Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study
The PROUD-PV and CONTINUATION-PV trials aimed to compare the novel monopegylated interferon ropeginterferon alfa-2b with hydroxyurea, the standard therapy for patients with polycythaemia vera, over 3 years of treatment. PROUD-PV and its extension study, CONTINUATION-PV, were phase 3, randomised, con...
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| Veröffentlicht in: | The Lancet. Haematology 2020-03, Vol.7 (3), p.e196-e208 |
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| creator | Gisslinger, Heinz Klade, Christoph Georgiev, Pencho Krochmalczyk, Dorota Gercheva-Kyuchukova, Liana Egyed, Miklos Rossiev, Viktor Dulicek, Petr Illes, Arpad Pylypenko, Halyna Sivcheva, Lylia Mayer, Jiri Yablokova, Vera Krejcy, Kurt Grohmann-Izay, Barbara Hasselbalch, Hans C Kralovics, Robert Kiladjian, Jean-Jacques Bauer, Franz Berbec, Nicoleta Besses Raebel, Carlos Borbenyi, Zita Bumbea, Horia Buxhofer-Ausch, Veronika Calbecka, Malgorzata Cayssials-Caylus, Emilie Cazzola, Mario Cerna, Olga Cucuianu, Andrei Dima, Delia Monica Forjan, Ernst Gheorghita, Emanuil Greil, Richard Hatalova, Antonia Hrubisko, Mikulas Jakucs, Janos Kaplan, Polina Klymenko, Sergiy Koschmieder, Steffen Lazaroiu, Mihaela Lysa, Tamila Masliak, Zvenyslava Masszi, Tamas Mihaylov, Georgi Myasnikov, Alexander Platzbecker, Uwe Puyade, Mathieu Rey, Jerome Roy, Lydia Schwarz, Jiri Skotnicki, Aleksander Sokolova, Irina Soroka-Wojtaszko, Maria Starzak-Gwozdz, Jolanta Stoeva, Vera Torregrosa-Diaz, Jose Miguel Vallova, Anna Volodicheva, Elena Warzocha, Krzysztof Willenbacher, Ella Wolf, Dominik |
| description | The PROUD-PV and CONTINUATION-PV trials aimed to compare the novel monopegylated interferon ropeginterferon alfa-2b with hydroxyurea, the standard therapy for patients with polycythaemia vera, over 3 years of treatment.
PROUD-PV and its extension study, CONTINUATION-PV, were phase 3, randomised, controlled, open-label, trials done in 48 clinics in Europe. Patients were eligible if 18 years or older with early stage polycythaemia vera (no history of cytoreductive treatment or less than 3 years of previous hydroxyurea treatment) diagnosed by WHO's 2008 criteria. Patients were randomly assigned 1:1 to ropeginterferon alfa-2b (subcutaneously every 2 weeks, starting at 100 μg) or hydroxyurea (orally starting at 500 mg/day). After 1 year, patients could opt to enter the extension part of the trial, CONTINUATION-PV. The primary endpoint in PROUD-PV was non-inferiority of ropeginterferon alfa-2b versus hydroxyurea regarding complete haematological response with normal spleen size (longitudinal diameter of ≤12 cm for women and ≤13 cm for men) at 12 months; in CONTINUATION-PV, the coprimary endpoints were complete haematological response with normalisation of spleen size and with improved disease burden (ie, splenomegaly, microvascular disturbances, pruritus, and headache). We present the final results of PROUD-PV and an interim analysis at 36 months of the CONTINUATION-PV study (per statistical analysis plan). Analyses for safety and efficacy were per-protocol. The trials were registered on EudraCT, 2012-005259-18 (PROUD-PV) and 2014-001357-17 (CONTINUATION-PV, which is ongoing).
