Randomized phase 2 trial of Intravenous Gamma Globulin (IVIG) for the treatment of acute vaso-occlusive crisis in patients with sickle cell disease: Lessons learned from the midpoint analysis
•We are evaluating a single 400 mg/kg dose of IVIG (Gamunex) in an ongoing phase II clinical study in SCD patients that are hospitalized for VOC. Here we report the results of a pre-specified, age stratified midpoint biomarker and safety analysis of this study, lessons learned and future plans.•A to...
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| Veröffentlicht in: | Complementary therapies in medicine 2020-08, Vol.52, p.102481-102481, Article 102481 |
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| creator | Manwani, Deepa Xu, Chunliang Lee, Sung Kyun Amatuni, George Cohen, Hillel W. Carullo, Veronica Morrone, Kerry Davila, Jennifer Shi, Patricia Ann Ireland, Karen Keenan, Janine Frenette, Paul S. |
| description | •We are evaluating a single 400 mg/kg dose of IVIG (Gamunex) in an ongoing phase II clinical study in SCD patients that are hospitalized for VOC. Here we report the results of a pre-specified, age stratified midpoint biomarker and safety analysis of this study, lessons learned and future plans.•A total of 37 acute pain crises were randomized at a ratio of 1 IVIG:1 equivalent-volume normal saline control at a dosing level of 400 mg/kg IVIG. A single dose was administered.•Baseline traits were not statistically different and the 2 groups were well matched.•The Gamunex was very well tolerated with no thrombosis, immune hemolysis or worsening renal function and no statistically significant differences for additional safety outcomes reported in either cohort.•Evaluation of neutrophil activation biomarkers showed significant improvement in the IVIG cohorts 24 h after IVIG administration, whereas in the placebo arm these values continued to increase as the VOC progressed – this includes percentage and absolute aged neutrophil counts as well as mean fluorescent intensity of activated Mac-1.•There was a non-significant trend towards a benefit for the intervention group in the |
| doi_str_mv | 10.1016/j.ctim.2020.102481 |
| format | Article |
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Sickle Cell Disease (SCD) is a chronic hemolytic disorder associated with frequent pain episodes, end organ damage and a shortened lifespan. Currently there exist no disease specific targeted therapies for the treatment of acute vaso-occlusive crisis (VOC) and management with analgesics and hydration is purely supportive. Improvement in understanding of disease pathophysiology has resulted in a great interest in disease modifying novel therapies and many are being evaluated in clinical trials. Here we report the results from the pre-specified mid-point analysis of the Phase 2 study of Intravenous Gamma Globulin (IVIG) for the treatment of acute VOC in patients with SCD and lessons learned.</description><identifier>ISSN: 0965-2299</identifier><identifier>EISSN: 1873-6963</identifier><identifier>DOI: 10.1016/j.ctim.2020.102481</identifier><identifier>PMID: 32951731</identifier><language>eng</language><publisher>Scotland: Elsevier Ltd</publisher><subject>Adolescent ; Adult ; Analgesics ; Anemia, Sickle Cell - complications ; Anemia, Sickle Cell - drug therapy ; Biomarkers ; Child ; Clinical outcomes ; Clinical trials ; Creatinine ; Double-Blind Method ; Drug dosages ; Female ; Flow cytometry ; Gamma globulin ; gamma-Globulins - therapeutic use ; Globulins ; Health services ; Humans ; Immune globulin ; Immunoglobulins ; Immunoglobulins, Intravenous - therapeutic use ; Immunologic Factors - therapeutic use ; Inflammation ; Intravenous administration ; IVIG ; Life span ; Male ; Medical treatment ; Narcotics ; Neutrophils ; Pain ; Pain Management - methods ; Patients ; Pharmacy ; Sickle ; Sickle cell disease ; Software ; Substance abuse treatment ; Thrombosis ; VOCs ; Volatile organic compounds ; Young Adult</subject><ispartof>Complementary therapies in medicine, 2020-08, Vol.52, p.102481-102481, Article 102481</ispartof><rights>2020 Elsevier Ltd</rights><rights>Copyright © 2020 Elsevier Ltd. All rights reserved.