Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr): results from three multicentre, single-arm, phase 2 studies

EINSTEIN-Jr Phase 2 Investigators, Paul Monagle, Anthonie W.A. Lensing, Kirstin Thelen, Ida Martinelli, Christoph Male, Amparo Santamaría, Elena Samochatova, Riten Kumar, Susanne Holzhauer, Paola Saracco, Paolo Simioni, Jeremy Robertson, Gernot Grangl, Jacqueline Halton, Phillip Connor, Guy Young, Angelo C. Molinari, Ulrike Nowak-Göttl, Gili KenetStefanie Kapsa, Stefan Willmann, Akos F. Pap, Michael Becka, Teresa Twomey, Jan Beyer-Westendorf, Martin H. Prins, Dagmar Kubitza

Research output: Contribution to journalArticle

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Abstract

Background: Rivaroxaban has been shown to be efficacious for treatment of venous thromboembolism in adults, and has a reduced risk of bleeding compared with standard anticoagulants. We aimed to develop paediatric rivaroxaban regimens for the treatment of venous thromboembolism in children and adolescents. Methods: In this phase 2 programme, we did three studies to evaluate rivaroxaban treatment in children younger than 6 months, aged 6 months to 5 years, and aged 6–17 years. Our studies used a multicentre, single-arm design at 54 sites in Australia, Europe, Israel, Japan, and north America. We included children with objectively confirmed venous thromboembolism previously treated with low-molecular weight heparin, fondaparinux, or a vitamin K antagonist for at least 2 months or, in children who had catheter-related venous thromboembolism for at least 6 weeks. We administered rivaroxaban orally in a bodyweight-adjusted 20 mg-equivalent dose, based on physiologically-based pharmacokinetic modelling predictions and EINSTEIN-Jr phase 1 data in young adults, in either a once-daily (tablets; for those aged 6–17 years), twice-daily (in suspension; for those aged 6 months to 11 years), or three times-daily (in suspension; for those younger than 6 months) dosing regimen for 30 days (or 7 days for those younger than 6 months). The primary aim was to define rivaroxaban treatment regimens that match the target adult exposure range. The principal safety outcome was major bleeding and clinically relevant non-major bleeding. Analyses were per-protocol. The predefined efficacy outcomes were symptomatic recurrent venous thromboembolism, asymptomatic deterioration on repeat imaging at the end of the study treatment period. These trials are registered at ClinicalTrials.gov, numbers NCT02564718, NCT02309411, and NCT02234843. Findings: Between Feb 11, 2013, and Dec 20, 2017, we enrolled 93 children (ten children younger than 6 months; 15 children aged 6 months to 1 year; 25 children aged 2–5 years; 32 children aged 6–11 years; and 11 children aged 12–17 years) into our study. 89 (96%) children completed study treatment (30 days of treatment, or 7 days in those younger than 6 months), and 93 (100%) children received at least one dose of study treatment and were evaluable for the primary endpoints. None of the children had a major bleed, and four (4%, 95% CI 1·2–10·6) of these children had a clinically relevant non-major bleed (three children aged 12–17 years with menorrhagia and one child aged 6–11 years with gingival bleeding). We found no symptomatic recurrent venous thromboembolism in any patients (0%, 0·0–3·9). 24 (32%) of 75 patients with repeat imaging had their thrombotic burden resolved, 43 (57%) patients improved, and eight (11%) patients were unchanged. No patient deteriorated. We confirmed therapeutic rivaroxaban exposures with once-daily dosing in children with bodyweights of at least 30 kg and with twice-daily dosing in children with bodyweights of at least 20 kg and less than 30 kg. Children with low bodyweights (<20 kg, particularly <12 kg) showed low exposures so, for future studies, rivaroxaban dosages were revised for these weight categories, to match the target adult exposure range. 61 (66%) of 93 children had adverse events during the study. Pyrexia was the most common adverse event (ten [11%] events), and anaemia and neutropenia or febrile neutropenia were the most frequent grade 3 or worse events (four [4%] events each). No children died or were discontinued from rivaroxaban because of adverse events. Interpretation: Treatment with bodyweight-adjusted rivaroxaban appears to be safe in children. The treatment regimens that we confirmed in children with bodyweights of at least 20 kg and the revised treatment regimens that we predicted in those with bodyweights less than 20 kg will be evaluated in the EINSTEIN-Jr phase 3 trial in children with acute venous thromboembolism. Funding: Bayer AG, Janssen Research and Development.

