fifty-one patients with nAMD who were either treatment naïve (n = 25) or previously were treated with anti-VEGF A therapy (n = 26). In the dose escalation, groups of 5 patients in 4 cohorts received ascending doses of OPT-302 (0.3 mg, 1 mg, or 2 mg) in combination with ranibizumab (0.5 mg), or as monotherapy (2 mg). In the dose expansion, 31 patients were randomized (3:1) to OPT-302 (2 mg) in combination with ranibizumab (n = 23) or as monotherapy (n = 8). Participants received three intravitreal treatments of OPT-302 once every 4 weeks either with or without ranibizumab. Safety and tolerability, OPT-302 pharmacokinetics and immunogenicity, effects on best-corrected visual acuity (BCVA), and anatomic changes. Intravitreal OPT-302 with or without ranibizumab was well tolerated with low systemic exposure, no dose-limiting toxicities and no immunogenicity. In patients receiving OPT-302 monotherapy, 7 of 13 (54%) did not require rescue anti-VEGF-A therapy and the mean change in BCVA from baseline to week 12 was +5.6 letters (range, 0–18 letters). Mean BCVA gains from baseline to week 12 following combination OPT-302 with ranibizumab were +10.8 letters (95% confidence interval [CI], 4–17; n = 18) in treatment-naïve patients and +4.9 letters (95% CI, 3–7; n = 19) in previously treated patients, respectively. Corresponding reductions in mean central subfield thickness at week 12 in both groups were –119 μm (95% CI, –176 to –62 μm) and –54 μm (95% CI, –82 to –26 μm), respectively, whilst 50% of treatment-naïve patients also showed no detectable choroidal neovascularization at week 12 on fluorescein angiography. Intravitreal OPT-302 inhibition of VEGF-C and -D was well tolerated, and OPT-302 combination therapy may overcome an escape mechanism to VEGF-A suppression in the management of nAMD.</description><identifier>ISSN: 2468-6530</identifier><identifier>EISSN: 2468-6530</identifier><identifier>DOI: 10.1016/j.oret.2019.10.008</identifier><identifier>PMID: 31924544</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Aged ; Angiogenesis Inhibitors - administration &amp; dosage ; Female ; Fluorescein Angiography - methods ; Follow-Up Studies ; Fundus Oculi ; Humans ; Macula Lutea - pathology ; Male ; Prospective Studies ; Tomography, Optical Coherence - methods ; Vascular Endothelial Growth Factor C - antagonists &amp; inhibitors ; Vascular Endothelial Growth Factor D - antagonists &amp; inhibitors ; Visual Acuity ; Wet Macular Degeneration - diagnosis ; Wet Macular Degeneration - drug therapy ; Wet Macular Degeneration - metabolism</subject><ispartof>Ophthalmology retina, 2020-03, Vol.4 (3), p.250-263</ispartof><rights>2019 American Academy of Ophthalmology</rights><rights>Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c427t-1db7f5e36be2c8ce8a6a6de1eabbea14cd6e86d6755d7eaf200c4fe863bfd9d43</citedby><cites>FETCH-LOGICAL-c427t-1db7f5e36be2c8ce8a6a6de1eabbea14cd6e86d6755d7eaf200c4fe863bfd9d43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31924544$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/1694339$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Dugel, Pravin U.</creatorcontrib><creatorcontrib>Boyer, David S.</creatorcontrib><creatorcontrib>Antoszyk, Andrew N.</creatorcontrib><creatorcontrib>Steinle, Nathan C.</creatorcontrib><creatorcontrib>Varenhorst, Michael P.</creatorcontrib><creatorcontrib>Pearlman, Joel A.</creatorcontrib><creatorcontrib>Gillies, Mark C.</creatorcontrib><creatorcontrib>Finger, Robert P.</creatorcontrib><creatorcontrib>Baldwin, Megan E.</creatorcontrib><creatorcontrib>Leitch, Ian M.