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A novel autologous bone graft substitute comprised of rhBMP6 blood coagulum as carrier tested in a randomized and controlled Phase I trial in patients with distal radial fractures
Bone morphogenetic proteins (BMPs) are known to induce new bone formation in vivo but treating trabecular bone defects with a BMP based therapeutic remains controversial. Here, we evaluated the safety and efficacy of a novel Autologous Bone Graft Substitute (ABGS) comprised of recombinant human BMP6...
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Published in: | Bone (New York, N.Y.) N.Y.), 2020-11, Vol.140, p.115551-115551, Article 115551 |
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creator | Durdevic, Dragan Vlahovic, Tomislav Pehar, Sanja Miklic, Dina Oppermann, Hermann Bordukalo-Niksic, Tatjana Gavrankapetanovic, Ismet Jamakosmanovic, Mehmed Milosevic, Milan Martinovic, Snjezana Sampath, T. Kuber Peric, Mihaela Grgurevic, Lovorka Vukicevic, Slobodan |
description | Bone morphogenetic proteins (BMPs) are known to induce new bone formation in vivo but treating trabecular bone defects with a BMP based therapeutic remains controversial. Here, we evaluated the safety and efficacy of a novel Autologous Bone Graft Substitute (ABGS) comprised of recombinant human BMP6 (rhBMP6) dispersed within an autologous blood coagulum (ABC) as a physiological natural carrier in patients with a closed distal radial fracture (DRF). We enrolled 32 patients in a randomized, standard of care (SoC) and placebo (PBO) controlled, double-blinded Phase I First in Human (FiH) clinical trial. ABGS was prepared from peripheral blood as 250 μg rhBMP6/mL ABC or PBO (1 mL ABC containing excipients only) and was administered dorsally via a syringe injection into the fracture site following closed fracture fixation with 3 Kirschner wires. Patients carried an immobilization for 5 weeks and were followed-up for 0 to 26 weeks by clinical examination, safety, serial radiographic analyses and CT. During the 13 weeks follow-up and at 26 weeks post study there were no serious adverse reactions recorded. The results showed that there were no detectable anti-rhBMP6 antibodies in the blood of any of the 32 patients at 13- and 26-weeks following treatment. Pharmacokinetic analyses of plasma from patients treated with ABGS showed no detectable rhBMP6 at any time point within the first 24 h following administration. The CT image and radiographic analyses score from patients treated with AGBS showed significantly accelerated bone healing as compared to PBO and SoC at 5 and 9 weeks (with high effect sizes and P = 0.027), while at week 13 all patients had similar healing outcomes. In conclusion, we show that intraosseous administration of ABGS (250 μg rhBMP6/mL ABC) into the distal radial fracture site demonstrated a good tolerability with no serious adverse reactions as well as early accelerated trabecular bone healing as compared to control PBO and SoC patients.
•Autologous bone graft substitute (ABGS) comprises of rhBMP6 and blood coagulum.•Randomized, controlled Phase I trial enrolled distal radial fracture patients.•32 patients were treated with ABGS.•During 26 weeks follow-up no serious adverse reactions were recorded.•An accelerated bone healing was observed in ABGS treated patients. |
doi_str_mv | 10.1016/j.bone.2020.115551 |
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•Autologous bone graft substitute (ABGS) comprises of rhBMP6 and blood coagulum.•Randomized, controlled Phase I trial enrolled distal radial fracture patients.•32 patients were treated with ABGS.•During 26 weeks follow-up no serious adverse reactions were recorded.•An accelerated bone healing was observed in ABGS treated patients.</description><identifier>ISSN: 8756-3282</identifier><identifier>EISSN: 1873-2763</identifier><identifier>DOI: 10.1016/j.bone.2020.115551</identifier><identifier>PMID: 32730930</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>BMPs ; Bone Morphogenetic Proteins ; Bone Substitutes ; Cancellous Bone ; Clinical trials ; Double-Blind Method ; Fracture Fixation ; Fracture Healing ; Fractures, Closed ; Humans ; Implants ; Injury/fracture healing ; Treatment Outcome</subject><ispartof>Bone (New York, N.Y.), 2020-11, Vol.140, p.115551-115551, Article 115551</ispartof><rights>2020 The