</rights><rights>2020. Elsevier Ltd</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c384t-3bdcf2b952907f710adedaf081dc3313f2b9f26fb026bf02ca7de4ff450d4ce73</citedby><cites>FETCH-LOGICAL-c384t-3bdcf2b952907f710adedaf081dc3313f2b9f26fb026bf02ca7de4ff450d4ce73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0965229919320606$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32951731$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Manwani, Deepa</creatorcontrib><creatorcontrib>Xu, Chunliang</creatorcontrib><creatorcontrib>Lee, Sung Kyun</creatorcontrib><creatorcontrib>Amatuni, George</creatorcontrib><creatorcontrib>Cohen, Hillel W.</creatorcontrib><creatorcontrib>Carullo, Veronica</creatorcontrib><creatorcontrib>Morrone, Kerry</creatorcontrib><creatorcontrib>Davila, Jennifer</creatorcontrib><creatorcontrib>Shi, Patricia Ann</creatorcontrib><creatorcontrib>Ireland, Karen</creatorcontrib><creatorcontrib>Keenan, Janine</creatorcontrib><creatorcontrib>Frenette, Paul S.</creatorcontrib><title>Randomized phase 2 trial of Intravenous Gamma Globulin (IVIG) for the treatment of acute vaso-occlusive crisis in patients with sickle cell disease: Lessons learned from the midpoint analysis</title><title>Complementary therapies in medicine</title><addtitle>Complement Ther Med</addtitle><description>•We are evaluating a single 400 mg/kg dose of IVIG (Gamunex) in an ongoing phase II clinical study in SCD patients that are hospitalized for VOC. Here we report the results of a pre-specified, age stratified midpoint biomarker and safety analysis of this study, lessons learned and future plans.•A total of 37 acute pain crises were randomized at a ratio of 1 IVIG:1 equivalent-volume normal saline control at a dosing level of 400 mg/kg IVIG. A single dose was administered.•Baseline traits were not statistically different and the 2 groups were well matched.•The Gamunex was very well tolerated with no thrombosis, immune hemolysis or worsening renal function and no statistically significant differences for additional safety outcomes reported in either cohort.•Evaluation of neutrophil activation biomarkers showed significant improvement in the IVIG cohorts 24 h after IVIG administration, whereas in the placebo arm these values continued to increase as the VOC progressed – this includes percentage and absolute aged neutrophil counts as well as mean fluorescent intensity of activated Mac-1.•There was a non-significant trend towards a benefit for the intervention group in the <14-year-old stratum (n = 16). In this younger age group, the median (range) length of vaso-occlusive crisis in the intervention group (n = 7) was 59.65 (48.52, 69.97) hours compared to 78.30 (59.21, 106.02) (p = 0.13) for the control group (n = 9). No effect was seen in the older cohort.•Younger patients may have a greater opportunity for reversibility of VOC. Neutrophil activation markers are potential biomarkers that need to be studied further.
Sickle Cell Disease (SCD) is a chronic hemolytic disorder associated with frequent pain episodes, end organ damage and a shortened lifespan. Currently there exist no disease specific targeted therapies for the treatment of acute vaso-occlusive crisis (VOC) and management with analgesics and hydration is purely supportive. Improvement in understanding of disease pathophysiology has resulted in a great interest in disease modifying novel therapies and many are being evaluated in clinical trials. Here we report the results from the pre-specified mid-point analysis of the Phase 2 study of Intravenous Gamma Globulin (IVIG) for the treatment of acute VOC in patients with SCD and lessons learned.