Recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema: a phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial
Hereditary angio-oedema is a recurrent, oedematous disorder caused by deficiency of functional C1 inhibitor. Infusions of plasma-derived C1 esterase inhibitor deter attacks of hereditary angio-oedema, but the prophylactic effect of recombinant human C1 esterase inhibitor has not been rigorously stud...
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| Veröffentlicht in: | The Lancet (British edition) 2017-09, Vol.390 (10102), p.1595-1602 |
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| creator | Riedl, Marc A Grivcheva-Panovska, Vesna Moldovan, Dumitru Baker, James Yang, William H Giannetti, Bruno M Reshef, Avner Andrejevic, Sladjana Lockey, Richard F Hakl, Roman Kivity, Shmuel Harper, Joseph R Relan, Anurag Cicardi, Marco |
| description | Hereditary angio-oedema is a recurrent, oedematous disorder caused by deficiency of functional C1 inhibitor. Infusions of plasma-derived C1 esterase inhibitor deter attacks of hereditary angio-oedema, but the prophylactic effect of recombinant human C1 esterase inhibitor has not been rigorously studied. We aimed to assess the efficacy of recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema.
We conducted this phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial at ten centres in Canada, the Czech Republic, Israel, Italy, Macedonia, Romania, Serbia, and the USA. We enrolled patients aged 13 years or older with functional C1-inhibitor concentrations of less than 50% of normal and a history of four or more attacks of hereditary angio-oedema per month for at least 3 months before study initiation. Patients were randomly assigned centrally (1:1:1:1:1:1), via an interactive response technology system with fixed allocation, to receive one of six treatment sequences. During each sequence, patients received intravenous recombinant human C1 esterase inhibitor (50 IU/kg; maximum 4200 IU) twice weekly, recombinant human C1 esterase inhibitor once weekly and placebo once weekly, and placebo twice weekly, each for 4 weeks with a 1 week washout period between crossover. All patients, investigators, and study personnel who participated in patient care were masked to group allocation during the study. The primary efficacy endpoint was the number of attacks of hereditary angio-oedema observed in each 4 week treatment period. Attack symptoms were recorded daily. The primary efficacy analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one injection of study medication. This study is registered with ClinicalTrials.gov, number NCT02247739.
Between Dec 29, 2014, and May 3, 2016, we enrolled 35 patients, of whom 32 (91%) underwent randomisation (intention-to-treat population) and 26 (81%) completed the study. The mean number of attacks of hereditary angio-oedema over 4 weeks was significantly reduced with recombinant human C1 esterase inhibitor twice weekly (2·7 attacks [SD 2·4]) and once weekly (4·4 attacks [3·2]) versus placebo (7·2 attacks [3·6]), with mean differences of −4·4 attacks (p |
| doi_str_mv | 10.1016/S0140-6736(17)31963-3 |
| format | Article |
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We conducted this phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial at ten centres in Canada, the Czech Republic, Israel, Italy, Macedonia, Romania, Serbia, and the USA. We enrolled patients aged 13 years or older with functional C1-inhibitor concentrations of less than 50% of normal and a history of four or more attacks of hereditary angio-oedema per month for at least 3 months before study initiation. Patients were randomly assigned centrally (1:1:1:1:1:1), via an interactive response technology system with fixed allocation, to receive one of six treatment sequences. During each sequence, patients received intravenous recombinant human C1 esterase inhibitor (50 IU/kg; maximum 4200 IU) twice weekly, recombinant human C1 esterase inhibitor once weekly and placebo once weekly, and placebo twice weekly, each for 4 weeks with a 1 week washout period between crossover. All patients, investigators, and study personnel who participated in patient care were masked to group allocation during the study. The primary efficacy endpoint was the number of attacks of hereditary angio-oedema observed in each 4 week treatment period. Attack symptoms were recorded daily. The primary efficacy analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one injection of study medication. This study is registered with ClinicalTrials.gov, number NCT02247739.
Between Dec 29, 2014, and May 3, 2016, we enrolled 35 patients, of whom 32 (91%) underwent randomisation (intention-to-treat population) and 26 (81%) completed the study. The mean number of attacks of hereditary angio-oedema over 4 weeks was significantly reduced with recombinant human C1 esterase inhibitor twice weekly (2·7 attacks [SD 2·4]) and once weekly (4·4 attacks [3·2]) versus placebo (7·2 attacks [3·6]), with mean differences of −4·4 attacks (p<0·0001) and −2·8 attacks (p=0·0004), respectively. We recorded adverse events in ten (34%) of 29 patients given twice-weekly recombinant human C1 esterase inhibitor, 13 (45%) of 29 patients given the once-weekly regimen, and eight (29%) of 28 patients given placebo. Headache (twice-weekly treatment) and nasopharyngitis (once-weekly treatment) were the most common adverse events. Two (7%) adverse events (fatigue and headache) were deemed possibly related to treatment with recombinant human C1 esterase inhibitor, but both resolved without additional treatment. No thrombotic or thromboembolic events, systemic allergic reactions (including anaphylaxis), or neutralising antibodies were reported.
