Tralokinumab plus topical corticosteroids for the treatment of moderate‐to‐severe atopic dermatitis: results from the double‐blind, randomized, multicentre, placebo‐controlled phase III ECZTRA 3 trial
Summary Background Tralokinumab is a fully human monoclonal antibody that specifically neutralizes interleukin‐13, a key driver of atopic dermatitis (AD). Objectives To evaluate the efficacy and safety of tralokinumab in combination with topical corticosteroids (TCS) in patients with moderate‐to‐sev...
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Veröffentlicht in: | British journal of dermatology (1951) 2021-03, Vol.184 (3), p.450-463 |
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creator | Silverberg, J.I. Toth, D. Bieber, T. Alexis, A.F. Elewski, B.E. Pink, A.E. Hijnen, D. Jensen, T.N. Bang, B. Olsen, C.K. Kurbasic, A. Weidinger, S. |
description | Summary
Background
Tralokinumab is a fully human monoclonal antibody that specifically neutralizes interleukin‐13, a key driver of atopic dermatitis (AD).
Objectives
To evaluate the efficacy and safety of tralokinumab in combination with topical corticosteroids (TCS) in patients with moderate‐to‐severe AD who were candidates for systemic therapy.
Methods
This was a double‐blind, placebo plus TCS controlled phase III trial. Patients were randomized 2 : 1 to subcutaneous tralokinumab 300 mg or placebo every 2 weeks (Q2W) with TCS as needed over 16 weeks. Patients who achieved an Investigator’s Global Assessment (IGA) score of 0/1 and/or 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16 with tralokinumab were rerandomized 1 : 1 to tralokinumab Q2W or every 4 weeks (Q4W), with TCS as needed, for another 16 weeks.
Results
At week 16, more patients treated with tralokinumab than with placebo achieved IGA 0/1: 38·9% vs. 26·2% [difference (95% confidence interval): 12·4% (2·9–21·9); P = 0·015] and EASI 75: 56·0% vs. 35·7% [20·2% (9·8–30·6); P |
doi_str_mv | 10.1111/bjd.19573 |
format | Article |
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Background
Tralokinumab is a fully human monoclonal antibody that specifically neutralizes interleukin‐13, a key driver of atopic dermatitis (AD).
Objectives
To evaluate the efficacy and safety of tralokinumab in combination with topical corticosteroids (TCS) in patients with moderate‐to‐severe AD who were candidates for systemic therapy.
Methods
This was a double‐blind, placebo plus TCS controlled phase III trial. Patients were randomized 2 : 1 to subcutaneous tralokinumab 300 mg or placebo every 2 weeks (Q2W) with TCS as needed over 16 weeks. Patients who achieved an Investigator’s Global Assessment (IGA) score of 0/1 and/or 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16 with tralokinumab were rerandomized 1 : 1 to tralokinumab Q2W or every 4 weeks (Q4W), with TCS as needed, for another 16 weeks.
Results
At week 16, more patients treated with tralokinumab than with placebo achieved IGA 0/1: 38·9% vs. 26·2% [difference (95% confidence interval): 12·4% (2·9–21·9); P = 0·015] and EASI 75: 56·0% vs. 35·7% [20·2% (9·8–30·6); P < 0·001]. Of the patients who were tralokinumab responders at week 16, 89·6% and 92·5% of those treated with tralokinumab Q2W and 77·6% and 90·8% treated with tralokinumab Q4W maintained an IGA 0/1 and EASI 75 response at week 32, respectively. Among patients who did not achieve IGA 0/1 and EASI 75 with tralokinumab Q2W at 16 weeks, 30·5% and 55·8% achieved these endpoints, respectively, at week 32. The overall incidence of adverse events was similar across treatment groups.
Conclusions
Tralokinumab 300 mg in combination with TCS as needed was effective and well tolerated in patients with moderate‐to‐severe AD.
What is already known about this topic?
Atopic dermatitis (AD) is a chronic interleukin (IL)‐13‐mediated disease.
In clinical practice, biologics are commonly initiated as add‐on therapy to topical corticosteroids (TCS).
Tralokinumab is a fully human monoclonal antibody that binds specifically to the IL‐13 cytokine with high affinity, thereby preventing receptor interaction and subsequent downstream signalling.
Tralokinumab combined with TCS showed early and sustained efficacy and safety in a 12‐week, phase IIb trial in moderate‐to‐severe AD.