Patients were recruited from Sept 17, 2013 to March 13, 2015 with 306 enrolled. 257 patients were randomly assigned, 127 were treated in each group (three patients withdrew consent in the hydroxyurea group), and 171 rolled over to the CONTINUATION-PV trial. Median follow-up was 182·1 weeks (IQR 166·3–201·7) in the ropeginterferon alfa-2b and 164·5 weeks (144·4–169·3) in the standard therapy group. In PROUD-PV, 26 (21%) of 122 patients in the ropeginterferon alfa-2b group and 34 (28%) of 123 patients in the standard therapy group met the composite primary endpoint of complete haematological response with normal spleen size. In CONTINUATION-PV, complete haematological response with improved disease burden was met in 50 (53%) of 95 patients in the ropeginterferon alfa-2b group versus 28 (38%) of 74 patients in the hydroxyurea group, p=0·044 at 36 months. Complete haematological response witho |
| doi_str_mv | 10.1016/S2352-3026(19)30236-4 |
| format | Article |
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PROUD-PV and its extension study, CONTINUATION-PV, were phase 3, randomised, controlled, open-label, trials done in 48 clinics in Europe. Patients were eligible if 18 years or older with early stage polycythaemia vera (no history of cytoreductive treatment or less than 3 years of previous hydroxyurea treatment) diagnosed by WHO's 2008 criteria. Patients were randomly assigned 1:1 to ropeginterferon alfa-2b (subcutaneously every 2 weeks, starting at 100 μg) or hydroxyurea (orally starting at 500 mg/day). After 1 year, patients could opt to enter the extension part of the trial, CONTINUATION-PV. The primary endpoint in PROUD-PV was non-inferiority of ropeginterferon alfa-2b versus hydroxyurea regarding complete haematological response with normal spleen size (longitudinal diameter of ≤12 cm for women and ≤13 cm for men) at 12 months; in CONTINUATION-PV, the coprimary endpoints were complete haematological response with normalisation of spleen size and with improved disease burden (ie, splenomegaly, microvascular disturbances, pruritus, and headache). We present the final results of PROUD-PV and an interim analysis at 36 months of the CONTINUATION-PV study (per statistical analysis plan). Analyses for safety and efficacy were per-protocol. The trials were registered on EudraCT, 2012-005259-18 (PROUD-PV) and 2014-001357-17 (CONTINUATION-PV, which is ongoing).
Patients were recruited from Sept 17, 2013 to March 13, 2015 with 306 enrolled. 257 patients were randomly assigned, 127 were treated in each group (three patients withdrew consent in the hydroxyurea group), and 171 rolled over to the CONTINUATION-PV trial. Median follow-up was 182·1 weeks (IQR 166·3–201·7) in the ropeginterferon alfa-2b and 164·5 weeks (144·4–169·3) in the standard therapy group. In PROUD-PV, 26 (21%) of 122 patients in the ropeginterferon alfa-2b group and 34 (28%) of 123 patients in the standard therapy group met the composite primary endpoint of complete haematological response with normal spleen size. In CONTINUATION-PV, complete haematological response with improved disease burden was met in 50 (53%) of 95 patients in the ropeginterferon alfa-2b group versus 28 (38%) of 74 patients in the hydroxyurea group, p=0·044 at 36 months. Complete haematological response without the spleen criterion in the ropeginterferon alfa-2b group versus standard therapy group were: 53 (43%) of 123 patients versus 57 (46%) of 125 patients, p=0·63 at 12 months (PROUD-PV), and 67 (71%) of 95 patients versus 38 (51%) of 74 patients, p=0·012 at 36 months (CONTINUATION-PV). The most frequently reported grade 3 and grade 4 treatment-related adverse events were increased γ-glutamyltransferase (seven [6%] of 127 patients) and increased alanine aminotransferase (four [3%] of 127 patients) in the ropeginterferon alfa-2b group, and leucopenia (six [5%] of 127 patients) and thrombocytopenia (five [4%] of 127 patients) in the standard therapy group. Treatment-related serious adverse events occurred in three (2%) of 127 patients in the ropeginterferon alfa-2b group and five (4%) of 127 patients in the hydroxyurea group. One treatment-related death was reported in the standard therapy group (acute leukaemia).