Original languageEnglish
Pages (from-to)e500-e509
JournalThe Lancet Haematology
Volume6
Issue number10
DOIs
Publication statusPublished - Oct 1 2019

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Venous Thromboembolism
Rivaroxaban
Therapeutics
Hemorrhage
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ASJC Scopus subject areas

  • Hematology

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Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr) : results from three multicentre, single-arm, phase 2 studies. / EINSTEIN-Jr Phase 2 Investigators; Monagle, Paul; Lensing, Anthonie W.A.; Thelen, Kirstin; Martinelli, Ida; Male, Christoph; Santamaría, Amparo; Samochatova, Elena; Kumar, Riten; Holzhauer, Susanne; Saracco, Paola; Simioni, Paolo; Robertson, Jeremy; Grangl, Gernot; Halton, Jacqueline; Connor, Phillip; Young, Guy; Molinari, Angelo C.; Nowak-Göttl, Ulrike; Kenet, Gili; Kapsa, Stefanie; Willmann, Stefan; Pap, Akos F.; Becka, Michael; Twomey, Teresa; Beyer-Westendorf, Jan; Prins, Martin H.; Kubitza, Dagmar.

In: The Lancet Haematology, Vol. 6, No. 10, 01.10.2019, p. e500-e509.

Research output: Contribution to journalArticle

EINSTEIN-Jr Phase 2 Investigators, Monagle, P, Lensing, AWA, Thelen, K, Martinelli, I, Male, C, Santamaría, A, Samochatova, E, Kumar, R, Holzhauer, S, Saracco, P, Simioni, P, Robertson, J, Grangl, G, Halton, J, Connor, P, Young, G, Molinari, AC, Nowak-Göttl, U, Kenet, G, Kapsa, S, Willmann, S, Pap, AF, Becka, M, Twomey, T, Beyer-Westendorf, J, Prins, MH & Kubitza, D 2019, 'Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr): results from three multicentre, single-arm, phase 2 studies', The Lancet Haematology, vol. 6, no. 10, pp. e500-e509. https://doi.org/10.1016/S2352-3026(19)30161-9
EINSTEIN-Jr Phase 2 Investigators ; Monagle, Paul ; Lensing, Anthonie W.A. ; Thelen, Kirstin ; Martinelli, Ida ; Male, Christoph ; Santamaría, Amparo ; Samochatova, Elena ; Kumar, Riten ; Holzhauer, Susanne ; Saracco, Paola ; Simioni, Paolo ; Robertson, Jeremy ; Grangl, Gernot ; Halton, Jacqueline ; Connor, Phillip ; Young, Guy ; Molinari, Angelo C. ; Nowak-Göttl, Ulrike ; Kenet, Gili ; Kapsa, Stefanie ; Willmann, Stefan ; Pap, Akos F. ; Becka, Michael ; Twomey, Teresa ; Beyer-Westendorf, Jan ; Prins, Martin H. ; Kubitza, Dagmar. / Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr) : results from three multicentre, single-arm, phase 2 studies. In: The Lancet Haematology. 2019 ; Vol. 6, No. 10. pp. e500-e509.
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abstract = "Background: Rivaroxaban has been shown to be efficacious for treatment of venous thromboembolism in adults, and has a reduced risk of bleeding compared with standard anticoagulants. We aimed to develop paediatric rivaroxaban regimens for the treatment of venous thromboembolism in children and adolescents. Methods: In this phase 2 programme, we did three studies to evaluate rivaroxaban treatment in children younger than 6 months, aged 6 months to 5 years, and aged 6–17 years. Our studies used a multicentre, single-arm design at 54 sites in Australia, Europe, Israel, Japan, and north America. We included children with objectively confirmed venous thromboembolism previously treated with low-molecular weight heparin, fondaparinux, or a vitamin K antagonist for at least 2 months or, in children who had catheter-related venous thromboembolism for at least 6 weeks. We administered rivaroxaban orally in a bodyweight-adjusted 20 mg-equivalent dose, based on physiologically-based pharmacokinetic modelling predictions and EINSTEIN-Jr phase 1 data in young adults, in either a once-daily (tablets; for those aged 6–17 years), twice-daily (in suspension; for those aged 6 months to 11 years), or three times-daily (in suspension; for those younger than 6 months) dosing regimen for 30 days (or 7 days for those younger than 6 months). The primary aim was to define rivaroxaban