A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis
Primary sclerosing cholangitis (PSC) is a rare, cholestatic liver disease with no currently approved therapies. Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist approved for the treatment of primary biliary cholangitis. We investigated the efficacy and safety of OCA in patients...
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| Veröffentlicht in: | Journal of hepatology 2020-07, Vol.73 (1), p.94-101 |
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| creator | Kowdley, Kris V. Vuppalanchi, Raj Levy, Cynthia Floreani, Annarosa Andreone, Pietro LaRusso, Nicholas F. Shrestha, Roshan Trotter, James Goldberg, David Rushbrook, Simon Hirschfield, Gideon M. Schiano, Thomas Jin, Yuying Pencek, Richard MacConell, Leigh Shapiro, David Bowlus, Christopher L. |
| description | Primary sclerosing cholangitis (PSC) is a rare, cholestatic liver disease with no currently approved therapies. Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist approved for the treatment of primary biliary cholangitis. We investigated the efficacy and safety of OCA in patients with PSC.
AESOP was a phase II, randomized, double-blind, placebo-controlled, dose-finding study. Eligible patients were 18 to 75 years of age with a diagnosis of PSC and serum alkaline phosphatase (ALP) ≥2× the upper limit of normal (ULN) and total bilirubin |
| doi_str_mv | 10.1016/j.jhep.2020.02.033 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8157171</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0168827820301604</els_id><sourcerecordid>2377340190</sourcerecordid><originalsourceid>FETCH-LOGICAL-c455t-ca51f9746810837bc598509c6212397a908fec5ba8cea8f6468f300cccc666bc3</originalsourceid><addsrcrecordid>eNp9kU9r3DAQxUVpaTZpv0APRcceamck2bIMpRBC_ywEeknOQh6Pd7V4ra3kDSSfPtruNrSX6DIg_eZp3jzGPggoBQh9uSk3a9qVEiSUIEtQ6hVbCA1QgK7Ea7bIkCmMbMwZO09pAwAK2uotO1NS6FrWYsFWVzy6qQ9b_0j9Z74bHVIXCgzTHMM4_rlbu0R8ueRp3vcPPAw8dDR7XIfRI3foez6EyHfRb1184AlHiiH5acUPiJtWfvbpHXszuDHR-1O9YHffv91e_yxufv1YXl_dFFjV9Vygq8XQNpU2AoxqOqxbU0OLWgqp2sa1YAbCunMGyZlBZ3BQAJiP1rpDdcG-HnV3-25LPVL24UZ7Gs4G5-3_L5Nf21W4t0bUjWhEFvh0Eojh957SbLc-IY3ZCIV9slI1japAtJBReUQx-02RhudvBNhDQnZjDwnZQ0IWpM0J5aaP_w743PI3kgx8OQKU13TvKdqEniak3kfC2fbBv6T_BCcHpCA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2377340190</pqid></control><display><type>article</type><title>A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis</title><source>Elsevier ScienceDirect Journals</source><creator>Kowdley, Kris V. ; Vuppalanchi, Raj ; Levy, Cynthia ; Floreani, Annarosa ; Andreone, Pietro ; LaRusso, Nicholas F. ; Shrestha, Roshan ; Trotter, James ; Goldberg, David ; Rushbrook, Simon ; Hirschfield, Gideon M. ; Schiano, Thomas ; Jin, Yuying ; Pencek, Richard ; MacConell, Leigh ; Shapiro, David ; Bowlus, Christopher L.</creator><creatorcontrib>Kowdley, Kris V. ; Vuppalanchi, Raj ; Levy, Cynthia ; Floreani, Annarosa ; Andreone, Pietro ; LaRusso, Nicholas F. ; Shrestha, Roshan ; Trotter, James ; Goldberg, David ; Rushbrook, Simon ; Hirschfield, Gideon M. ; Schiano, Thomas ; Jin, Yuying ; Pencek, Richard ; MacConell, Leigh ; Shapiro, David ; Bowlus, Christopher L. ; AESOP Study Investigators</creatorcontrib><description>Primary sclerosing cholangitis (PSC) is a rare, cholestatic liver disease with no currently approved therapies. Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist approved for the treatment of primary biliary cholangitis. We investigated the efficacy and safety of OCA in patients with PSC.