In patients with early polycythaemia vera, who predominantly presented without splenomegaly, ropeginterferon alfa-2b was effective in inducing haematological responses; non-inferiority to hydroxyurea regarding haematological response and normal spleen size was not shown at 12 months. However, response to ropeginterferon alfa-2b continued to increase over time with improved responses compared with hydroxyurea at 36 months. Considering the high and durable haematological and molecular responses and its good tolerability, ropeginterferon alfa-2b offers a valuable and safe long-term treatment option with features distinct from hydroxyurea.
AOP Orphan Pharmaceuticals AG.</description><identifier>ISSN: 2352-3026</identifier><identifier>EISSN: 2352-3026</identifier><identifier>DOI: 10.1016/S2352-3026(19)30236-4</identifier><identifier>PMID: 32014125</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Aged ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Antiviral Agents - therapeutic use ; Equivalence Trials as Topic ; Female ; Follow-Up Studies ; Humans ; Interferon alpha-2 - therapeutic use ; Interferon-alpha - therapeutic use ; Male ; Middle Aged ; Polycythemia Vera - drug therapy ; Polycythemia Vera - pathology ; Polyethylene Glycols - therapeutic use ; Prognosis ; Recombinant Proteins - therapeutic use</subject><ispartof>The Lancet. Haematology, 2020-03, Vol.7 (3), p.e196-e208</ispartof><rights>2020 Elsevier Ltd</rights><rights>Copyright © 2020 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c417t-60a7af228ca0a2ed70a83e3e9c734c3f87e723253adc1ede8854054fdce72fe73</citedby><cites>FETCH-LOGICAL-c417t-60a7af228ca0a2ed70a83e3e9c734c3f87e723253adc1ede8854054fdce72fe73</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/32014125$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gisslinger, Heinz</creatorcontrib><creatorcontrib>Klade, Christoph</creatorcontrib><creatorcontrib>Georgiev, Pencho</creatorcontrib><creatorcontrib>Krochmalczyk, Dorota</creatorcontrib><creatorcontrib>Gercheva-Kyuchukova, Liana</creatorcontrib><creatorcontrib>Egyed, Miklos</creatorcontrib><creatorcontrib>Rossiev, Viktor</creatorcontrib><creatorcontrib>Dulicek, Petr</creatorcontrib><creatorcontrib>Illes, Arpad</creatorcontrib><creatorcontrib>Pylypenko, Halyna</creatorcontrib><creatorcontrib>Sivcheva, Lylia</creatorcontrib><creatorcontrib>Mayer, Jiri</creatorcontrib><creatorcontrib>Yablokova, Vera</creatorcontrib><creatorcontrib>Krejcy, Kurt</creatorcontrib><creatorcontrib>Grohmann-Izay, Barbara</creatorcontrib><creatorcontrib>Hasselbalch, Hans C</creatorcontrib><creatorcontrib>Kralovics, Robert</creatorcontrib><creatorcontrib>Kiladjian, Jean-Jacques</creatorcontrib><creatorcontrib>Bauer, Franz</creatorcontrib><creatorcontrib>Berbec, Nicoleta</creatorcontrib><creatorcontrib>Besses Raebel, Carlos</creatorcontrib><creatorcontrib>Borbenyi, Zita</creatorcontrib><creatorcontrib>Bumbea, Horia</creatorcontrib><creatorcontrib>Buxhofer-Ausch, Veronika</creatorcontrib><creatorcontrib>Calbecka, Malgorzata</creatorcontrib><creatorcontrib>Cayssials-Caylus, Emilie</creatorcontrib><creatorcontrib>Cazzola, Mario</creatorcontrib><creatorcontrib>Cerna, Olga</creatorcontrib><creatorcontrib>Cucuianu, Andrei</creatorcontrib><creatorcontrib>Dima, Delia