Chemokine receptor CCR1 antagonist CCX354-C treatment for rheumatoid arthritis: CARAT-2, a randomised, placebo controlled clinical trial
Identifieur interne : 002876 ( Main/Exploration ); précédent : 002875; suivant : 002877Chemokine receptor CCR1 antagonist CCX354-C treatment for rheumatoid arthritis: CARAT-2, a randomised, placebo controlled clinical trial
Auteurs : Paul P. Tak [Royaume-Uni] ; Andra Balanescu [Roumanie] ; Vira Tseluyko [Ukraine] ; Silvia Bojin [Roumanie] ; Edit Drescher [Hongrie] ; Dan Dairaghi [États-Unis] ; Shichang Miao [États-Unis] ; Vittorio Marchesin [États-Unis] ; Juan Jaen [États-Unis] ; Thomas J. Schall [États-Unis] ; Pirow Bekker [États-Unis]Source :
- Annals of the Rheumatic Diseases [ 0003-4967 ] ; 2013-03.
English descriptors
- Teeft :
- Abdominal pain, Adverse events, Alanine transaminase elevations, American college, Antagonist, Arthritis, Arthritis rheum, Arthritis trial, Asterisk, Baseline, Baseline characteristics, Baseline factors, Blood pressure, Blue line, Bone turnover markers, Bowel disease, Ccr1, Ccr1 antagonist, Ccr1 blockade, Ccr1 chemokines, Ccr1 plasma coverage, Ccr5 blockade, Chemokine, Chemokine receptor, Clinical trial, Clinical trials, Covariance model, Critical manuscript review, Daily dose, Daily group, Daily groups, Daily kits, Data analysis, Data interpretation, Disease activity, Eligible population, Eligible subjects, Eligible subjects subjects, Epidemiological, Epidemiological research, Epidemiological research figure, Error rate, Erythrocyte sedimentation rate, Ethics committee approval, Further study, Higher doses, Ineligible subjects, Ipth levels, Joint count eligibility criteria, Linear contrasts, Macrophage, Median percentage change, Medication, Methotrexate, Migration studies, Osteoclast, Physician assessment, Placebo, Placebo group, Placebo groups, Plasma exposure, Procollagen type, Receptor, Rheum, Rheumatoid, Rheumatoid arthritis, Rheumatology, Safety analyses, Safety population, Siemens healthcare diagnostics, Small molecule ccr1 antagonist, Soluble bone turnover markers, Statistical power, Statistical testing, Study centre, Study design, Study medication, Study period, Study protocol, Study subjects, Study visits, Subject assessment, Supplementary appendix, Synovial tissue, Time points, Treatment group, Treatment groups, Treatment period, Trough plasma concentration, Upper limit, Visual analogue scale.
Abstract
Objectives CCX354-C is a specific, orally administered antagonist of the C-C chemokine receptor 1, which regulates migration of monocytes and macrophages to synovial tissue. This clinical trial evaluated the safety and efficacy of CCX354-C in patients with rheumatoid arthritis (RA). Methods CARAT-2 is a 12-week double-blind, randomised, placebo controlled trial in 160 patients with RA, with 68 tender joint count and 66 swollen joint count ≥8 and C-reactive protein (CRP) >5 mg/l, despite being on methotrexate for at least 16 weeks. Subjects received placebo, CCX354-C 100 mg twice daily, or 200 mg once daily for 12 weeks. Endpoints included safety (primary) and RA disease activity assessments based on American College of Rheumatology (ACR) response, and changes in 28-joint disease activity score–CRP, individual ACR components, as well as soluble bone turnover markers. Results CCX354-C was generally well tolerated by study subjects. The ACR20 response at week 12 was 39% in the placebo group, 43% in the 100 mg twice daily group (difference and 95% CI compared with placebo, 4.5 (−14.1 to 23.1); p=0.62) and 52% in the 200 mg once daily group (13.0 (−5.8 to 31.8); p=0.17) in the intention-to-treat population, and 30% in the placebo group, 44% in the 100 mg twice daily group (14.4 (−5.9 to 34.8); p=0.17), and 56% in the 200 mg once daily group (25.8 (5.3 to 46.4); p=0.01) in the prespecified population of patients satisfying CRP and joint count eligibility criteria at the screening and day 1 (predose) visits. Conclusions CCX354-C exhibited a good safety and tolerability profile and evidence of clinical activity in RA.
