A Novel Immune Modulator for Patients With Necrotizing Soft Tissue Infections (NSTI): Results of a Multicenter, Phase 3 Randomized Controlled Trial of Reltecimod (AB 103)
BACKGROUND AND OBJECTIVE:Reltecimod, a CD 28 T-lymphocyte receptor mimetic, inhibits T-cell stimulation by an array of bacterial pathogens. A previous phase 2 trial demonstrated improved resolution of organ dysfunction after NSTI. We hypothesized that early administration of reltecimod would improve...
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| Veröffentlicht in: | Annals of surgery 2020-09, Vol.272 (3), p.469-478 |
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| creator | Bulger, Eileen M. May, Addison K. Robinson, Bryce R. H. Evans, David C. Henry, Sharon Green, John M. Toschlog, Eric Sperry, Jason L. Fagenholz, Peter Martin, Niels D. Dankner, Wayne M. Maislin, Greg Wilfret, David Bernard, Andrew C. |
| description | BACKGROUND AND OBJECTIVE:Reltecimod, a CD 28 T-lymphocyte receptor mimetic, inhibits T-cell stimulation by an array of bacterial pathogens. A previous phase 2 trial demonstrated improved resolution of organ dysfunction after NSTI. We hypothesized that early administration of reltecimod would improve outcome in severe NSTI.
METHODS:Randomized, double-blind, placebo-controlled trial of single dose reltecimod (0.5 mg/kg) administered within 6 hours of NSTI diagnosis at 65 of 93 study sites. Inclusionsurgical confirmation of NSTI and organ dysfunction [modified Sequential Organ Failure Assessment Score (mSOFA) score ≥3]. Primary analysis was modified Intent-to-Treat (mITT), responder analysis using a previously validated composite endpoint, necrotizing infection clinical composite endpoint, defined asalive at day 28, ≤3 debridements, no amputation beyond first operation, and day 14 mSOFA ≤1 with ≥3 point reduction (organ dysfunction resolution). A prespecified, per protocol (PP) analysis excluded 17 patients with major protocol violations before unblinding.
RESULTS:Two hundred ninety patients were enrolled, mITT (Reltecimod 142, Placebo 148)mean age 55 ± 15 years, 60% male, 42.4% diabetic, 28.6% perineal infection, screening mSOFA mean 5.5 ± 2.4. Twenty-eight-day mortality was 15% in both groups. mITT necrotizing infection clinical composite endpoint success was 48.6% reltecimod versus 39.9% placebo, P = 0.135 and PP was 54.3% reltecimod versus 40.3% placebo, P = 0.021. Resolution of organ dysfunction was 65.1% reltecimod versus 52.6% placebo, P = 0.041, mITT and 70.9% versus 53.4%, P = 0.005, PP.
CONCLUSION:Early administration of reltecimod in severe NSTI resulted in a significant improvement in the primary composite endpoint in the PP population but not in the mITT population. Reltecimod was associated with improved resolution of organ dysfunction and hospital discharge status. |
| doi_str_mv | 10.1097/SLA.0000000000004102 |
| format | Article |
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METHODS:Randomized, double-blind, placebo-controlled trial of single dose reltecimod (0.5 mg/kg) administered within 6 hours of NSTI diagnosis at 65 of 93 study sites. Inclusionsurgical confirmation of NSTI and organ dysfunction [modified Sequential Organ Failure Assessment Score (mSOFA) score ≥3]. Primary analysis was modified Intent-to-Treat (mITT), responder analysis using a previously validated composite endpoint, necrotizing infection clinical composite endpoint, defined asalive at day 28, ≤3 debridements, no amputation beyond first operation, and day 14 mSOFA ≤1 with ≥3 point reduction (organ dysfunction resolution). A prespecified, per protocol (PP) analysis excluded 17 patients with major protocol violations before unblinding.
RESULTS:Two hundred ninety patients were enrolled, mITT (Reltecimod 142, Placebo 148)mean age 55 ± 15 years, 60% male, 42.4% diabetic, 28.6% perineal infection, screening mSOFA mean 5.5 ± 2.4. Twenty-eight-day mortality was 15% in both groups. mITT necrotizing infection clinical composite endpoint success was 48.6% reltecimod versus 39.9% placebo, P = 0.135 and PP was 54.3% reltecimod versus 40.3% placebo, P = 0.021. Resolution of organ dysfunction was 65.1% reltecimod versus 52.6% placebo, P = 0.041, mITT and 70.9% versus 53.4%, P = 0.005, PP.