Monica</creatorcontrib><creatorcontrib>Forjan, Ernst</creatorcontrib><creatorcontrib>Gheorghita, Emanuil</creatorcontrib><creatorcontrib>Greil, Richard</creatorcontrib><creatorcontrib>Hatalova, Antonia</creatorcontrib><creatorcontrib>Hrubisko, Mikulas</creatorcontrib><creatorcontrib>Jakucs, Janos</creatorcontrib><creatorcontrib>Kaplan, Polina</creatorcontrib><creatorcontrib>Klymenko, Sergiy</creatorcontrib><creatorcontrib>Koschmieder, Steffen</creatorcontrib><creatorcontrib>Lazaroiu, Mihaela</creatorcontrib><creatorcontrib>Lysa, Tamila</creatorcontrib><creatorcontrib>Masliak, Zvenyslava</creatorcontrib><creatorcontrib>Masszi, Tamas</creatorcontrib><creatorcontrib>Mihaylov, Georgi</creatorcontrib><creatorcontrib>Myasnikov, Alexander</creatorcontrib><creatorcontrib>Platzbecker, Uwe</creatorcontrib><creatorcontrib>Puyade, Mathieu</creatorcontrib><creatorcontrib>Rey, Jerome</creatorcontrib><creatorcontrib>Roy, Lydia</creatorcontrib><creatorcontrib>Schwarz, Jiri</creatorcontrib><creatorcontrib>Skotnicki, Aleksander</creatorcontrib><creatorcontrib>Sokolova, Irina</creatorcontrib><creatorcontrib>Soroka-Wojtaszko, Maria</creatorcontrib><creatorcontrib>Starzak-Gwozdz, Jolanta</creatorcontrib><creatorcontrib>Stoeva, Vera</creatorcontrib><creatorcontrib>Torregrosa-Diaz, Jose Miguel</creatorcontrib><creatorcontrib>Vallova, Anna</creatorcontrib><creatorcontrib>Volodicheva, Elena</creatorcontrib><creatorcontrib>Warzocha, Krzysztof</creatorcontrib><creatorcontrib>Willenbacher, Ella</creatorcontrib><creatorcontrib>Wolf, Dominik</creatorcontrib><creatorcontrib>PROUD-PV Study Group</creatorcontrib><title>Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study</title><title>The Lancet. Haematology</title><addtitle>Lancet Haematol</addtitle><description>The PROUD-PV and CONTINUATION-PV trials aimed to compare the novel monopegylated interferon ropeginterferon alfa-2b with hydroxyurea, the standard therapy for patients with polycythaemia vera, over 3 years of treatment.
PROUD-PV and its extension study, CONTINUATION-PV, were phase 3, randomised, controlled, open-label, trials done in 48 clinics in Europe. Patients were eligible if 18 years or older with early stage polycythaemia vera (no history of cytoreductive treatment or less than 3 years of previous hydroxyurea treatment) diagnosed by WHO's 2008 criteria. Patients were randomly assigned 1:1 to ropeginterferon alfa-2b (subcutaneously every 2 weeks, starting at 100 μg) or hydroxyurea (orally starting at 500 mg/day). After 1 year, patients could opt to enter the extension part of the trial, CONTINUATION-PV. The primary endpoint in PROUD-PV was non-inferiority of ropeginterferon alfa-2b versus hydroxyurea regarding complete haematological response with normal spleen size (longitudinal diameter of ≤12 cm for women and ≤13 cm for men) at 12 months; in CONTINUATION-PV, the coprimary endpoints were complete haematological response with normalisation of spleen size and with improved disease burden (ie, splenomegaly, microvascular disturbances, pruritus, and headache). We present the final results of PROUD-PV and an interim analysis at 36 months of the CONTINUATION-PV study (per statistical analysis plan). Analyses for safety and efficacy were per-protocol. The trials were registered on EudraCT, 2012-005259-18 (PROUD-PV) and 2014-001357-17 (CONTINUATION-PV, which is ongoing).