Url:
DOI: 10.1136/annrheumdis-2011-201605
Affiliations:
- Hongrie, Roumanie, Royaume-Uni, Ukraine, États-Unis
- Californie, Hollande-Septentrionale
- Amsterdam
- Université d'Amsterdam
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Schall</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>ChemoCentryx, Inc, Mountain View, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Bekker, Pirow" sort="Bekker, Pirow" uniqKey="Bekker P" first="Pirow" last="Bekker">Pirow Bekker</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>ChemoCentryx, Inc, Mountain View, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author></analytic><monogr></monogr><series><title level="j">Annals of the Rheumatic Diseases</title><title level="j" type="abbrev">Ann Rheum Dis</title><idno type="ISSN">0003-4967</idno><idno type="eISSN">1468-2060</idno><imprint><publisher>BMJ Publishing Group Ltd and European League Against Rheumatism</publisher><date type="published" when="2013-03">2013-03</date><biblScope unit="volume">72</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="337">337</biblScope></imprint><idno type="ISSN">0003-4967</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0003-4967</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="Teeft" xml:lang="en"><term>Abdominal pain</term><term>Adverse events</term><term>Alanine transaminase elevations</term><term>American college</term><term>Antagonist</term><term>Arthritis</term><term>Arthritis rheum</term><term>Arthritis trial</term><term>Asterisk</term><term>Baseline</term><term>Baseline characteristics</term><term>Baseline factors</term><term>Blood pressure</term><term>Blue line</term><term>Bone turnover markers</term><term>Bowel disease</term><term>Ccr1</term><term>Ccr1 antagonist</term><term>Ccr1 blockade</term><term>Ccr1 chemokines</term><term>Ccr1 plasma coverage</term><term>Ccr5 blockade</term><term>Chemokine</term><term>Chemokine receptor</term><term>Clinical trial</term><term>Clinical trials</term><term>Covariance model</term><term>Critical manuscript review</term><term>Daily dose</term><term>Daily group</term><term>Daily groups</term><term>Daily kits</term><term>Data analysis</term><term>Data interpretation</term><term>Disease activity</term><term>Eligible population</term><term>Eligible subjects</term><term>Eligible subjects subjects</term><term>Epidemiological</term><term>Epidemiological research</term><term>Epidemiological research figure</term><term>Error rate</term><term>Erythrocyte sedimentation rate</term><term>Ethics committee approval</term><term>Further study</term><term>Higher doses</term><term>Ineligible subjects</term><term>Ipth levels</term><term>Joint count eligibility criteria</term><term>Linear contrasts</term><term>Macrophage</term><term>Median percentage change</term><term>Medication</term><term>Methotrexate</term><term>Migration studies</term><term>Osteoclast</term><term>Physician assessment</term><term>Placebo</term><term>Placebo group</term><term>Placebo groups</term><term>Plasma exposure</term><term>Procollagen type</term><term>Receptor</term><term>Rheum</term><term>Rheumatoid</term><term>Rheumatoid arthritis</term><term>Rheumatology</term><term>Safety analyses</term><term>Safety population</term><term>Siemens healthcare diagnostics</term><term>Small molecule ccr1 antagonist</term><term>Soluble bone turnover markers</term><term>Statistical power</term><term>Statistical testing</term><term>Study centre</term><term>Study design</term><term>Study medication</term><term>Study period</term><term>Study protocol</term><term>Study subjects</term><term>Study visits</term><term>Subject assessment</term><term>Supplementary appendix</term><term>Synovial tissue</term><term>Time points</term><term>Treatment group</term><term>Treatment groups</term><term>Treatment