treatment regimens that match the target adult exposure range. The principal safety outcome was major bleeding and clinically relevant non-major bleeding. Analyses were per-protocol. The predefined efficacy outcomes were symptomatic recurrent venous thromboembolism, asymptomatic deterioration on repeat imaging at the end of the study treatment period. These trials are registered at ClinicalTrials.gov, numbers NCT02564718, NCT02309411, and NCT02234843. Findings: Between Feb 11, 2013, and Dec 20, 2017, we enrolled 93 children (ten children younger than 6 months; 15 children aged 6 months to 1 year; 25 children aged 2–5 years; 32 children aged 6–11 years; and 11 children aged 12–17 years) into our study. 89 (96{\%}) children completed study treatment (30 days of treatment, or 7 days in those younger than 6 months), and 93 (100{\%}) children received at least one dose of study treatment and were evaluable for the primary endpoints. None of the children had a major bleed, and four (4{\%}, 95{\%} CI 1·2–10·6) of these children had a clinically relevant non-major bleed (three children aged 12–17 years with menorrhagia and one child aged 6–11 years with gingival bleeding). We found no symptomatic recurrent venous thromboembolism in any patients (0{\%}, 0·0–3·9). 24 (32{\%}) of 75 patients with repeat imaging had their thrombotic burden resolved, 43 (57{\%}) patients improved, and eight (11{\%}) patients were unchanged. No patient deteriorated. We confirmed therapeutic rivaroxaban exposures with once-daily dosing in children with bodyweights of at least 30 kg and with twice-daily dosing in children with bodyweights of at least 20 kg and less than 30 kg. Children with low bodyweights (<20 kg, particularly <12 kg) showed low exposures so, for future studies, rivaroxaban dosages were revised for these weight categories, to match the target adult exposure range. 61 (66{\%}) of 93 children had adverse events during the study. Pyrexia was the most common adverse event (ten [11{\%}] events), and anaemia and neutropenia or febrile neutropenia were the most frequent grade 3 or worse events (four [4{\%}] events each). No children died or were discontinued from rivaroxaban because of adverse events. Interpretation: Treatment with bodyweight-adjusted rivaroxaban appears to be safe in children. The treatment regimens that we confirmed in children with bodyweights of at least 20 kg and the revised treatment regimens that we predicted in those with bodyweights less than 20 kg will be evaluated in the EINSTEIN-Jr phase 3 trial in children with acute venous thromboembolism. Funding: Bayer AG, Janssen Research and Development.",
author = "{EINSTEIN-Jr Phase 2 Investigators} and Paul Monagle and Lensing, {Anthonie W.A.} and Kirstin Thelen and Ida Martinelli and Christoph Male and Amparo Santamar{\'i}a and Elena Samochatova and Riten Kumar and Susanne Holzhauer and Paola Saracco and Paolo Simioni and Jeremy Robertson and Gernot Grangl and Jacqueline Halton and Phillip Connor and Guy Young and Molinari, {Angelo C.} and Ulrike Nowak-G{\"o}ttl and Gili Kenet and Stefanie Kapsa and Stefan Willmann and Pap, {Akos F.} and Michael Becka and Teresa Twomey and Jan Beyer-Westendorf and Prins, {Martin H.} and Dagmar Kubitza and Werner Streif and Jorge Carniero and Sandra Logetto and Leonardo Brandao and Pascal Amedro and Damien Bonnet and Sven Dietrich and Krisztian Kallay and Shoshana Revel-Vilk and Hannah Tamary and Paola Giordano and Maria Abbattista and Andrea Artoni and Daniela Tormene and Hiroshi Ono and {Te Loo}, {Maroeska WM} and {Van Ommen}, Heleen and Veening, {Margreet A.} and Suiker, {Monique H.} and Marjolein Peters and Anastasia Shamardina and Nizhny Novgorod and Lyudmila Zubarovskaya",
year = "2019",
month = "10",
day = "1",
doi = "10.1016/S2352-3026(19)30161-9",
language = "English",
volume = "6",
pages = "e500--e509",
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TY - JOUR