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Analgesics</subject><subject>Anemia, Sickle Cell - complications</subject><subject>Anemia, Sickle Cell - drug therapy</subject><subject>Biomarkers</subject><subject>Child</subject><subject>Clinical outcomes</subject><subject>Clinical trials</subject><subject>Creatinine</subject><subject>Double-Blind Method</subject><subject>Drug dosages</subject><subject>Female</subject><subject>Flow cytometry</subject><subject>Gamma globulin</subject><subject>gamma-Globulins - therapeutic use</subject><subject>Globulins</subject><subject>Health services</subject><subject>Humans</subject><subject>Immune globulin</subject><subject>Immunoglobulins</subject><subject>Immunoglobulins, Intravenous - therapeutic use</subject><subject>Immunologic Factors - therapeutic use</subject><subject>Inflammation</subject><subject>Intravenous administration</subject><subject>IVIG</subject><subject>Life span</subject><subject>Male</subject><subject>Medical treatment</subject><subject>Narcotics</subject><subject>Neutrophils</subject><subject>Pain</subject><subject>Pain Management - methods</subject><subject>Patients</subject><subject>Pharmacy</subject><subject>Sickle</subject><subject>Sickle cell disease</subject><subject>Software</subject><subject>Substance abuse treatment</subject><subject>Thrombosis</subject><subject>VOCs</subject><subject>Volatile organic compounds</subject><subject>Young Adult</subject><issn>0965-2299</issn><issn>1873-6963</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9kc2KFDEUhYMoTjv6Ai4k4GZcVJuf-pXZyKBtQ4Mg6jakkhs6bVJpk1TL-HK-mqnp0YULV4Hc75x7uAeh55SsKaHt68NaZevXjLDlg9U9fYBWtO941Q4tf4hWZGibirFhuEBPUjoQQgbe8cfogrOhoR2nK_Trk5x08PYnaHzcywSY4RytdDgYvJ1ylCeYwpzwRnov8caFcXZ2wlfbr9vNK2xCxHkPRQIye5jyIpNqzoBPMoUqKOXmZE-AVbTJJlykR5ltIRP-YfMeJ6u-uTIG57C2CUqEN3gHKYUpYQcyTiWZicHf7fFWH4Mta-Qk3W0xfIoeGekSPLt_L9GX9-8-33yodh8325u3u0rxvs4VH7UybBwaNpDOdJRIDVoa0lOtOKd8mRnWmpGwdjSEKdlpqI2pG6JrBR2_RFdn32MM32dIWXibltBygnIeweq6bgmvm6agL_9BD2GOJe8dxeuu5wMpFDtTKoaUIhhxjNbLeCsoEUu94iCWesVSrzjXW0Qv7q3n0YP-K_nTZwGuzwCUW5wsRJFUObYCbSOoLHSw__P_DQAlubA</recordid><startdate>202008</startdate><enddate>202008</enddate><creator>Manwani, Deepa</creator><creator>Xu, Chunliang</creator><creator>Lee, Sung Kyun</creator><creator>Amatuni, George</creator><creator>Cohen, Hillel W.</creator><creator>Carullo, Veronica</creator><creator>Morrone, Kerry</creator><creator>Davila, Jennifer</creator><creator>Shi, Patricia Ann</creator><creator>Ireland, Karen</creator><creator>Keenan, Janine</creator><creator>Frenette, Paul S.</creator><general>Elsevier Ltd</general><general>Elsevier Limited</general><scope>6I.</scope><scope>AAFTH</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>7TS</scope><scope>7X7</scope><scope>7XB</scope><scope>88C</scope><scope>88E</scope><scope>88G</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9-</scope><scope>K9.</scope><scope>KB0</scope><scope>M0R</scope><scope>M0S</scope><scope>M0T</scope><scope>M1P</scope><scope>M2M</scope><scope>M2O</scope><scope>M7N</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PSYQQ</scope><scope>Q9U</scope><scope>7X8</scope></search><sort><creationdate>202008</creationdate><title>Randomized phase 2 trial of Intravenous Gamma Globulin (IVIG) for the treatment of acute vaso-occlusive crisis in patients with sickle cell disease: Lessons learned from the midpoint analysis</title><author>Manwani, Deepa ; Xu, Chunliang ; Lee, Sung Kyun ; Amatuni, George ; Cohen, Hillel W. ; Carullo, Veronica ; Morrone, Kerry ; Davila, Jennifer ; Shi, Patricia Ann ; Ireland, Karen ; Keenan, Janine ; Frenette, Paul S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c384t-3bdcf2b952907f710adedaf081dc3313f2b9f26fb026bf02ca7de4ff450d4ce73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Analgesics</topic><topic>Anemia, Sickle Cell - 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Academic</collection><jtitle>Complementary therapies in medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Manwani, Deepa</au><au>Xu, Chunliang</au><au>Lee, Sung Kyun</au><au>Amatuni, George</au><au>Cohen, Hillel W.