CONCLUSION:Early administration of reltecimod in severe NSTI resulted in a significant improvement in the primary composite endpoint in the PP population but not in the mITT population. Reltecimod was associated with improved resolution of organ dysfunction and hospital discharge status.</description><identifier>ISSN: 0003-4932</identifier><identifier>EISSN: 1528-1140</identifier><identifier>DOI: 10.1097/SLA.0000000000004102</identifier><identifier>PMID: 32657946</identifier><language>eng</language><publisher>United States: Lippincott Williams & Wilkins</publisher><subject>CD28 Antigens - administration & dosage ; Debridement - methods ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Administration Schedule ; Fasciitis, Necrotizing - therapy ; Female ; Humans ; Immunologic Factors - administration & dosage ; Male ; Middle Aged ; Treatment Outcome</subject><ispartof>Annals of surgery, 2020-09, Vol.272 (3), p.469-478</ispartof><rights>Lippincott Williams & Wilkins</rights><rights>Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c3502-520e6dadbf5cbd162edbc2662925762f7c66938d9b07692dcb9016c715ff09c53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32657946$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bulger, Eileen M.</creatorcontrib><creatorcontrib>May, Addison K.</creatorcontrib><creatorcontrib>Robinson, Bryce R. H.</creatorcontrib><creatorcontrib>Evans, David C.</creatorcontrib><creatorcontrib>Henry, Sharon</creatorcontrib><creatorcontrib>Green, John M.</creatorcontrib><creatorcontrib>Toschlog, Eric</creatorcontrib><creatorcontrib>Sperry, Jason L.</creatorcontrib><creatorcontrib>Fagenholz, Peter</creatorcontrib><creatorcontrib>Martin, Niels D.</creatorcontrib><creatorcontrib>Dankner, Wayne M.</creatorcontrib><creatorcontrib>Maislin, Greg</creatorcontrib><creatorcontrib>Wilfret, David</creatorcontrib><creatorcontrib>Bernard, Andrew C.</creatorcontrib><creatorcontrib>ACCUTE Study Investigators</creatorcontrib><title>A Novel Immune Modulator for Patients With Necrotizing Soft Tissue Infections (NSTI): Results of a Multicenter, Phase 3 Randomized Controlled Trial of Reltecimod (AB 103)</title><title>Annals of surgery</title><addtitle>Ann Surg</addtitle><description>BACKGROUND AND OBJECTIVE:Reltecimod, a CD 28 T-lymphocyte receptor mimetic, inhibits T-cell stimulation by an array of bacterial pathogens. A previous phase 2 trial demonstrated improved resolution of organ dysfunction after NSTI. We hypothesized that early administration of reltecimod would improve outcome in severe NSTI.
METHODS:Randomized, double-blind, placebo-controlled trial of single dose reltecimod (0.5 mg/kg) administered within 6 hours of NSTI diagnosis at 65 of 93 study sites. Inclusionsurgical confirmation of NSTI and organ dysfunction [modified Sequential Organ Failure Assessment Score (mSOFA) score ≥3]. Primary analysis was modified Intent-to-Treat (mITT), responder analysis using a previously validated composite endpoint, necrotizing infection clinical composite endpoint, defined asalive at day 28, ≤3 debridements, no amputation beyond first operation, and day 14 mSOFA ≤1 with ≥3 point reduction (organ dysfunction resolution). A prespecified, per protocol (PP) analysis excluded 17 patients with major protocol violations before unblinding.
RESULTS:Two hundred ninety patients were enrolled, mITT (Reltecimod 142, Placebo 148)mean age 55 ± 15 years, 60% male, 42.4% diabetic, 28.6% perineal infection, screening mSOFA mean 5.5 ± 2.4. Twenty-eight-day mortality was 15% in both groups. mITT necrotizing infection clinical composite endpoint success was 48.6% reltecimod versus 39.9% placebo, P = 0.135 and PP was 54.3% reltecimod versus 40.3% placebo, P = 0.021. Resolution of organ dysfunction was 65.1% reltecimod versus 52.6% placebo, P = 0.041, mITT and 70.9% versus 53.4%, P = 0.005, PP.