AESOP was a phase II, randomized, double-blind, placebo-controlled, dose-finding study. Eligible patients were 18 to 75 years of age with a diagnosis of PSC and serum alkaline phosphatase (ALP) ≥2× the upper limit of normal (ULN) and total bilirubin <2.5× ULN. Patients were randomized 1:1:1 to receive placebo, OCA 1.5–3.0 mg, or OCA 5–10 mg once daily for a 24-week, double-blind phase followed by a 2-year, long-term safety extension (LTSE). Primary endpoints were change in ALP from baseline to week 24, and safety.
The intent-to-treat population comprised 76 patients randomized to placebo (n = 25), OCA 1.5–3.0 mg (n = 25), and OCA 5–10 mg (n = 26). At week 24, serum ALP was significantly reduced with OCA 5–10 mg vs. placebo (least-square [LS] mean difference = −83.4 [SE = 40.3] U/L; 95% CI −164.28 to −2.57; p = 0.043). Serum ALP was not significantly reduced with OCA 1.5–3.0 mg vs. placebo at week 24 (LS mean [SE] difference = −78.29 [41.81] U/L; 95% CI −162.08 to 5.50; p = 0.067). Total bilirubin remained comparable to baseline in all groups. The most common treatment-emergent adverse event was dose-related pruritus (placebo 46%; OCA 1.5–3.0 mg 60%; OCA 5–10 mg 67%). Reductions in ALP were maintained during the LTSE, and no new safety signals emerged.
Treatment with OCA 5–10 mg reduced serum ALP in patients with PSC. Mild to moderate dose-related pruritus was the most common adverse event.
ClinicalTrials.gov: NCT02177136; EudraCT: 2014-002205-38.
Primary sclerosing cholangitis (PSC) is a long-term disease that damages the bile ducts in the liver over time. In the AESOP clinical study in patients with PSC, obeticholic acid reduced serum alkaline phosphatase (a potential marker of disease severity) during an initial 24-week treatment period. The result was sustained during the 2-year, long-term extension of the study. The most common side effect of obeticholic acid in the study was itchy skin, which is consistent with earlier clinical studies.
[Display omitted]
•Novel treatments for PSC are an urgent unmet need.•This phase II study evaluated OCA in patients with PSC.•OCA 5–10 mg significantly reduced serum ALP levels at 24 weeks.•The safety profile of OCA was consistent with previous studies.</description><identifier>ISSN: 0168-8278</identifier><identifier>EISSN: 1600-0641</identifier><identifier>DOI: 10.1016/j.jhep.2020.02.033</identifier><identifier>PMID: 32165251</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Cholestasis ; Farnesoid X receptor ; Ursodeoxycholic acid</subject><ispartof>Journal of hepatology, 2020-07, Vol.73 (1), p.94-101</ispartof><rights>2020 European Association for the Study of the Liver</rights><rights>Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c455t-ca51f9746810837bc598509c6212397a908fec5ba8cea8f6468f300cccc666bc3</citedby><cites>FETCH-LOGICAL-c455t-ca51f9746810837bc598509c6212397a908fec5ba8cea8f6468f300cccc666bc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0168827820301604$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32165251$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kowdley, Kris V.</creatorcontrib><creatorcontrib>Vuppalanchi, Raj</creatorcontrib><creatorcontrib>Levy, Cynthia</creatorcontrib><creatorcontrib>Floreani, Annarosa</creatorcontrib><creatorcontrib>Andreone, Pietro</creatorcontrib><creatorcontrib>LaRusso, Nicholas F.</creatorcontrib><creatorcontrib>Shrestha, Roshan</creatorcontrib><creatorcontrib>Trotter, James</creatorcontrib><creatorcontrib>Goldberg, David</creatorcontrib><creatorcontrib>Rushbrook, Simon</creatorcontrib><creatorcontrib>Hirschfield, Gideon M.</creatorcontrib><creatorcontrib>Schiano, Thomas</creatorcontrib><creatorcontrib>Jin, Yuying</creatorcontrib><creatorcontrib>Pencek, Richard</creatorcontrib><creatorcontrib>MacConell, Leigh</creatorcontrib><creatorcontrib>Shapiro, David</creatorcontrib><creatorcontrib>Bowlus, Christopher L.</creatorcontrib><creatorcontrib>AESOP Study Investigators</creatorcontrib><title>A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis</title><title>Journal of hepatology</title><addtitle>J Hepatol</addtitle><description>Primary sclerosing cholangitis (PSC) is a rare, cholestatic liver disease with no currently approved therapies. Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist approved for the treatment of primary biliary cholangitis. We investigated the efficacy and safety of OCA in patients with PSC.