period</term><term>Trough plasma concentration</term><term>Upper limit</term><term>Visual analogue scale</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Objectives CCX354-C is a specific, orally administered antagonist of the C-C chemokine receptor 1, which regulates migration of monocytes and macrophages to synovial tissue. This clinical trial evaluated the safety and efficacy of CCX354-C in patients with rheumatoid arthritis (RA). Methods CARAT-2 is a 12-week double-blind, randomised, placebo controlled trial in 160 patients with RA, with 68 tender joint count and 66 swollen joint count ≥8 and C-reactive protein (CRP) >5 mg/l, despite being on methotrexate for at least 16 weeks. Subjects received placebo, CCX354-C 100 mg twice daily, or 200 mg once daily for 12 weeks. Endpoints included safety (primary) and RA disease activity assessments based on American College of Rheumatology (ACR) response, and changes in 28-joint disease activity score–CRP, individual ACR components, as well as soluble bone turnover markers. Results CCX354-C was generally well tolerated by study subjects. The ACR20 response at week 12 was 39% in the placebo group, 43% in the 100 mg twice daily group (difference and 95% CI compared with placebo, 4.5 (−14.1 to 23.1); p=0.62) and 52% in the 200 mg once daily group (13.0 (−5.8 to 31.8); p=0.17) in the intention-to-treat population, and 30% in the placebo group, 44% in the 100 mg twice daily group (14.4 (−5.9 to 34.8); p=0.17), and 56% in the 200 mg once daily group (25.8 (5.3 to 46.4); p=0.01) in the prespecified population of patients satisfying CRP and joint count eligibility criteria at the screening and day 1 (predose) visits. Conclusions CCX354-C exhibited a good safety and tolerability profile and evidence of clinical activity in RA.</div></front></TEI><affiliations><list><country><li>Hongrie</li><li>Roumanie</li><li>Royaume-Uni</li><li>Ukraine</li><li>États-Unis</li></country><region><li>Californie</li><li>Hollande-Septentrionale</li></region><settlement><li>Amsterdam</li></settlement><orgName><li>Université d'Amsterdam</li></orgName></list><tree><country name="Royaume-Uni"><region name="Hollande-Septentrionale"><name sortKey="Tak, Paul P" sort="Tak, Paul P" uniqKey="Tak P" first="Paul P" last="Tak">Paul P. Tak</name></region></country><country name="Roumanie"><noRegion><name sortKey="Balanescu, Andra" sort="Balanescu, Andra" uniqKey="Balanescu A" first="Andra" last="Balanescu">Andra Balanescu</name></noRegion><name sortKey="Bojin, Silvia" sort="Bojin, Silvia" uniqKey="Bojin S" first="Silvia" last="Bojin">Silvia Bojin</name></country><country name="Ukraine"><noRegion><name sortKey="Tseluyko, Vira" sort="Tseluyko, Vira" uniqKey="Tseluyko V" first="Vira" last="Tseluyko">Vira Tseluyko</name></noRegion></country><country name="Hongrie"><noRegion><name sortKey="Drescher, Edit" sort="Drescher, Edit" uniqKey="Drescher E" first="Edit" last="Drescher">Edit Drescher</name></noRegion></country><country name="États-Unis"><region name="Californie"><name sortKey="Dairaghi, Dan" sort="Dairaghi, Dan" uniqKey="Dairaghi D" first="Dan" last="Dairaghi">Dan Dairaghi</name></region><name sortKey="Bekker, Pirow" sort="Bekker, Pirow" uniqKey="Bekker P" first="Pirow" last="Bekker">Pirow Bekker</name><name sortKey="Jaen, Juan" sort="Jaen, Juan" uniqKey="Jaen J" first="Juan" last="Jaen">Juan Jaen</name><name sortKey="Marchesin, Vittorio" sort="Marchesin, Vittorio" uniqKey="Marchesin V" first="Vittorio" last="Marchesin">Vittorio Marchesin</name><name sortKey="Miao, Shichang" sort="Miao, Shichang" uniqKey="Miao S" first="Shichang" last="Miao">Shichang Miao</name><name sortKey="Schall, Thomas J" sort="Schall, Thomas J" uniqKey="Schall T" first="Thomas J" last="Schall">Thomas J. 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