</creatorcontrib><title>Phase 1 Study of OPT-302 Inhibition of Vascular Endothelial Growth Factors C and D for Neovascular Age-Related Macular Degeneration</title><title>Ophthalmology retina</title><addtitle>Ophthalmol Retina</addtitle><description>OPT-302 is a novel inhibitor of vascular endothelial growth factor (VEGF)-C and VEGF-D. A phase 1 trial assessed the safety of intravitreal OPT-302 as monotherapy or combined with ranibizumab (Lucentis; Genentech, South San Francisco, CA) in patients with neovascular age-related macular degeneration (nAMD). Open-label, dose escalation followed by a randomized dose expansion. Fifty-one patients with nAMD who were either treatment naïve (n = 25) or previously were treated with anti-VEGF A therapy (n = 26). In the dose escalation, groups of 5 patients in 4 cohorts received ascending doses of OPT-302 (0.3 mg, 1 mg, or 2 mg) in combination with ranibizumab (0.5 mg), or as monotherapy (2 mg). In the dose expansion, 31 patients were randomized (3:1) to OPT-302 (2 mg) in combination with ranibizumab (n = 23) or as monotherapy (n = 8). Participants received three intravitreal treatments of OPT-302 once every 4 weeks either with or without ranibizumab. Safety and tolerability, OPT-302 pharmacokinetics and immunogenicity, effects on best-corrected visual acuity (BCVA), and anatomic changes. Intravitreal OPT-302 with or without ranibizumab was well tolerated with low systemic exposure, no dose-limiting toxicities and no immunogenicity. In patients receiving OPT-302 monotherapy, 7 of 13 (54%) did not require rescue anti-VEGF-A therapy and the mean change in BCVA from baseline to week 12 was +5.6 letters (range, 0–18 letters). Mean BCVA gains from baseline to week 12 following combination OPT-302 with ranibizumab were +10.8 letters (95% confidence interval [CI], 4–17; n = 18) in treatment-naïve patients and +4.9 letters (95% CI, 3–7; n = 19) in previously treated patients, respectively. Corresponding reductions in mean central subfield thickness at week 12 in both groups were –119 μm (95% CI, –176 to –62 μm) and –54 μm (95% CI, –82 to –26 μm), respectively, whilst 50% of treatment-naïve patients also showed no detectable choroidal neovascularization at week 12 on fluorescein angiography. Intravitreal OPT-302 inhibition of VEGF-C and -D was well tolerated, and OPT-302 combination therapy may overcome an escape mechanism to VEGF-A suppression in the management of nAMD.</description><subject>Aged</subject><subject>Angiogenesis Inhibitors - administration &amp; dosage</subject><subject>Female</subject><subject>Fluorescein Angiography - methods</subject><subject>Follow-Up Studies</subject><subject>Fundus Oculi</subject><subject>Humans</subject><subject>Macula Lutea - pathology</subject><subject>Male</subject><subject>Prospective Studies</subject><subject>Tomography, Optical Coherence - methods</subject><subject>Vascular Endothelial Growth Factor C - antagonists &amp; inhibitors</subject><subject>Vascular Endothelial Growth Factor D - antagonists &amp; inhibitors</subject><subject>Visual Acuity</subject><subject>Wet Macular Degeneration - diagnosis</subject><subject>Wet Macular Degeneration - drug therapy</subject><subject>Wet Macular Degeneration - metabolism</subject><issn>2468-6530</issn><issn>2468-6530</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtPwzAQhC0Eggr4AxyQxT3FdhwnkbhUbXlIvMTrGjn2pnGVxpXtFnHmj5MogDhx2tVoZlb7IXRCyZgSKs6XY-sgjBmheSeMCcl20IhxkUUiicnun_0AHXu_JITQjAmRkn10ENOc8YTzEfp8rKUHTPFz2OgPbCv88PgSxYThm7Y2pQnGtr36Jr3aNNLheattqKExssFXzr6HGl9KFazzeIplq_EMV9bhe7Dbn8hkAdETNDKAxndy0GawgBac7PuP0F4lGw_H3_MQvV7OX6bX0e3D1c10chspztIQUV2mVQKxKIGpTEEmhRQaKMiyBEm50gIyoUWaJDoFWTFCFK86KS4rnWseH6Kzodf6YAqvTABVK9u2oEJBRc7jOO9MbDApZ713UBVrZ1bSfRSUFD35Yln05IuefK915LvQ6RBab8oV6N_ID-fOcDEYoPtva8D156FVoI3rr2tr_uv_AoVSlZE</recordid><startdate>202003</startdate><enddate>202003</enddate><creator>Dugel, Pravin U.