Authors</rights><rights>Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c400t-3766305c76d0aa7d91f702ccf94cf36f1a1100fdd966895976f3115ca096edc63</citedby><cites>FETCH-LOGICAL-c400t-3766305c76d0aa7d91f702ccf94cf36f1a1100fdd966895976f3115ca096edc63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32730930$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Durdevic, Dragan</creatorcontrib><creatorcontrib>Vlahovic, Tomislav</creatorcontrib><creatorcontrib>Pehar, Sanja</creatorcontrib><creatorcontrib>Miklic, Dina</creatorcontrib><creatorcontrib>Oppermann, Hermann</creatorcontrib><creatorcontrib>Bordukalo-Niksic, Tatjana</creatorcontrib><creatorcontrib>Gavrankapetanovic, Ismet</creatorcontrib><creatorcontrib>Jamakosmanovic, Mehmed</creatorcontrib><creatorcontrib>Milosevic, Milan</creatorcontrib><creatorcontrib>Martinovic, Snjezana</creatorcontrib><creatorcontrib>Sampath, T. Kuber</creatorcontrib><creatorcontrib>Peric, Mihaela</creatorcontrib><creatorcontrib>Grgurevic, Lovorka</creatorcontrib><creatorcontrib>Vukicevic, Slobodan</creatorcontrib><title>A novel autologous bone graft substitute comprised of rhBMP6 blood coagulum as carrier tested in a randomized and controlled Phase I trial in patients with distal radial fractures</title><title>Bone (New York, N.Y.)</title><addtitle>Bone</addtitle><description>Bone morphogenetic proteins (BMPs) are known to induce new bone formation in vivo but treating trabecular bone defects with a BMP based therapeutic remains controversial. Here, we evaluated the safety and efficacy of a novel Autologous Bone Graft Substitute (ABGS) comprised of recombinant human BMP6 (rhBMP6) dispersed within an autologous blood coagulum (ABC) as a physiological natural carrier in patients with a closed distal radial fracture (DRF). We enrolled 32 patients in a randomized, standard of care (SoC) and placebo (PBO) controlled, double-blinded Phase I First in Human (FiH) clinical trial. ABGS was prepared from peripheral blood as 250 μg rhBMP6/mL ABC or PBO (1 mL ABC containing excipients only) and was administered dorsally via a syringe injection into the fracture site following closed fracture fixation with 3 Kirschner wires. Patients carried an immobilization for 5 weeks and were followed-up for 0 to 26 weeks by clinical examination, safety, serial radiographic analyses and CT. During the 13 weeks follow-up and at 26 weeks post study there were no serious adverse reactions recorded. The results showed that there were no detectable anti-rhBMP6 antibodies in the blood of any of the 32 patients at 13- and 26-weeks following treatment. Pharmacokinetic analyses of plasma from patients treated with ABGS showed no detectable rhBMP6 at any time point within the first 24 h following administration. The CT image and radiographic analyses score from patients treated with AGBS showed significantly accelerated bone healing as compared to PBO and SoC at 5 and 9 weeks (with high effect sizes and P = 0.027), while at week 13 all patients had similar healing outcomes. In conclusion, we show that intraosseous administration of ABGS (250 μg rhBMP6/mL ABC) into the distal radial fracture site demonstrated a good tolerability with no serious adverse reactions as well as early accelerated trabecular bone healing as compared to control PBO and SoC patients.
•Autologous bone graft substitute (ABGS) comprises of rhBMP6 and blood coagulum.•Randomized, controlled Phase I trial enrolled distal radial fracture patients.•32 patients were treated with ABGS.•During 26 weeks follow-up no serious adverse reactions were recorded.•An accelerated bone healing was observed in ABGS treated patients.</description><subject>BMPs</subject><subject>Bone Morphogenetic Proteins</subject><subject>Bone Substitutes</subject><subject>Cancellous Bone</subject><subject>Clinical trials</subject><subject>Double-Blind Method</subject><subject>Fracture Fixation</subject><subject>Fracture Healing</subject><subject>Fractures, Closed</subject><subject>Humans</subject><subject>Implants</subject><subject>Injury/fracture healing</subject><subject>Treatment Outcome</subject><issn>8756-3282</issn><issn>1873-2763</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9kctuFDEQRS1ERIbAD7BAXrLpwY9pu1tiEyIekRKRBaytGj9mPHK3Bz-C4Lfyg7g1gWVWdlWdulLdi9AbStaUUPH-sN7G2a4ZYa1B-76nz9CKDpJ3TAr-HK0G2YuOs4Gdo5c5HwghfJT0BTrnTHIycrJCD5d4jvc2YKglhriLNeNFFe8SuIJz3ebiSy0W6zgdk8_W4Ohw2n-8vRN4G2I0bQK7GuqEIWMNKXmbcLG5NNTPGHCC2cTJ_2l1-zV8LimG0Mq7PWSLr3FJHsICH6F4O5eMf_myx8bn0voJzDJ2CXSpyeZX6MxByPb143uBfnz-9P3qa3fz7cv11eVNpzeElI5LITjptRSGAEgzUicJ09qNG-24cBQoJcQZMwoxjP0ohePNRg1kFNZowS_Qu5PuMcWftR2kJp-1DQFm23xSbMNGOQxUDg1lJ1SnmHOyTjWvJki_FSVqCUsd1GKrWsJSp7Da0ttH_bqdrPm_8i-dBnw4AbZded9sVVk3e7Q1PlldlIn-Kf2_FIeopw</recordid><startdate>202011</startdate><enddate>202011</enddate><creator>Durdevic, Dragan</creator><creator>Vlahovic, Tomislav</creator><creator>Pehar, Sanja</creator><creator>Miklic, Dina</creator><creator>Oppermann, Hermann</creator><creator>Bordukalo-Niksic, Tatjana</creator><creator>Gavrankapetanovic, Ismet</creator><creator>Jamakosmanovic, Mehmed</creator><creator>Milosevic, Milan</creator><creator>Martinovic, Snjezana</creator><creator>Sampath, T. Kuber</creator><creator>Peric, Mihaela</creator><creator>Grgurevic, Lovorka</creator><creator>Vukicevic, Slobodan</creator><general>Elsevier Inc</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>7X8</scope></search><sort><creationdate>202011</creationdate><title>A novel autologous bone graft substitute comprised of rhBMP6 blood coagulum as carrier tested in a randomized and controlled Phase I trial in patients with distal radial fractures</title><author>Durdevic, Dragan ; Vlahovic, Tomislav ; Pehar, Sanja ; Miklic, Dina ; Oppermann, Hermann ; Bordukalo-Niksic, Tatjana ; Gavrankapetanovic, Ismet ; Jamakosmanovic, Mehmed ; Milosevic, Milan ; Martinovic, Snjezana ; Sampath, T. 