Prophylaxis with recombinant human C1 esterase inhibitor provided clinically relevant reductions in frequency of hereditary angio-oedema attacks and was well tolerated. In view of the pharmacokinetic profile of recombinant human C1 esterase inhibitor, our results suggest that efficacy of C1-inhibitor replacement therapy might not be a direct function of plasma trough concentrations of C1 inhibitor.
Pharming Technologies.</description><identifier>ISSN: 0140-6736</identifier><identifier>EISSN: 1474-547X</identifier><identifier>DOI: 10.1016/S0140-6736(17)31963-3</identifier><identifier>PMID: 28754491</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Adolescent ; Adult ; Aged ; Androgens ; Angioedema ; Angioedemas, Hereditary - blood ; Angioedemas, Hereditary - prevention & control ; Clinical trials ; Complement C1 Inhibitor Protein - adverse effects ; Complement C1 Inhibitor Protein - pharmacokinetics ; Complement C1 Inhibitor Protein - therapeutic use ; Cross-Over Studies ; Dose-Response Relationship, Drug ; Double-Blind Method ; Double-blind studies ; Drug Administration Schedule ; Drug therapy ; Edema ; Esterase ; Evidence-based medicine ; FDA approval ; Female ; Genetic disorders ; Humans ; Infusions, Intravenous ; Inhibitor drugs ; Male ; Metabolic Clearance Rate - physiology ; Middle Aged ; Prophylaxis ; Recombinant Proteins - adverse effects ; Recombinant Proteins - blood ; Recombinant Proteins - pharmacokinetics ; Recombinant Proteins - therapeutic use ; Treatment Outcome ; Young Adult</subject><ispartof>The Lancet (British edition), 2017-09, Vol.390 (10102), p.1595-1602</ispartof><rights>2017 Elsevier Ltd</rights><rights>Copyright © 2017 Elsevier Ltd. All rights reserved.</rights><rights>Copyright Elsevier Limited Sep 30, 2017</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c393t-6dc15ebafa519d2a35c399ae147d9665e3ef84efad6de0d762f97e1deb2cbe683</citedby><cites>FETCH-LOGICAL-c393t-6dc15ebafa519d2a35c399ae147d9665e3ef84efad6de0d762f97e1deb2cbe683</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/1945865762?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995,64385,64389,72469</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28754491$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Riedl, Marc A</creatorcontrib><creatorcontrib>Grivcheva-Panovska, Vesna</creatorcontrib><creatorcontrib>Moldovan, Dumitru</creatorcontrib><creatorcontrib>Baker, James</creatorcontrib><creatorcontrib>Yang, William H</creatorcontrib><creatorcontrib>Giannetti, Bruno M</creatorcontrib><creatorcontrib>Reshef, Avner</creatorcontrib><creatorcontrib>Andrejevic, Sladjana</creatorcontrib><creatorcontrib>Lockey, Richard F</creatorcontrib><creatorcontrib>Hakl, Roman</creatorcontrib><creatorcontrib>Kivity, Shmuel</creatorcontrib><creatorcontrib>Harper, Joseph R</creatorcontrib><creatorcontrib>Relan, Anurag</creatorcontrib><creatorcontrib>Cicardi, Marco</creatorcontrib><title>Recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema: a phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial</title><title>The Lancet (British edition)</title><addtitle>Lancet</addtitle><description>Hereditary angio-oedema is a recurrent, oedematous disorder caused by deficiency of functional C1 inhibitor. Infusions of plasma-derived C1 esterase inhibitor deter attacks of hereditary angio-oedema, but the prophylactic effect of recombinant human C1 esterase inhibitor has not been rigorously studied. We aimed to assess the efficacy of recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema.
We conducted this phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial at ten centres in Canada, the Czech Republic, Israel, Italy, Macedonia, Romania, Serbia, and the USA. We enrolled patients aged 13 years or older with functional C1-inhibitor concentrations of less than 50% of normal and a history of four or more attacks of hereditary angio-oedema per month for at least 3 months before study initiation. Patients were randomly assigned centrally (1:1:1:1:1:1), via an interactive response technology system with fixed allocation, to receive one of six treatment sequences. During each sequence, patients received intravenous recombinant human C1 esterase inhibitor (50 IU/kg; maximum 4200 IU) twice weekly, recombinant human C1 esterase inhibitor once weekly and placebo once weekly, and placebo twice weekly, each for 4 weeks with a 1 week washout period between crossover. All patients, investigators, and study personnel who participated in patient care were masked to group allocation during the study. The primary efficacy endpoint was the number of attacks of hereditary angio-oedema observed in each 4 week treatment period. Attack symptoms were recorded daily. The primary efficacy analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one injection of study medication. This study is registered with ClinicalTrials.gov, number NCT02247739.