</creator><creator>Boyer, David S.</creator><creator>Antoszyk, Andrew N.</creator><creator>Steinle, Nathan C.</creator><creator>Varenhorst, Michael P.</creator><creator>Pearlman, Joel A.</creator><creator>Gillies, Mark C.</creator><creator>Finger, Robert P.</creator><creator>Baldwin, Megan E.</creator><creator>Leitch, Ian M.</creator><general>Elsevier Inc</general><general>Elsevier</general><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>OTOTI</scope></search><sort><creationdate>202003</creationdate><title>Phase 1 Study of OPT-302 Inhibition of Vascular Endothelial Growth Factors C and D for Neovascular Age-Related Macular Degeneration</title><author>Dugel, Pravin U. ; Boyer, David S. ; Antoszyk, Andrew N. ; Steinle, Nathan C. ; Varenhorst, Michael P. ; Pearlman, Joel A. ; Gillies, Mark C. ; Finger, Robert P. ; Baldwin, Megan E. ; Leitch, Ian M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c427t-1db7f5e36be2c8ce8a6a6de1eabbea14cd6e86d6755d7eaf200c4fe863bfd9d43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Aged</topic><topic>Angiogenesis Inhibitors - administration &amp; dosage</topic><topic>Female</topic><topic>Fluorescein Angiography - methods</topic><topic>Follow-Up Studies</topic><topic>Fundus Oculi</topic><topic>Humans</topic><topic>Macula Lutea - pathology</topic><topic>Male</topic><topic>Prospective Studies</topic><topic>Tomography, Optical Coherence - methods</topic><topic>Vascular Endothelial Growth Factor C - antagonists &amp; inhibitors</topic><topic>Vascular Endothelial Growth Factor D - antagonists &amp; inhibitors</topic><topic>Visual Acuity</topic><topic>Wet Macular Degeneration - diagnosis</topic><topic>Wet Macular Degeneration - drug therapy</topic><topic>Wet Macular Degeneration - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dugel, Pravin U.</creatorcontrib><creatorcontrib>Boyer, David S.</creatorcontrib><creatorcontrib>Antoszyk, Andrew N.</creatorcontrib><creatorcontrib>Steinle, Nathan C.</creatorcontrib><creatorcontrib>Varenhorst, Michael P.</creatorcontrib><creatorcontrib>Pearlman, Joel A.</creatorcontrib><creatorcontrib>Gillies, Mark C.</creatorcontrib><creatorcontrib>Finger, Robert P.</creatorcontrib><creatorcontrib>Baldwin, Megan E.</creatorcontrib><creatorcontrib>Leitch, Ian M.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>OSTI.GOV</collection><jtitle>Ophthalmology retina</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dugel, Pravin U.</au><au>Boyer, David S.</au><au>Antoszyk, Andrew N.</au><au>Steinle, Nathan C.</au><au>Varenhorst, Michael P.</au><au>Pearlman, Joel A.</au><au>Gillies, Mark C.</au><au>Finger, Robert P.</au><au>Baldwin, Megan E.</au><au>Leitch, Ian M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Phase 1 Study of OPT-302 Inhibition of Vascular Endothelial Growth Factors C and D for Neovascular Age-Related Macular Degeneration</atitle><jtitle>Ophthalmology retina</jtitle><addtitle>Ophthalmol Retina</addtitle><date>2020-03</date><risdate>2020</risdate><volume>4</volume><issue>3</issue><spage>250</spage><epage>263</epage><pages>250-263</pages><issn>2468-6530</issn><eissn>2468-6530</eissn><abstract>OPT-302 is a novel inhibitor of vascular endothelial growth factor (VEGF)-C and VEGF-D. A phase 1 trial assessed the safety of intravitreal OPT-302 as monotherapy or combined with ranibizumab (Lucentis; Genentech, South San Francisco, CA) in patients with neovascular age-related macular