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Kuber</creatorcontrib><creatorcontrib>Peric, Mihaela</creatorcontrib><creatorcontrib>Grgurevic, Lovorka</creatorcontrib><creatorcontrib>Vukicevic, Slobodan</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect: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>MEDLINE - Academic</collection><jtitle>Bone (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Durdevic, Dragan</au><au>Vlahovic, Tomislav</au><au>Pehar, Sanja</au><au>Miklic, Dina</au><au>Oppermann, Hermann</au><au>Bordukalo-Niksic, Tatjana</au><au>Gavrankapetanovic, Ismet</au><au>Jamakosmanovic, Mehmed</au><au>Milosevic, Milan</au><au>Martinovic, Snjezana</au><au>Sampath, T. Kuber</au><au>Peric, Mihaela</au><au>Grgurevic, Lovorka</au><au>Vukicevic, Slobodan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A novel autologous bone graft substitute comprised of rhBMP6 blood coagulum as carrier tested in a randomized and controlled Phase I trial in patients with distal radial fractures</atitle><jtitle>Bone (New York, N.Y.)</jtitle><addtitle>Bone</addtitle><date>2020-11</date><risdate>2020</risdate><volume>140</volume><spage>115551</spage><epage>115551</epage><pages>115551-115551</pages><artnum>115551</artnum><issn>8756-3282</issn><eissn>1873-2763</eissn><abstract>Bone morphogenetic proteins (BMPs) are known to induce new bone formation in vivo but treating trabecular bone defects with a BMP based therapeutic remains controversial. Here, we evaluated the safety and efficacy of a novel Autologous Bone Graft Substitute (ABGS) comprised of recombinant human BMP6 (rhBMP6) dispersed within an autologous blood coagulum (ABC) as a physiological natural carrier in patients with a closed distal radial fracture (DRF). We enrolled 32 patients in a randomized, standard of care (SoC) and placebo (PBO) controlled, double-blinded Phase I First in Human (FiH) clinical trial. ABGS was prepared from peripheral blood as 250 μg rhBMP6/mL ABC or PBO (1 mL ABC containing excipients only) and was administered dorsally via a syringe injection into the fracture site following closed fracture fixation with 3 Kirschner wires. Patients carried an immobilization for 5 weeks and were followed-up for 0 to 26 weeks by clinical examination, safety, serial radiographic analyses and CT. During the 13 weeks follow-up and at 26 weeks post study there were no serious adverse reactions recorded. The results showed that there were no detectable anti-rhBMP6 antibodies in the blood of any of the 32 patients at 13- and 26-weeks following treatment. Pharmacokinetic analyses of plasma from patients treated with ABGS showed no detectable rhBMP6 at any time point within the first 24 h following administration. The CT image and radiographic analyses score from patients treated with AGBS showed significantly accelerated bone healing as compared to PBO and SoC at 5 and 9 weeks (with high effect sizes and P = 0.027), while at week 13 all patients had similar healing outcomes. In conclusion, we show that intraosseous administration of ABGS (250 μg rhBMP6/mL ABC) into the distal radial fracture site demonstrated a good tolerability with no serious adverse reactions as well as early accelerated trabecular bone healing as compared to control PBO and SoC patients.
•Autologous bone graft substitute (ABGS) comprises of rhBMP6 and blood coagulum.•Randomized, controlled Phase I trial enrolled distal radial fracture patients.•32 patients were treated with ABGS.•During 26 weeks follow-up no serious adverse reactions were recorded.•An accelerated bone healing was observed in ABGS treated patients.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>32730930</pmid><doi>10.1016/j.bone.2020.115551</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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subjects | BMPs Bone Morphogenetic Proteins Bone Substitutes Cancellous Bone Clinical trials Double-Blind Method Fracture Fixation Fracture Healing Fractures, Closed Humans Implants Injury/fracture healing Treatment Outcome |
title | A novel autologous bone graft substitute comprised of rhBMP6 blood coagulum as carrier tested in a randomized and controlled Phase I trial in patients with distal radial fractures |
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