CONCLUSION:Early administration of reltecimod in severe NSTI resulted in a significant improvement in the primary composite endpoint in the PP population but not in the mITT population. Reltecimod was associated with improved resolution of organ dysfunction and hospital discharge status.</description><subject>CD28 Antigens - administration & dosage</subject><subject>Debridement - methods</subject><subject>Dose-Response Relationship, Drug</subject><subject>Double-Blind Method</subject><subject>Drug Administration Schedule</subject><subject>Fasciitis, Necrotizing - therapy</subject><subject>Female</subject><subject>Humans</subject><subject>Immunologic Factors - administration & dosage</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Treatment Outcome</subject><issn>0003-4932</issn><issn>1528-1140</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkN9qFDEUxoModlt9A5FcttCpSWYmM_Fuu_hnYbuW3RUvh0xy4kYzk5JkLPaRfEpTV0W80MAh5xy-3wfnQ-gZJReUiObFdjW_IH-8ihL2AM1ozdqC0oo8RLO8LYtKlOwIHcf4iRBataR5jI5KxutGVHyGvs3x2n8Bh5fDMI2Ar7yenEw-YJPrWiYLY4r4g017vAYVfLJ3dvyIt94kvLMxToCXowGVrB8jPl1vd8uzl3gDcXKZ8wZLfJVbq7IPhHN8vZcRcIk3ctR-sHeg8cKPKXjncrsLVrp7agMugbKD1_h0fokpKc-eoEdGughPf_4n6P3rV7vF22L17s1yMV8VqqwJK2pGgGupe1OrXlPOQPeKcc4EqxvOTKM4F2WrRU8aLphWvSCUq4bWxhCh6vIEVQfffG2MAUx3E-wgw9eOku4--i5H3_0dfcaeH7CbqR9A_4Z-ZZ0F7UFw6_NtIX520y2Ebg_Spf3_vKt_oD90vG4LRhghIg9FLirK74EMn3M</recordid><startdate>20200901</startdate><enddate>20200901</enddate><creator>Bulger, Eileen M.</creator><creator>May, Addison K.</creator><creator>Robinson, Bryce R. H.</creator><creator>Evans, David C.</creator><creator>Henry, Sharon</creator><creator>Green, John M.</creator><creator>Toschlog, Eric</creator><creator>Sperry, Jason L.</creator><creator>Fagenholz, Peter</creator><creator>Martin, Niels D.</creator><creator>Dankner, Wayne M.</creator><creator>Maislin, Greg</creator><creator>Wilfret, David</creator><creator>Bernard, Andrew C.</creator><general>Lippincott Williams & Wilkins</general><general>Copyright Wolters Kluwer Health, Inc. All rights reserved</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></search><sort><creationdate>20200901</creationdate><title>A Novel Immune Modulator for Patients With Necrotizing Soft Tissue Infections (NSTI): Results of a Multicenter, Phase 3 Randomized Controlled Trial of Reltecimod (AB 103)</title><author>Bulger, Eileen M. ; May, Addison K. ; Robinson, Bryce R. H. ; Evans, David C. ; Henry, Sharon ; Green, John M. ; Toschlog, Eric ; Sperry, Jason L. ; Fagenholz, Peter ; Martin, Niels D. ; Dankner, Wayne M. ; Maislin, Greg ; Wilfret, David ; Bernard, Andrew C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3502-520e6dadbf5cbd162edbc2662925762f7c66938d9b07692dcb9016c715ff09c53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>CD28 Antigens - administration & dosage</topic><topic>Debridement - methods</topic><topic>Dose-Response Relationship, Drug</topic><topic>Double-Blind Method</topic><topic>Drug Administration Schedule</topic><topic>Fasciitis, Necrotizing - therapy</topic><topic>Female</topic><topic>Humans</topic><topic>Immunologic Factors - administration & dosage</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Treatment Outcome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bulger, Eileen M.</creatorcontrib><creatorcontrib>May, Addison K.</creatorcontrib><creatorcontrib>Robinson, Bryce R. H.</creatorcontrib><creatorcontrib>Evans, David C.</creatorcontrib><creatorcontrib>Henry, Sharon</creatorcontrib><creatorcontrib>Green, John M.</creatorcontrib><creatorcontrib>Toschlog, Eric</creatorcontrib><creatorcontrib>Sperry, Jason L.</creatorcontrib><creatorcontrib>Fagenholz, Peter</creatorcontrib><creatorcontrib>Martin, Niels D.</creatorcontrib><creatorcontrib>Dankner, Wayne M.</creatorcontrib><creatorcontrib>Maislin, Greg</creatorcontrib><creatorcontrib>Wilfret, David</creatorcontrib><creatorcontrib>Bernard, Andrew C.