Patients were recruited from Sept 17, 2013 to March 13, 2015 with 306 enrolled. 257 patients were randomly assigned, 127 were treated in each group (three patients withdrew consent in the hydroxyurea group), and 171 rolled over to the CONTINUATION-PV trial. Median follow-up was 182·1 weeks (IQR 166·3–201·7) in the ropeginterferon alfa-2b and 164·5 weeks (144·4–169·3) in the standard therapy group. In PROUD-PV, 26 (21%) of 122 patients in the ropeginterferon alfa-2b group and 34 (28%) of 123 patients in the standard therapy group met the composite primary endpoint of complete haematological response with normal spleen size. In CONTINUATION-PV, complete haematological response with improved disease burden was met in 50 (53%) of 95 patients in the ropeginterferon alfa-2b group versus 28 (38%) of 74 patients in the hydroxyurea group, p=0·044 at 36 months. Complete haematological response without the spleen criterion in the ropeginterferon alfa-2b group versus standard therapy group were: 53 (43%) of 123 patients versus 57 (46%) of 125 patients, p=0·63 at 12 months (PROUD-PV), and 67 (71%) of 95 patients versus 38 (51%) of 74 patients, p=0·012 at 36 months (CONTINUATION-PV). The most frequently reported grade 3 and grade 4 treatment-related adverse events were increased γ-glutamyltransferase (seven [6%] of 127 patients) and increased alanine aminotransferase (four [3%] of 127 patients) in the ropeginterferon alfa-2b group, and leucopenia (six [5%] of 127 patients) and thrombocytopenia (five [4%] of 127 patients) in the standard therapy group. Treatment-related serious adverse events occurred in three (2%) of 127 patients in the ropeginterferon alfa-2b group and five (4%) of 127 patients in the hydroxyurea group. One treatment-related death was reported in the standard therapy group (acute leukaemia).
In patients with early polycythaemia vera, who predominantly presented without splenomegaly, ropeginterferon alfa-2b was effective in inducing haematological responses; non-inferiority to hydroxyurea regarding haematological response and normal spleen size was not shown at 12 months. However, response to ropeginterferon alfa-2b continued to increase over time with improved responses compared with hydroxyurea at 36 months. Considering the high and durable haematological and molecular responses and its good tolerability, ropeginterferon alfa-2b offers a valuable and safe long-term treatment option with features distinct from hydroxyurea.
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Klade, Christoph ; Georgiev, Pencho ; Krochmalczyk, Dorota ; Gercheva-Kyuchukova, Liana ; Egyed, Miklos ; Rossiev, Viktor ; Dulicek, Petr ; Illes, Arpad ; Pylypenko, Halyna ; Sivcheva, Lylia ; Mayer, Jiri ; Yablokova, Vera ; Krejcy, Kurt ; Grohmann-Izay, Barbara ; Hasselbalch, Hans C ; Kralovics, Robert ; Kiladjian, Jean-Jacques ; Bauer, Franz ; Berbec, Nicoleta ; Besses Raebel, Carlos ; Borbenyi, Zita ; Bumbea, Horia ; Buxhofer-Ausch, Veronika ; Calbecka, Malgorzata ; Cayssials-Caylus, Emilie ; Cazzola, Mario ; Cerna, Olga ; Cucuianu, Andrei ; Dima, Delia Monica ; Forjan, Ernst ; Gheorghita, Emanuil ; Greil, Richard ; Hatalova, Antonia ; Hrubisko, Mikulas ; Jakucs, Janos ; Kaplan, Polina ; Klymenko, Sergiy ; Koschmieder, Steffen ; Lazaroiu, Mihaela ; Lysa, Tamila ; Masliak, Zvenyslava ; Masszi, Tamas ; Mihaylov, Georgi ; Myasnikov, Alexander ; Platzbecker, Uwe ; Puyade, Mathieu ; Rey, Jerome ; Roy, Lydia ; Schwarz, Jiri ; Skotnicki, Aleksander ; Sokolova, Irina ; Soroka-Wojtaszko, Maria ; Starzak-Gwozdz, Jolanta ; Stoeva, Vera ; Torregrosa-Diaz, Jose Miguel ; Vallova, Anna ; Volodicheva, Elena ; Warzocha, Krzysztof ; Willenbacher, Ella ; Wolf, Dominik</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c417t-60a7af228ca0a2ed70a83e3e9c734c3f87e723253adc1ede8854054fdce72fe73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Aged</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Antiviral Agents - therapeutic use</topic><topic>Equivalence Trials as Topic</topic><topic>Female</topic><topic>Follow-Up Studies</topic><topic>Humans</topic><topic>Interferon alpha-2 - therapeutic use</topic><topic>Interferon-alpha - therapeutic use</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Polycythemia Vera - drug therapy</topic><topic>Polycythemia Vera - pathology</topic><topic>Polyethylene Glycols - therapeutic use</topic><topic>Prognosis</topic><topic>Recombinant Proteins - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gisslinger, Heinz</creatorcontrib><creatorcontrib>Klade, Christoph</creatorcontrib><creatorcontrib>Georgiev, Pencho</creatorcontrib><creatorcontrib>Krochmalczyk, Dorota</creatorcontrib><creatorcontrib>Gercheva-Kyuchukova, Liana</creatorcontrib><creatorcontrib>Egyed, Miklos</creatorcontrib><creatorcontrib>Rossiev, Viktor</creatorcontrib><creatorcontrib>Dulicek, Petr</creatorcontrib><creatorcontrib>Illes, Arpad</creatorcontrib><creatorcontrib>Pylypenko, Halyna</creatorcontrib><creatorcontrib>Sivcheva, Lylia</creatorcontrib><creatorcontrib>Mayer, Jiri</creatorcontrib><creatorcontrib>Yablokova, Vera</creatorcontrib><creatorcontrib>Krejcy, Kurt</creatorcontrib><creatorcontrib>Grohmann-Izay, Barbara</creatorcontrib><creatorcontrib>Hasselbalch, Hans C</creatorcontrib><creatorcontrib>Kralovics, Robert</creatorcontrib><creatorcontrib>Kiladjian, Jean-Jacques</creatorcontrib><creatorcontrib>Bauer, Franz</creatorcontrib><creatorcontrib>Berbec, Nicoleta</creatorcontrib><creatorcontrib>Besses Raebel, Carlos</creatorcontrib><creatorcontrib>Borbenyi, Zita</creatorcontrib><creatorcontrib>Bumbea, Horia</creatorcontrib><creatorcontrib>Buxhofer-Ausch, Veronika</creatorcontrib><creatorcontrib>Calbecka, Malgorzata</creatorcontrib><creatorcontrib>Cayssials-Caylus, Emilie</creatorcontrib><creatorcontrib>Cazzola, Mario</creatorcontrib><creatorcontrib>Cerna, Olga</creatorcontrib><creatorcontrib>Cucuianu, Andrei</creatorcontrib><creatorcontrib>Dima, Delia Monica</creatorcontrib><creatorcontrib>Forjan, Ernst</creatorcontrib><creatorcontrib>Gheorghita, Emanuil</creatorcontrib><creatorcontrib>Greil, Richard</creatorcontrib><creatorcontrib>Hatalova, Antonia</creatorcontrib><creatorcontrib>Hrubisko, Mikulas</creatorcontrib><creatorcontrib>Jakucs, Janos</creatorcontrib><creatorcontrib>Kaplan, Polina</creatorcontrib><creatorcontrib>Klymenko, Sergiy</creatorcontrib><creatorcontrib>Koschmieder, Steffen</creatorcontrib><creatorcontrib>Lazaroiu, Mihaela</creatorcontrib><creatorcontrib>Lysa, Tamila</creatorcontrib><creatorcontrib>Masliak, Zvenyslava</creatorcontrib><