AESOP was a phase II, randomized, double-blind, placebo-controlled, dose-finding study. Eligible patients were 18 to 75 years of age with a diagnosis of PSC and serum alkaline phosphatase (ALP) ≥2× the upper limit of normal (ULN) and total bilirubin <2.5× ULN. Patients were randomized 1:1:1 to receive placebo, OCA 1.5–3.0 mg, or OCA 5–10 mg once daily for a 24-week, double-blind phase followed by a 2-year, long-term safety extension (LTSE). Primary endpoints were change in ALP from baseline to week 24, and safety.
The intent-to-treat population comprised 76 patients randomized to placebo (n = 25), OCA 1.5–3.0 mg (n = 25), and OCA 5–10 mg (n = 26). At week 24, serum ALP was significantly reduced with OCA 5–10 mg vs. placebo (least-square [LS] mean difference = −83.4 [SE = 40.3] U/L; 95% CI −164.28 to −2.57; p = 0.043). Serum ALP was not significantly reduced with OCA 1.5–3.0 mg vs. placebo at week 24 (LS mean [SE] difference = −78.29 [41.81] U/L; 95% CI −162.08 to 5.50; p = 0.067). Total bilirubin remained comparable to baseline in all groups. The most common treatment-emergent adverse event was dose-related pruritus (placebo 46%; OCA 1.5–3.0 mg 60%; OCA 5–10 mg 67%). Reductions in ALP were maintained during the LTSE, and no new safety signals emerged.
Treatment with OCA 5–10 mg reduced serum ALP in patients with PSC. Mild to moderate dose-related pruritus was the most common adverse event.
ClinicalTrials.gov: NCT02177136; EudraCT: 2014-002205-38.
Primary sclerosing cholangitis (PSC) is a long-term disease that damages the bile ducts in the liver over time. In the AESOP clinical study in patients with PSC, obeticholic acid reduced serum alkaline phosphatase (a potential marker of disease severity) during an initial 24-week treatment period. The result was sustained during the 2-year, long-term extension of the study. The most common side effect of obeticholic acid in the study was itchy skin, which is consistent with earlier clinical studies.
[Display omitted]
•Novel treatments for PSC are an urgent unmet need.•This phase II study evaluated OCA in patients with PSC.•OCA 5–10 mg significantly reduced serum ALP levels at 24 weeks.•The safety profile of OCA was consistent with previous studies.</description><subject>Cholestasis</subject><subject>Farnesoid X receptor</subject><subject>Ursodeoxycholic acid</subject><issn>0168-8278</issn><issn>1600-0641</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9kU9r3DAQxUVpaTZpv0APRcceamck2bIMpRBC_ywEeknOQh6Pd7V4ra3kDSSfPtruNrSX6DIg_eZp3jzGPggoBQh9uSk3a9qVEiSUIEtQ6hVbCA1QgK7Ea7bIkCmMbMwZO09pAwAK2uotO1NS6FrWYsFWVzy6qQ9b_0j9Z74bHVIXCgzTHMM4_rlbu0R8ueRp3vcPPAw8dDR7XIfRI3foez6EyHfRb1184AlHiiH5acUPiJtWfvbpHXszuDHR-1O9YHffv91e_yxufv1YXl_dFFjV9Vygq8XQNpU2AoxqOqxbU0OLWgqp2sa1YAbCunMGyZlBZ3BQAJiP1rpDdcG-HnV3-25LPVL24UZ7Gs4G5-3_L5Nf21W4t0bUjWhEFvh0Eojh957SbLc-IY3ZCIV9slI1japAtJBReUQx-02RhudvBNhDQnZjDwnZQ0IWpM0J5aaP_w743PI3kgx8OQKU13TvKdqEniak3kfC2fbBv6T_BCcHpCA</recordid><startdate>20200701</startdate><enddate>20200701</enddate><creator>Kowdley, Kris V.</creator><creator>Vuppalanchi, Raj</creator><creator>Levy, Cynthia</creator><creator>Floreani, Annarosa</creator><creator>Andreone, Pietro</creator><creator>LaRusso, Nicholas F.</creator><creator>Shrestha, Roshan</creator><creator>Trotter, James</creator><creator>Goldberg, David</creator><creator>Rushbrook, Simon</creator><creator>Hirschfield, Gideon M.