What does this study add?
This is the first phase III trial evaluating a targeted anti‐IL‐13 biologic in combination with TCS.
These data demonstrate that tralokinumab plus TCS can achieve significant improvements in AD signs and symptoms and quality of life, as well as exert a steroid‐sparing effect.
Response with tralokinumab in combination with TCS was maintained over 32 weeks.
Tralokinumab may be considered a targeted biological treatment option for patients with moderate‐to‐severe AD.
Linked Comment: Morra and Drucker. Br J Dermatol 2021; 184:386–387.
Plain language summary available online</description><identifier>ISSN: 0007-0963</identifier><identifier>EISSN: 1365-2133</identifier><identifier>DOI: 10.1111/bjd.19573</identifier><identifier>PMID: 33000503</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Adverse events ; Atopic dermatitis ; Clinical Trial ; Corticosteroids ; Dermatitis ; Double-blind studies ; Eczema ; Immunoglobulin A ; Monoclonal antibodies ; Original ; Placebos</subject><ispartof>British journal of dermatology (1951), 2021-03, Vol.184 (3), p.450-463</ispartof><rights>2020 The Authors. published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists</rights><rights>2020 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.</rights><rights>2020. This article is published under http://creativecommons.org/licenses/by-nc/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5093-4d71f9a0f401a8fde450721b6b80ea449601dd2a7b4c8c850a0a36910f535b0c3</citedby><cites>FETCH-LOGICAL-c5093-4d71f9a0f401a8fde450721b6b80ea449601dd2a7b4c8c850a0a36910f535b0c3</cites><orcidid>0000-0001-5151-5539 ; 0000-0003-3686-7805 ; 0000-0002-1475-2874 ; 0000-0003-3379-3425 ; 0000-0002-8800-3817 ; 0000-0003-1837-3393 ; 0000-0002-1910-2619 ; 0000-0003-3944-252X ; 0000-0002-6449-7066</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fbjd.19573$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fbjd.19573$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,1411,27903,27904,45553,45554</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33000503$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Silverberg, J.I.</creatorcontrib><creatorcontrib>Toth, D.</creatorcontrib><creatorcontrib>Bieber, T.</creatorcontrib><creatorcontrib>Alexis, A.F.</creatorcontrib><creatorcontrib>Elewski, B.E.</creatorcontrib><creatorcontrib>Pink, A.E.</creatorcontrib><creatorcontrib>Hijnen, D.</creatorcontrib><creatorcontrib>Jensen, T.N.</creatorcontrib><creatorcontrib>Bang, B.</creatorcontrib><creatorcontrib>Olsen, C.K.</creatorcontrib><creatorcontrib>Kurbasic, A.</creatorcontrib><creatorcontrib>Weidinger, S.</creatorcontrib><creatorcontrib>ECZTRA 3 study investigators</creatorcontrib><creatorcontrib>the ECZTRA 3 study investigators</creatorcontrib><title>Tralokinumab plus topical corticosteroids for the treatment of moderate‐to‐severe atopic dermatitis: results from the double‐blind, randomized, multicentre, placebo‐controlled phase III ECZTRA 3 trial</title><title>British journal of dermatology (1951)</title><addtitle>Br J Dermatol</addtitle><description>Summary
Background
Tralokinumab is a fully human monoclonal antibody that specifically neutralizes interleukin‐13, a key driver of atopic dermatitis (AD).
Objectives
To evaluate the efficacy and safety of tralokinumab in combination with topical corticosteroids (TCS) in patients with moderate‐to‐severe AD who were candidates for systemic therapy.
Methods
This was a double‐blind, placebo plus TCS controlled phase III trial. Patients were randomized 2 : 1 to subcutaneous tralokinumab 300 mg or placebo every 2 weeks (Q2W) with TCS as needed over 16 weeks. Patients who achieved an Investigator’s Global Assessment (IGA) score of 0/1 and/or 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16 with tralokinumab were rerandomized 1 : 1 to tralokinumab Q2W or every 4 weeks (Q4W), with TCS as needed, for another 16 weeks.