creatorcontrib>Masszi, Tamas</creatorcontrib><creatorcontrib>Mihaylov, Georgi</creatorcontrib><creatorcontrib>Myasnikov, Alexander</creatorcontrib><creatorcontrib>Platzbecker, Uwe</creatorcontrib><creatorcontrib>Puyade, Mathieu</creatorcontrib><creatorcontrib>Rey, Jerome</creatorcontrib><creatorcontrib>Roy, Lydia</creatorcontrib><creatorcontrib>Schwarz, Jiri</creatorcontrib><creatorcontrib>Skotnicki, Aleksander</creatorcontrib><creatorcontrib>Sokolova, Irina</creatorcontrib><creatorcontrib>Soroka-Wojtaszko, Maria</creatorcontrib><creatorcontrib>Starzak-Gwozdz, Jolanta</creatorcontrib><creatorcontrib>Stoeva, Vera</creatorcontrib><creatorcontrib>Torregrosa-Diaz, Jose Miguel</creatorcontrib><creatorcontrib>Vallova, Anna</creatorcontrib><creatorcontrib>Volodicheva, Elena</creatorcontrib><creatorcontrib>Warzocha, Krzysztof</creatorcontrib><creatorcontrib>Willenbacher, Ella</creatorcontrib><creatorcontrib>Wolf, Dominik</creatorcontrib><creatorcontrib>PROUD-PV Study Group</creatorcontrib><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>The Lancet. Haematology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gisslinger, Heinz</au><au>Klade, Christoph</au><au>Georgiev, Pencho</au><au>Krochmalczyk, Dorota</au><au>Gercheva-Kyuchukova, Liana</au><au>Egyed, Miklos</au><au>Rossiev, Viktor</au><au>Dulicek, Petr</au><au>Illes, Arpad</au><au>Pylypenko, Halyna</au><au>Sivcheva, Lylia</au><au>Mayer, Jiri</au><au>Yablokova, Vera</au><au>Krejcy, Kurt</au><au>Grohmann-Izay, Barbara</au><au>Hasselbalch, Hans C</au><au>Kralovics, Robert</au><au>Kiladjian, Jean-Jacques</au><au>Bauer, Franz</au><au>Berbec, Nicoleta</au><au>Besses Raebel, Carlos</au><au>Borbenyi, Zita</au><au>Bumbea, Horia</au><au>Buxhofer-Ausch, Veronika</au><au>Calbecka, Malgorzata</au><au>Cayssials-Caylus, Emilie</au><au>Cazzola, Mario</au><au>Cerna, Olga</au><au>Cucuianu, Andrei</au><au>Dima, Delia Monica</au><au>Forjan, Ernst</au><au>Gheorghita, Emanuil</au><au>Greil, Richard</au><au>Hatalova, Antonia</au><au>Hrubisko, Mikulas</au><au>Jakucs, Janos</au><au>Kaplan, Polina</au><au>Klymenko, Sergiy</au><au>Koschmieder, Steffen</au><au>Lazaroiu, Mihaela</au><au>Lysa, Tamila</au><au>Masliak, Zvenyslava</au><au>Masszi, Tamas</au><au>Mihaylov, Georgi</au><au>Myasnikov, Alexander</au><au>Platzbecker, Uwe</au><au>Puyade, Mathieu</au><au>Rey, Jerome</au><au>Roy, Lydia</au><au>Schwarz, Jiri</au><au>Skotnicki, Aleksander</au><au>Sokolova, Irina</au><au>Soroka-Wojtaszko, Maria</au><au>Starzak-Gwozdz, Jolanta</au><au>Stoeva, Vera</au><au>Torregrosa-Diaz, Jose Miguel</au><au>Vallova, Anna</au><au>Volodicheva, Elena</au><au>Warzocha, Krzysztof</au><au>Willenbacher, Ella</au><au>Wolf, Dominik</au><aucorp>PROUD-PV Study Group</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study</atitle><jtitle>The Lancet. Haematology</jtitle><addtitle>Lancet Haematol</addtitle><date>2020-03</date><risdate>2020</risdate><volume>7</volume><issue>3</issue><spage>e196</spage><epage>e208</epage><pages>e196-e208</pages><issn>2352-3026</issn><eissn>2352-3026</eissn><abstract>The PROUD-PV and CONTINUATION-PV trials aimed to compare the novel monopegylated interferon ropeginterferon alfa-2b with hydroxyurea, the standard therapy for patients with polycythaemia vera, over 3 years of treatment.