</au><au>Carullo, Veronica</au><au>Morrone, Kerry</au><au>Davila, Jennifer</au><au>Shi, Patricia Ann</au><au>Ireland, Karen</au><au>Keenan, Janine</au><au>Frenette, Paul S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Randomized phase 2 trial of Intravenous Gamma Globulin (IVIG) for the treatment of acute vaso-occlusive crisis in patients with sickle cell disease: Lessons learned from the midpoint analysis</atitle><jtitle>Complementary therapies in medicine</jtitle><addtitle>Complement Ther Med</addtitle><date>2020-08</date><risdate>2020</risdate><volume>52</volume><spage>102481</spage><epage>102481</epage><pages>102481-102481</pages><artnum>102481</artnum><issn>0965-2299</issn><eissn>1873-6963</eissn><abstract>•We are evaluating a single 400 mg/kg dose of IVIG (Gamunex) in an ongoing phase II clinical study in SCD patients that are hospitalized for VOC. Here we report the results of a pre-specified, age stratified midpoint biomarker and safety analysis of this study, lessons learned and future plans.•A total of 37 acute pain crises were randomized at a ratio of 1 IVIG:1 equivalent-volume normal saline control at a dosing level of 400 mg/kg IVIG. A single dose was administered.•Baseline traits were not statistically different and the 2 groups were well matched.•The Gamunex was very well tolerated with no thrombosis, immune hemolysis or worsening renal function and no statistically significant differences for additional safety outcomes reported in either cohort.•Evaluation of neutrophil activation biomarkers showed significant improvement in the IVIG cohorts 24 h after IVIG administration, whereas in the placebo arm these values continued to increase as the VOC progressed – this includes percentage and absolute aged neutrophil counts as well as mean fluorescent intensity of activated Mac-1.•There was a non-significant trend towards a benefit for the intervention group in the <14-year-old stratum (n = 16). In this younger age group, the median (range) length of vaso-occlusive crisis in the intervention group (n = 7) was 59.65 (48.52, 69.97) hours compared to 78.30 (59.21, 106.02) (p = 0.13) for the control group (n = 9). No effect was seen in the older cohort.•Younger patients may have a greater opportunity for reversibility of VOC. Neutrophil activation markers are potential biomarkers that need to be studied further.
Sickle Cell Disease (SCD) is a chronic hemolytic disorder associated with frequent pain episodes, end organ damage and a shortened lifespan. Currently there exist no disease specific targeted therapies for the treatment of acute vaso-occlusive crisis (VOC) and management with analgesics and hydration is purely supportive. Improvement in understanding of disease pathophysiology has resulted in a great interest in disease modifying novel therapies and many are being evaluated in clinical trials. Here we report the results from the pre-specified mid-point analysis of the Phase 2 study of Intravenous Gamma Globulin (IVIG) for the treatment of acute VOC in patients with SCD and lessons learned.</abstract><cop>Scotland</cop><pub>Elsevier Ltd</pub><pmid>32951731</pmid><doi>10.1016/j.ctim.2020.102481</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Complementary therapies in medicine, 2020-08, Vol.52, p.102481-102481, Article 102481 |
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| subjects | Adolescent Adult Analgesics Anemia, Sickle Cell - complications Anemia, Sickle Cell - drug therapy Biomarkers Child Clinical outcomes Clinical trials Creatinine Double-Blind Method Drug dosages Female Flow cytometry Gamma globulin gamma-Globulins - therapeutic use Globulins Health services Humans Immune globulin Immunoglobulins Immunoglobulins, Intravenous - therapeutic use Immunologic Factors - therapeutic use Inflammation Intravenous administration IVIG Life span Male Medical treatment Narcotics Neutrophils Pain Pain Management - methods Patients Pharmacy Sickle Sickle cell disease Software Substance abuse treatment Thrombosis VOCs Volatile organic compounds Young Adult |
| title | Randomized phase 2 trial of Intravenous Gamma Globulin (IVIG) for the treatment of acute vaso-occlusive crisis in patients with sickle cell disease: Lessons learned from the midpoint analysis |
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