Results
At week 16, more patients treated with tralokinumab than with placebo achieved IGA 0/1: 38·9% vs. 26·2% [difference (95% confidence interval): 12·4% (2·9–21·9); P = 0·015] and EASI 75: 56·0% vs. 35·7% [20·2% (9·8–30·6); P < 0·001]. Of the patients who were tralokinumab responders at week 16, 89·6% and 92·5% of those treated with tralokinumab Q2W and 77·6% and 90·8% treated with tralokinumab Q4W maintained an IGA 0/1 and EASI 75 response at week 32, respectively. Among patients who did not achieve IGA 0/1 and EASI 75 with tralokinumab Q2W at 16 weeks, 30·5% and 55·8% achieved these endpoints, respectively, at week 32. The overall incidence of adverse events was similar across treatment groups.
Conclusions
Tralokinumab 300 mg in combination with TCS as needed was effective and well tolerated in patients with moderate‐to‐severe AD.
What is already known about this topic?
Atopic dermatitis (AD) is a chronic interleukin (IL)‐13‐mediated disease.
In clinical practice, biologics are commonly initiated as add‐on therapy to topical corticosteroids (TCS).
Tralokinumab is a fully human monoclonal antibody that binds specifically to the IL‐13 cytokine with high affinity, thereby preventing receptor interaction and subsequent downstream signalling.
Tralokinumab combined with TCS showed early and sustained efficacy and safety in a 12‐week, phase IIb trial in moderate‐to‐severe AD.
What does this study add?
This is the first phase III trial evaluating a targeted anti‐IL‐13 biologic in combination with TCS.
These data demonstrate that tralokinumab plus TCS can achieve significant improvements in AD signs and symptoms and quality of life, as well as exert a steroid‐sparing effect.
Response with tralokinumab in combination with TCS was maintained over 32 weeks.
Tralokinumab may be considered a targeted biological treatment option for patients with moderate‐to‐severe AD.
Linked Comment: Morra and Drucker. Br J Dermatol 2021; 184:386–387.
Plain language summary available online</description><subject>Adverse events</subject><subject>Atopic dermatitis</subject><subject>Clinical Trial</subject><subject>Corticosteroids</subject><subject>Dermatitis</subject><subject>Double-blind studies</subject><subject>Eczema</subject><subject>Immunoglobulin A</subject><subject>Monoclonal antibodies</subject><subject>Original</subject><subject>Placebos</subject><issn>0007-0963</issn><issn>1365-2133</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><recordid>eNp1ks9uEzEQh1cIREPhwAsgS1xAatpxvH97QCqhQFAlJBQuXKxZe5Y4eNfB9haVE4_Ao_EMPAlOUipAYg9ey_P588_yZNlDDsc8fSftWh_zpqjErWzCRVlMZ1yI29kEAKopNKU4yO6FsAbgAgq4mx0IkUoFiEn2Y-nRuk9mGHts2caOgUW3MQotU85Ho1yI5J3RgXXOs7giFj1h7GmIzHWsd5o8Rvr57Xt0aQh0SZ4Y7iQs1XqMJppwyjyF0cak8a7febQbW7vd2Foz6CPmcdCuN18pzfuEGpXO8HSUUqGidmtXLq04a0mzzQoDscViwc7nH5bvzphIwQza-9mdDm2gB9f_w-z9y_Pl_PX04u2rxfzsYqoKaMQ01xXvGoQuB451pykvoJrxtmxrIMzzpgSu9QyrNle1qgtAQFE2HLpCFC0ocZg923s3Y9uT3mVFKzfe9OivpEMj_64MZiU_uktZNXXJa5EET64F3n0eKUTZm6DIWhzIjUHO8ryq02NWW_TxP-jajX5I10tUU3Fe8B31dE8p70Lw1N2E4SC3fSJTn8hdnyT20Z_pb8jfjZGAkz3wxVi6-r9JPn_zYq_8BY9_0Bs</recordid><startdate>202103</startdate><enddate>202103</enddate><creator>Silverberg, J.I.</creator><creator>Toth, D.</creator><creator>Bieber, T.</creator><creator>Alexis, A.F.</creator><creator>Elewski, B.E.</creator><creator>Pink, A.E.</creator><creator>Hijnen, D.</creator><creator>Jensen, T.N.</creator><creator>Bang, B.</creator><creator>Olsen, C.K.</creator><creator>Kurbasic, A.</creator><creator>Weidinger, S.