T1 - Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr)

T2 - results from three multicentre, single-arm, phase 2 studies

AU - EINSTEIN-Jr Phase 2 Investigators

AU - Monagle, Paul

AU - Lensing, Anthonie W.A.

AU - Thelen, Kirstin

AU - Martinelli, Ida

AU - Male, Christoph

AU - Santamaría, Amparo

AU - Samochatova, Elena

AU - Kumar, Riten

AU - Holzhauer, Susanne

AU - Saracco, Paola

AU - Simioni, Paolo

AU - Robertson, Jeremy

AU - Grangl, Gernot

AU - Halton, Jacqueline

AU - Connor, Phillip

AU - Young, Guy

AU - Molinari, Angelo C.

AU - Nowak-Göttl, Ulrike

AU - Kenet, Gili

AU - Kapsa, Stefanie

AU - Willmann, Stefan

AU - Pap, Akos F.

AU - Becka, Michael

AU - Twomey, Teresa

AU - Beyer-Westendorf, Jan

AU - Prins, Martin H.

AU - Kubitza, Dagmar

AU - Streif, Werner

AU - Carniero, Jorge

AU - Logetto, Sandra

AU - Brandao, Leonardo

AU - Amedro, Pascal

AU - Bonnet, Damien

AU - Dietrich, Sven

AU - Kallay, Krisztian

AU - Revel-Vilk, Shoshana

AU - Tamary, Hannah

AU - Giordano, Paola

AU - Abbattista, Maria

AU - Artoni, Andrea

AU - Tormene, Daniela

AU - Ono, Hiroshi

AU - Te Loo, Maroeska WM

AU - Van Ommen, Heleen

AU - Veening, Margreet A.

AU - Suiker, Monique H.