Between Dec 29, 2014, and May 3, 2016, we enrolled 35 patients, of whom 32 (91%) underwent randomisation (intention-to-treat population) and 26 (81%) completed the study. The mean number of attacks of hereditary angio-oedema over 4 weeks was significantly reduced with recombinant human C1 esterase inhibitor twice weekly (2·7 attacks [SD 2·4]) and once weekly (4·4 attacks [3·2]) versus placebo (7·2 attacks [3·6]), with mean differences of −4·4 attacks (p<0·0001) and −2·8 attacks (p=0·0004), respectively. We recorded adverse events in ten (34%) of 29 patients given twice-weekly recombinant human C1 esterase inhibitor, 13 (45%) of 29 patients given the once-weekly regimen, and eight (29%) of 28 patients given placebo. Headache (twice-weekly treatment) and nasopharyngitis (once-weekly treatment) were the most common adverse events. Two (7%) adverse events (fatigue and headache) were deemed possibly related to treatment with recombinant human C1 esterase inhibitor, but both resolved without additional treatment. No thrombotic or thromboembolic events, systemic allergic reactions (including anaphylaxis), or neutralising antibodies were reported.
Prophylaxis with recombinant human C1 esterase inhibitor provided clinically relevant reductions in frequency of hereditary angio-oedema attacks and was well tolerated. In view of the pharmacokinetic profile of recombinant human C1 esterase inhibitor, our results suggest that efficacy of C1-inhibitor replacement therapy might not be a direct function of plasma trough concentrations of C1 inhibitor.
Pharming Technologies.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Androgens</subject><subject>Angioedema</subject><subject>Angioedemas, Hereditary - blood</subject><subject>Angioedemas, Hereditary - prevention & control</subject><subject>Clinical trials</subject><subject>Complement C1 Inhibitor Protein - adverse effects</subject><subject>Complement C1 Inhibitor Protein - pharmacokinetics</subject><subject>Complement C1 Inhibitor Protein - therapeutic use</subject><subject>Cross-Over Studies</subject><subject>Dose-Response Relationship, Drug</subject><subject>Double-Blind Method</subject><subject>Double-blind studies</subject><subject>Drug Administration Schedule</subject><subject>Drug therapy</subject><subject>Edema</subject><subject>Esterase</subject><subject>Evidence-based medicine</subject><subject>FDA approval</subject><subject>Female</subject><subject>Genetic disorders</subject><subject>Humans</subject><subject>Infusions, Intravenous</subject><subject>Inhibitor drugs</subject><subject>Male</subject><subject>Metabolic Clearance Rate - physiology</subject><subject>Middle Aged</subject><subject>Prophylaxis</subject><subject>Recombinant Proteins - adverse effects</subject><subject>Recombinant Proteins - blood</subject><subject>Recombinant Proteins - pharmacokinetics</subject><subject>Recombinant Proteins - therapeutic use</subject><subject>Treatment Outcome</subject><subject>Young 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human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema: a phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial</title><author>Riedl, Marc A ; Grivcheva-Panovska, Vesna ; Moldovan, Dumitru ; Baker, James ; Yang, William H ; Giannetti, Bruno M ; Reshef, Avner ; Andrejevic, Sladjana ; Lockey, Richard F ; Hakl, Roman ; Kivity, Shmuel ; Harper, Joseph R ; Relan, Anurag ; Cicardi, Marco</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c393t-6dc15ebafa519d2a35c399ae147d9665e3ef84efad6de0d762f97e1deb2cbe683</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>Androgens</topic><topic>Angioedema</topic><topic>Angioedemas, Hereditary - blood</topic><topic>Angioedemas, Hereditary - prevention & control</topic><topic>Clinical trials</topic><topic>Complement C1 Inhibitor Protein - 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Editorial</collection><jtitle>The Lancet (British edition)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Riedl, Marc A</au><au>Grivcheva-Panovska, Vesna</au><au>Moldovan, Dumitru</au><au>Baker, James</au><au>Yang, William H</au><au>Giannetti, Bruno M</au><au>Reshef, Avner</au><au>Andrejevic, Sladjana</au><au>Lockey, Richard F</au><au>Hakl, Roman</au><au>Kivity, Shmuel</au><au>Harper, Joseph R</au><au>Relan, Anurag</au><au>Cicardi, Marco</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema: a phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial</atitle><jtitle>The Lancet (British edition)</jtitle><addtitle>Lancet</addtitle><date>2017-09-30</date><risdate>2017</risdate><volume>390</volume><issue>10102</issue><spage>1595</spage><epage>1602</epage><pages>1595-1602</pages><issn>0140-6736</issn><eissn>1474-547X</eissn><abstract>Hereditary angio-oedema is a recurrent, oedematous disorder caused by deficiency of functional C1 inhibitor. Infusions of plasma-derived C1 esterase inhibitor deter attacks of hereditary angio-oedema, but the prophylactic effect of recombinant human C1 esterase inhibitor has not been rigorously studied. We aimed to assess the efficacy of recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema.