</creator><creator>Schiano, Thomas</creator><creator>Jin, Yuying</creator><creator>Pencek, Richard</creator><creator>MacConell, Leigh</creator><creator>Shapiro, David</creator><creator>Bowlus, Christopher L.</creator><general>Elsevier B.V</general><scope>6I.</scope><scope>AAFTH</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20200701</creationdate><title>A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis</title><author>Kowdley, Kris V. ; 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Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist approved for the treatment of primary biliary cholangitis. We investigated the efficacy and safety of OCA in patients with PSC.
AESOP was a phase II, randomized, double-blind, placebo-controlled, dose-finding study. Eligible patients were 18 to 75 years of age with a diagnosis of PSC and serum alkaline phosphatase (ALP) ≥2× the upper limit of normal (ULN) and total bilirubin <2.5× ULN. Patients were randomized 1:1:1 to receive placebo, OCA 1.5–3.0 mg, or OCA 5–10 mg once daily for a 24-week, double-blind phase followed by a 2-year, long-term safety extension (LTSE). Primary endpoints were change in ALP from baseline to week 24, and safety.
The intent-to-treat population comprised 76 patients randomized to placebo (n = 25), OCA 1.5–3.0 mg (n = 25), and OCA 5–10 mg (n = 26). At week 24, serum ALP was significantly reduced with OCA 5–10 mg vs. placebo (least-square [LS] mean difference = −83.4 [SE = 40.3] U/L; 95% CI −164.28 to −2.57; p = 0.043). Serum ALP was not significantly reduced with OCA 1.5–3.0 mg vs. placebo at week 24 (LS mean [SE] difference = −78.29 [41.81] U/L; 95% CI −162.08 to 5.50; p = 0.067). Total bilirubin remained comparable to baseline in all groups. The most common treatment-emergent adverse event was dose-related pruritus (placebo 46%; OCA 1.5–3.0 mg 60%; OCA 5–10 mg 67%). Reductions in ALP were maintained during the LTSE, and no new safety signals emerged.
Treatment with OCA 5–10 mg reduced serum ALP in patients with PSC. Mild to moderate dose-related pruritus was the most common adverse event.
ClinicalTrials.gov: NCT02177136; EudraCT: 2014-002205-38.
Primary sclerosing cholangitis (PSC) is a long-term disease that damages the bile ducts in the liver over time. In the AESOP clinical study in patients with PSC, obeticholic acid reduced serum alkaline phosphatase (a potential marker of disease severity) during an initial 24-week treatment period. The result was sustained during the 2-year, long-term extension of the study. The most common side effect of obeticholic acid in the study was itchy skin, which is consistent with earlier clinical studies.
[Display omitted]
•Novel treatments for PSC are an urgent unmet need.•This phase II study evaluated OCA in patients with PSC.•OCA 5–10 mg significantly reduced serum ALP levels at 24 weeks.•The safety profile of OCA was consistent with previous studies.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>32165251</pmid><doi>10.1016/j.jhep.2020.02.033</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| source | Elsevier ScienceDirect Journals |
| subjects | Cholestasis Farnesoid X receptor Ursodeoxycholic acid |
| title | A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis |
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