degeneration (nAMD). Open-label, dose escalation followed by a randomized dose expansion. Fifty-one patients with nAMD who were either treatment naïve (n = 25) or previously were treated with anti-VEGF A therapy (n = 26). In the dose escalation, groups of 5 patients in 4 cohorts received ascending doses of OPT-302 (0.3 mg, 1 mg, or 2 mg) in combination with ranibizumab (0.5 mg), or as monotherapy (2 mg). In the dose expansion, 31 patients were randomized (3:1) to OPT-302 (2 mg) in combination with ranibizumab (n = 23) or as monotherapy (n = 8). Participants received three intravitreal treatments of OPT-302 once every 4 weeks either with or without ranibizumab. Safety and tolerability, OPT-302 pharmacokinetics and immunogenicity, effects on best-corrected visual acuity (BCVA), and anatomic changes. Intravitreal OPT-302 with or without ranibizumab was well tolerated with low systemic exposure, no dose-limiting toxicities and no immunogenicity. In patients receiving OPT-302 monotherapy, 7 of 13 (54%) did not require rescue anti-VEGF-A therapy and the mean change in BCVA from baseline to week 12 was +5.6 letters (range, 0–18 letters). Mean BCVA gains from baseline to week 12 following combination OPT-302 with ranibizumab were +10.8 letters (95% confidence interval [CI], 4–17; n = 18) in treatment-naïve patients and +4.9 letters (95% CI, 3–7; n = 19) in previously treated patients, respectively. Corresponding reductions in mean central subfield thickness at week 12 in both groups were –119 μm (95% CI, –176 to –62 μm) and –54 μm (95% CI, –82 to –26 μm), respectively, whilst 50% of treatment-naïve patients also showed no detectable choroidal neovascularization at week 12 on fluorescein angiography. Intravitreal OPT-302 inhibition of VEGF-C and -D was well tolerated, and OPT-302 combination therapy may overcome an escape mechanism to VEGF-A suppression in the management of nAMD.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>31924544</pmid><doi>10.1016/j.oret.2019.10.008</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 2468-6530
ispartof Ophthalmology retina, 2020-03, Vol.4 (3), p.250-263
issn 2468-6530
2468-6530
language eng
recordid cdi_osti_scitechconnect_1694339
source MEDLINE; Alma/SFX Local Collection
subjects Aged
Angiogenesis Inhibitors - administration & dosage
Female
Fluorescein Angiography - methods
Follow-Up Studies
Fundus Oculi
Humans
Macula Lutea - pathology
Male
Prospective Studies
Tomography, Optical Coherence - methods
Vascular Endothelial Growth Factor C - antagonists & inhibitors
Vascular Endothelial Growth Factor D - antagonists & inhibitors
Visual Acuity
Wet Macular Degeneration - diagnosis
Wet Macular Degeneration - drug therapy
Wet Macular Degeneration - metabolism
title Phase 1 Study of OPT-302 Inhibition of Vascular Endothelial Growth Factors C and D for Neovascular Age-Related Macular Degeneration
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T17%3A34%3A53IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-elsevier_osti_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Phase%201%20Study%20of%20OPT-302%20Inhibition%20of%20Vascular%20Endothelial%20Growth%20Factors%20C%20and%20D%20for%20Neovascular%20Age-Related%20Macular%20Degeneration&rft.jtitle=Ophthalmology%20retina&rft.au=Dugel,%20Pravin%20U.&rft.date=2020-03&rft.volume=4&rft.issue=3&rft.spage=250&rft.epage=263&rft.pages=250-263&rft.issn=2468-6530&rft.eissn=2468-6530&rft_id=info:doi/10.1016/j.oret.2019.10.008&rft_dat=%3Celsevier_osti_%3ES2468653019305986%3C/elsevier_osti_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/31924544&rft_els_id=S2468653019305986&rfr_iscdi=true