</creator><general>Oxford University Press</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-5151-5539</orcidid><orcidid>https://orcid.org/0000-0003-3686-7805</orcidid><orcidid>https://orcid.org/0000-0002-1475-2874</orcidid><orcidid>https://orcid.org/0000-0003-3379-3425</orcidid><orcidid>https://orcid.org/0000-0002-8800-3817</orcidid><orcidid>https://orcid.org/0000-0003-1837-3393</orcidid><orcidid>https://orcid.org/0000-0002-1910-2619</orcidid><orcidid>https://orcid.org/0000-0003-3944-252X</orcidid><orcidid>https://orcid.org/0000-0002-6449-7066</orcidid></search><sort><creationdate>202103</creationdate><title>Tralokinumab plus topical corticosteroids for the treatment of moderate‐to‐severe atopic dermatitis: results from the double‐blind, randomized, multicentre, placebo‐controlled phase III ECZTRA 3 trial</title><author>Silverberg, J.I. ; Toth, D. ; Bieber, T. ; Alexis, A.F. ; Elewski, B.E. ; Pink, A.E. ; Hijnen, D. ; Jensen, T.N. ; Bang, B. ; Olsen, C.K. ; Kurbasic, A. ; Weidinger, S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5093-4d71f9a0f401a8fde450721b6b80ea449601dd2a7b4c8c850a0a36910f535b0c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adverse events</topic><topic>Atopic dermatitis</topic><topic>Clinical Trial</topic><topic>Corticosteroids</topic><topic>Dermatitis</topic><topic>Double-blind studies</topic><topic>Eczema</topic><topic>Immunoglobulin A</topic><topic>Monoclonal antibodies</topic><topic>Original</topic><topic>Placebos</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Silverberg, J.I.</creatorcontrib><creatorcontrib>Toth, D.</creatorcontrib><creatorcontrib>Bieber, T.</creatorcontrib><creatorcontrib>Alexis, A.F.</creatorcontrib><creatorcontrib>Elewski, B.E.</creatorcontrib><creatorcontrib>Pink, A.E.</creatorcontrib><creatorcontrib>Hijnen, D.</creatorcontrib><creatorcontrib>Jensen, T.N.</creatorcontrib><creatorcontrib>Bang, B.</creatorcontrib><creatorcontrib>Olsen, C.K.</creatorcontrib><creatorcontrib>Kurbasic, A.</creatorcontrib><creatorcontrib>Weidinger, S.</creatorcontrib><creatorcontrib>ECZTRA 3 study investigators</creatorcontrib><creatorcontrib>the ECZTRA 3 study investigators</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Wiley Free Content</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of dermatology (1951)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Silverberg, J.I.</au><au>Toth, D.</au><au>Bieber, T.</au><au>Alexis, A.F.</au><au>Elewski, B.E.</au><au>Pink, A.E.</au><au>Hijnen, D.</au><au>Jensen, T.N.</au><au>Bang, B.</au><au>Olsen, C.K.</au><au>Kurbasic, A.</au><au>Weidinger, S.</au><aucorp>ECZTRA 3 study investigators</aucorp><aucorp>the ECZTRA 3 study investigators</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tralokinumab plus topical corticosteroids for the treatment of moderate‐to‐severe atopic dermatitis: results from the double‐blind, randomized, multicentre, placebo‐controlled phase III ECZTRA 3 trial</atitle><jtitle>British journal of dermatology (1951)</jtitle><addtitle>Br J Dermatol</addtitle><date>2021-03</date><risdate>2021</risdate><volume>184</volume><issue>3</issue><spage>450</spage><epage>463</epage><pages>450-463</pages><issn>0007-0963</issn><eissn>1365-2133</eissn><abstract>Summary
Background
Tralokinumab is a fully human monoclonal antibody that specifically neutralizes interleukin‐13, a key driver of atopic dermatitis (AD).
Objectives
To evaluate the efficacy and safety of tralokinumab in combination with topical corticosteroids (TCS) in patients with moderate‐to‐severe AD who were candidates for systemic therapy.
Methods
This was a double‐blind, placebo plus TCS controlled phase III trial. Patients were randomized 2 : 1 to subcutaneous tralokinumab 300 mg or placebo every 2 weeks (Q2W) with TCS as needed over 16 weeks. Patients who achieved an Investigator’s Global Assessment (IGA) score of 0/1 and/or 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16 with tralokinumab were rerandomized 1 : 1 to tralokinumab Q2W or every 4 weeks (Q4W), with TCS as needed, for another 16 weeks.