PROUD-PV and its extension study, CONTINUATION-PV, were phase 3, randomised, controlled, open-label, trials done in 48 clinics in Europe. Patients were eligible if 18 years or older with early stage polycythaemia vera (no history of cytoreductive treatment or less than 3 years of previous hydroxyurea treatment) diagnosed by WHO's 2008 criteria. Patients were randomly assigned 1:1 to ropeginterferon alfa-2b (subcutaneously every 2 weeks, starting at 100 μg) or hydroxyurea (orally starting at 500 mg/day). After 1 year, patients could opt to enter the extension part of the trial, CONTINUATION-PV. The primary endpoint in PROUD-PV was non-inferiority of ropeginterferon alfa-2b versus hydroxyurea regarding complete haematological response with normal spleen size (longitudinal diameter of ≤12 cm for women and ≤13 cm for men) at 12 months; in CONTINUATION-PV, the coprimary endpoints were complete haematological response with normalisation of spleen size and with improved disease burden (ie, splenomegaly, microvascular disturbances, pruritus, and headache). We present the final results of PROUD-PV and an interim analysis at 36 months of the CONTINUATION-PV study (per statistical analysis plan). Analyses for safety and efficacy were per-protocol. The trials were registered on EudraCT, 2012-005259-18 (PROUD-PV) and 2014-001357-17 (CONTINUATION-PV, which is ongoing).
Patients were recruited from Sept 17, 2013 to March 13, 2015 with 306 enrolled. 257 patients were randomly assigned, 127 were treated in each group (three patients withdrew consent in the hydroxyurea group), and 171 rolled over to the CONTINUATION-PV trial. Median follow-up was 182·1 weeks (IQR 166·3–201·7) in the ropeginterferon alfa-2b and 164·5 weeks (144·4–169·3) in the standard therapy group. In PROUD-PV, 26 (21%) of 122 patients in the ropeginterferon alfa-2b group and 34 (28%) of 123 patients in the standard therapy group met the composite primary endpoint of complete haematological response with normal spleen size. In CONTINUATION-PV, complete haematological response with improved disease burden was met in 50 (53%) of 95 patients in the ropeginterferon alfa-2b group versus 28 (38%) of 74 patients in the hydroxyurea group, p=0·044 at 36 months. Complete haematological response without the spleen criterion in the ropeginterferon alfa-2b group versus standard therapy group were: 53 (43%) of 123 patients versus 57 (46%) of 125 patients, p=0·63 at 12 months (PROUD-PV), and 67 (71%) of 95 patients versus 38 (51%) of 74 patients, p=0·012 at 36 months (CONTINUATION-PV). The most frequently reported grade 3 and grade 4 treatment-related adverse events were increased γ-glutamyltransferase (seven [6%] of 127 patients) and increased alanine aminotransferase (four [3%] of 127 patients) in the ropeginterferon alfa-2b group, and leucopenia (six [5%] of 127 patients) and thrombocytopenia (five [4%] of 127 patients) in the standard therapy group. Treatment-related serious adverse events occurred in three (2%) of 127 patients in the ropeginterferon alfa-2b group and five (4%) of 127 patients in the hydroxyurea group. One treatment-related death was reported in the standard therapy group (acute leukaemia).
In patients with early polycythaemia vera, who predominantly presented without splenomegaly, ropeginterferon alfa-2b was effective in inducing haematological responses; non-inferiority to hydroxyurea regarding haematological response and normal spleen size was not shown at 12 months. However, response to ropeginterferon alfa-2b continued to increase over time with improved responses compared with hydroxyurea at 36 months. Considering the high and durable haematological and molecular responses and its good tolerability, ropeginterferon alfa-2b offers a valuable and safe long-term treatment option with features distinct from hydroxyurea.
AOP Orphan Pharmaceuticals AG.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>32014125</pmid><doi>10.1016/S2352-3026(19)30236-4</doi></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2352-3026 |
| ispartof | The Lancet. Haematology, 2020-03, Vol.7 (3), p.e196-e208 |
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| subjects | Aged Antineoplastic Combined Chemotherapy Protocols - therapeutic use Antiviral Agents - therapeutic use Equivalence Trials as Topic Female Follow-Up Studies Humans Interferon alpha-2 - therapeutic use Interferon-alpha - therapeutic use Male Middle Aged Polycythemia Vera - drug therapy Polycythemia Vera - pathology Polyethylene Glycols - therapeutic use Prognosis Recombinant Proteins - therapeutic use |
| title | Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study |
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