We conducted this phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial at ten centres in Canada, the Czech Republic, Israel, Italy, Macedonia, Romania, Serbia, and the USA. We enrolled patients aged 13 years or older with functional C1-inhibitor concentrations of less than 50% of normal and a history of four or more attacks of hereditary angio-oedema per month for at least 3 months before study initiation. Patients were randomly assigned centrally (1:1:1:1:1:1), via an interactive response technology system with fixed allocation, to receive one of six treatment sequences. During each sequence, patients received intravenous recombinant human C1 esterase inhibitor (50 IU/kg; maximum 4200 IU) twice weekly, recombinant human C1 esterase inhibitor once weekly and placebo once weekly, and placebo twice weekly, each for 4 weeks with a 1 week washout period between crossover. All patients, investigators, and study personnel who participated in patient care were masked to group allocation during the study. The primary efficacy endpoint was the number of attacks of hereditary angio-oedema observed in each 4 week treatment period. Attack symptoms were recorded daily. The primary efficacy analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one injection of study medication. This study is registered with ClinicalTrials.gov, number NCT02247739.
Between Dec 29, 2014, and May 3, 2016, we enrolled 35 patients, of whom 32 (91%) underwent randomisation (intention-to-treat population) and 26 (81%) completed the study. The mean number of attacks of hereditary angio-oedema over 4 weeks was significantly reduced with recombinant human C1 esterase inhibitor twice weekly (2·7 attacks [SD 2·4]) and once weekly (4·4 attacks [3·2]) versus placebo (7·2 attacks [3·6]), with mean differences of −4·4 attacks (p<0·0001) and −2·8 attacks (p=0·0004), respectively. We recorded adverse events in ten (34%) of 29 patients given twice-weekly recombinant human C1 esterase inhibitor, 13 (45%) of 29 patients given the once-weekly regimen, and eight (29%) of 28 patients given placebo. Headache (twice-weekly treatment) and nasopharyngitis (once-weekly treatment) were the most common adverse events. Two (7%) adverse events (fatigue and headache) were deemed possibly related to treatment with recombinant human C1 esterase inhibitor, but both resolved without additional treatment. No thrombotic or thromboembolic events, systemic allergic reactions (including anaphylaxis), or neutralising antibodies were reported.
Prophylaxis with recombinant human C1 esterase inhibitor provided clinically relevant reductions in frequency of hereditary angio-oedema attacks and was well tolerated. In view of the pharmacokinetic profile of recombinant human C1 esterase inhibitor, our results suggest that efficacy of C1-inhibitor replacement therapy might not be a direct function of plasma trough concentrations of C1 inhibitor.
Pharming Technologies.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>28754491</pmid><doi>10.1016/S0140-6736(17)31963-3</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0140-6736 |
| ispartof | The Lancet (British edition), 2017-09, Vol.390 (10102), p.1595-1602 |
| issn | 0140-6736 1474-547X |
| language | eng |
| recordid | cdi_proquest_journals_1945865762 |
| source | MEDLINE; Elsevier ScienceDirect Journals Complete; ProQuest Central UK/Ireland |
| subjects | Adolescent Adult Aged Androgens Angioedema Angioedemas, Hereditary - blood Angioedemas, Hereditary - prevention & control Clinical trials Complement C1 Inhibitor Protein - adverse effects Complement C1 Inhibitor Protein - pharmacokinetics Complement C1 Inhibitor Protein - therapeutic use Cross-Over Studies Dose-Response Relationship, Drug Double-Blind Method Double-blind studies Drug Administration Schedule Drug therapy Edema Esterase Evidence-based medicine FDA approval Female Genetic disorders Humans Infusions, Intravenous Inhibitor drugs Male Metabolic Clearance Rate - physiology Middle Aged Prophylaxis Recombinant Proteins - adverse effects Recombinant Proteins - blood Recombinant Proteins - pharmacokinetics Recombinant Proteins - therapeutic use Treatment Outcome Young Adult |
| title | Recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema: a phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial |
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