Results
At week 16, more patients treated with tralokinumab than with placebo achieved IGA 0/1: 38·9% vs. 26·2% [difference (95% confidence interval): 12·4% (2·9–21·9); P = 0·015] and EASI 75: 56·0% vs. 35·7% [20·2% (9·8–30·6); P < 0·001]. Of the patients who were tralokinumab responders at week 16, 89·6% and 92·5% of those treated with tralokinumab Q2W and 77·6% and 90·8% treated with tralokinumab Q4W maintained an IGA 0/1 and EASI 75 response at week 32, respectively. Among patients who did not achieve IGA 0/1 and EASI 75 with tralokinumab Q2W at 16 weeks, 30·5% and 55·8% achieved these endpoints, respectively, at week 32. The overall incidence of adverse events was similar across treatment groups.
Conclusions
Tralokinumab 300 mg in combination with TCS as needed was effective and well tolerated in patients with moderate‐to‐severe AD.
What is already known about this topic?
Atopic dermatitis (AD) is a chronic interleukin (IL)‐13‐mediated disease.
In clinical practice, biologics are commonly initiated as add‐on therapy to topical corticosteroids (TCS).
Tralokinumab is a fully human monoclonal antibody that binds specifically to the IL‐13 cytokine with high affinity, thereby preventing receptor interaction and subsequent downstream signalling.
Tralokinumab combined with TCS showed early and sustained efficacy and safety in a 12‐week, phase IIb trial in moderate‐to‐severe AD.
What does this study add?
This is the first phase III trial evaluating a targeted anti‐IL‐13 biologic in combination with TCS.
These data demonstrate that tralokinumab plus TCS can achieve significant improvements in AD signs and symptoms and quality of life, as well as exert a steroid‐sparing effect.
Response with tralokinumab in combination with TCS was maintained over 32 weeks.
Tralokinumab may be considered a targeted biological treatment option for patients with moderate‐to‐severe AD.
Linked Comment: Morra and Drucker. Br J Dermatol 2021; 184:386–387.
Plain language summary available online</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>33000503</pmid><doi>10.1111/bjd.19573</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0001-5151-5539</orcidid><orcidid>https://orcid.org/0000-0003-3686-7805</orcidid><orcidid>https://orcid.org/0000-0002-1475-2874</orcidid><orcidid>https://orcid.org/0000-0003-3379-3425</orcidid><orcidid>https://orcid.org/0000-0002-8800-3817</orcidid><orcidid>https://orcid.org/0000-0003-1837-3393</orcidid><orcidid>https://orcid.org/0000-0002-1910-2619</orcidid><orcidid>https://orcid.org/0000-0003-3944-252X</orcidid><orcidid>https://orcid.org/0000-0002-6449-7066</orcidid><oa>free_for_read</oa></addata></record> |
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ispartof | British journal of dermatology (1951), 2021-03, Vol.184 (3), p.450-463 |
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source | Wiley Online Library Journals Frontfile Complete; Oxford University Press Journals All Titles (1996-Current) |
subjects | Adverse events Atopic dermatitis Clinical Trial Corticosteroids Dermatitis Double-blind studies Eczema Immunoglobulin A Monoclonal antibodies Original Placebos |
title | Tralokinumab plus topical corticosteroids for the treatment of moderate‐to‐severe atopic dermatitis: results from the double‐blind, randomized, multicentre, placebo‐controlled phase III ECZTRA 3 trial |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-24T04%3A41%3A12IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Tralokinumab%20plus%20topical%20corticosteroids%20for%20the%20treatment%20of%20moderate%E2%80%90to%E2%80%90severe%20atopic%20dermatitis:%20results%20from%20the%20double%E2%80%90blind,%20randomized,%20multicentre,%20placebo%E2%80%90controlled%20phase%20III%20ECZTRA%203%20trial&rft.jtitle=British%20journal%20of%20dermatology%20(1951)&rft.au=Silverberg,%20J.I.&rft.aucorp=ECZTRA%203%20study%20investigators&rft.date=2021-03&rft.volume=184&rft.issue=3&rft.spage=450&rft.epage=463&rft.pages=450-463&rft.issn=0007-0963&rft.eissn=1365-2133&rft_id=info:doi/10.1111/bjd.19573&rft_dat=%3Cproquest_pubme%3E2447836573%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2497115173&rft_id=info:pmid/33000503&rfr_iscdi=true |