</creatorcontrib><creatorcontrib>ACCUTE Study Investigators</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Annals of surgery</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bulger, Eileen M.</au><au>May, Addison K.</au><au>Robinson, Bryce R. H.</au><au>Evans, David C.</au><au>Henry, Sharon</au><au>Green, John M.</au><au>Toschlog, Eric</au><au>Sperry, Jason L.</au><au>Fagenholz, Peter</au><au>Martin, Niels D.</au><au>Dankner, Wayne M.</au><au>Maislin, Greg</au><au>Wilfret, David</au><au>Bernard, Andrew C.</au><aucorp>ACCUTE Study Investigators</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Novel Immune Modulator for Patients With Necrotizing Soft Tissue Infections (NSTI): Results of a Multicenter, Phase 3 Randomized Controlled Trial of Reltecimod (AB 103)</atitle><jtitle>Annals of surgery</jtitle><addtitle>Ann Surg</addtitle><date>2020-09-01</date><risdate>2020</risdate><volume>272</volume><issue>3</issue><spage>469</spage><epage>478</epage><pages>469-478</pages><issn>0003-4932</issn><eissn>1528-1140</eissn><abstract>BACKGROUND AND OBJECTIVE:Reltecimod, a CD 28 T-lymphocyte receptor mimetic, inhibits T-cell stimulation by an array of bacterial pathogens. A previous phase 2 trial demonstrated improved resolution of organ dysfunction after NSTI. We hypothesized that early administration of reltecimod would improve outcome in severe NSTI.
METHODS:Randomized, double-blind, placebo-controlled trial of single dose reltecimod (0.5 mg/kg) administered within 6 hours of NSTI diagnosis at 65 of 93 study sites. Inclusionsurgical confirmation of NSTI and organ dysfunction [modified Sequential Organ Failure Assessment Score (mSOFA) score ≥3]. Primary analysis was modified Intent-to-Treat (mITT), responder analysis using a previously validated composite endpoint, necrotizing infection clinical composite endpoint, defined asalive at day 28, ≤3 debridements, no amputation beyond first operation, and day 14 mSOFA ≤1 with ≥3 point reduction (organ dysfunction resolution). A prespecified, per protocol (PP) analysis excluded 17 patients with major protocol violations before unblinding.
RESULTS:Two hundred ninety patients were enrolled, mITT (Reltecimod 142, Placebo 148)mean age 55 ± 15 years, 60% male, 42.4% diabetic, 28.6% perineal infection, screening mSOFA mean 5.5 ± 2.4. Twenty-eight-day mortality was 15% in both groups. mITT necrotizing infection clinical composite endpoint success was 48.6% reltecimod versus 39.9% placebo, P = 0.135 and PP was 54.3% reltecimod versus 40.3% placebo, P = 0.021. Resolution of organ dysfunction was 65.1% reltecimod versus 52.6% placebo, P = 0.041, mITT and 70.9% versus 53.4%, P = 0.005, PP.
CONCLUSION:Early administration of reltecimod in severe NSTI resulted in a significant improvement in the primary composite endpoint in the PP population but not in the mITT population. Reltecimod was associated with improved resolution of organ dysfunction and hospital discharge status.</abstract><cop>United States</cop><pub>Lippincott Williams & Wilkins</pub><pmid>32657946</pmid><doi>10.1097/SLA.0000000000004102</doi><tpages>10</tpages></addata></record> |
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| ispartof | Annals of surgery, 2020-09, Vol.272 (3), p.469-478 |
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| source | Journals@Ovid Ovid Autoload; MEDLINE; PubMed Central |
| subjects | CD28 Antigens - administration & dosage Debridement - methods Dose-Response Relationship, Drug Double-Blind Method Drug Administration Schedule Fasciitis, Necrotizing - therapy Female Humans Immunologic Factors - administration & dosage Male Middle Aged Treatment Outcome |
| title | A Novel Immune Modulator for Patients With Necrotizing Soft Tissue Infections (NSTI): Results of a Multicenter, Phase 3 Randomized Controlled Trial of Reltecimod (AB 103) |
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