AU - Peters, Marjolein

AU - Shamardina, Anastasia

AU - Novgorod, Nizhny

AU - Zubarovskaya, Lyudmila

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Background: Rivaroxaban has been shown to be efficacious for treatment of venous thromboembolism in adults, and has a reduced risk of bleeding compared with standard anticoagulants. We aimed to develop paediatric rivaroxaban regimens for the treatment of venous thromboembolism in children and adolescents. Methods: In this phase 2 programme, we did three studies to evaluate rivaroxaban treatment in children younger than 6 months, aged 6 months to 5 years, and aged 6–17 years. Our studies used a multicentre, single-arm design at 54 sites in Australia, Europe, Israel, Japan, and north America. We included children with objectively confirmed venous thromboembolism previously treated with low-molecular weight heparin, fondaparinux, or a vitamin K antagonist for at least 2 months or, in children who had catheter-related venous thromboembolism for at least 6 weeks. We administered rivaroxaban orally in a bodyweight-adjusted 20 mg-equivalent dose, based on physiologically-based pharmacokinetic modelling predictions and EINSTEIN-Jr phase 1 data in young adults, in either a once-daily (tablets; for those aged 6–17 years), twice-daily (in suspension; for those aged 6 months to 11 years), or three times-daily (in suspension; for those younger than 6 months) dosing regimen for 30 days (or 7 days for those younger than 6 months). The primary aim was to define rivaroxaban treatment regimens that match the target adult exposure range. The principal safety outcome was major bleeding and clinically relevant non-major bleeding. Analyses were per-protocol. The predefined efficacy outcomes were symptomatic recurrent venous thromboembolism, asymptomatic deterioration on repeat imaging at the end of the study treatment period. These trials are registered at ClinicalTrials.gov, numbers NCT02564718, NCT02309411, and NCT02234843. Findings: Between Feb 11, 2013, and Dec 20, 2017, we enrolled 93 children (ten children younger than 6 months; 15 children aged 6 months to 1 year; 25 children aged 2–5 years; 32 children aged 6–11 years; and 11 children aged 12–17 years) into our study. 89 (96%) children completed study treatment (30 days of treatment, or 7 days in those younger than 6 months), and 93 (100%) children received at least one dose of study treatment and were evaluable for the primary endpoints. None of the children had a major bleed, and four (4%, 95% CI 1·2–10·6) of these children had a clinically relevant non-major bleed (three children aged 12–17 years with menorrhagia and one child aged 6–11 years with gingival bleeding). We found no symptomatic recurrent venous thromboembolism in any patients (0%, 0·0–3·9). 24 (32%) of 75 patients with repeat imaging had their thrombotic burden resolved, 43 (57%) patients improved, and eight (11%) patients were unchanged. No patient deteriorated. We confirmed therapeutic rivaroxaban exposures with once-daily dosing in children with bodyweights of at least 30 kg and with twice-daily dosing in children with bodyweights of at least 20 kg and less than 30 kg. Children with low bodyweights (<20 kg, particularly <12 kg) showed low exposures so, for future studies, rivaroxaban dosages were revised for these weight categories, to match the target adult exposure range. 61 (66%) of 93 children had adverse events during the study. Pyrexia was the most common adverse event (ten [11%] events), and anaemia and neutropenia or febrile neutropenia were the most frequent grade 3 or worse events (four [4%] events each). No children died or were discontinued from rivaroxaban because of adverse events. Interpretation: Treatment with bodyweight-adjusted rivaroxaban appears to be safe in children. The treatment regimens that we confirmed in children with bodyweights of at least 20 kg and the revised treatment regimens that we predicted in those with bodyweights less than 20 kg will be evaluated in the EINSTEIN-Jr phase 3 trial in children with acute venous thromboembolism. Funding: Bayer AG, Janssen Research and Development.

AB - Background: Rivaroxaban has been shown to be efficacious for treatment of venous thromboembolism in adults, and has a reduced risk of bleeding compared with standard anticoagulants. We aimed to develop paediatric rivaroxaban regimens for the treatment of venous thromboembolism in children and adolescents. Methods: In this phase 2 programme, we did three studies to evaluate rivaroxaban treatment in children younger than 6 months, aged 6 months to 5 years, and aged 6–17 years. Our studies used a multicentre, single-arm design at 54 sites in Australia, Europe, Israel, Japan, and north America. We included children with objectively confirmed venous thromboembolism previously treated with low-molecular weight heparin, fondaparinux, or a vitamin K antagonist for at least 2 months or, in children who had catheter-related venous thromboembolism for at least 6 weeks. We administered rivaroxaban orally in a bodyweight-adjusted 20 mg-equivalent dose, based on physiologically-based pharmacokinetic modelling predictions and EINSTEIN-Jr phase 1 data in young adults, in either a once-daily (tablets; for those aged 6–17 years), twice-daily (in suspension; for those aged 6 months to 11 years), or three times-daily (in suspension; for those younger than 6 months) dosing regimen for 30 days (or 7 days for those younger than 6 months). The primary aim was to define rivaroxaban treatment regimens that match the target adult exposure range. The principal safety outcome was major bleeding and clinically relevant non-major bleeding. Analyses were per-protocol. The predefined efficacy outcomes were symptomatic recurrent venous thromboembolism, asymptomatic deterioration on repeat imaging at the end of the study treatment period. These trials are registered at ClinicalTrials.gov, numbers NCT02564718, NCT02309411, and NCT02234843. Findings: Between Feb 11, 2013, and Dec 20, 2017, we enrolled 93 children (ten children younger than 6 months; 15 children aged 6 months to 1 year; 25 children aged 2–5 years; 32 children aged 6–11 years; and 11 children aged 12–17 years) into our study. 89 (96%) children completed study treatment (30 days of treatment, or 7 days in those younger than 6 months), and 93 (100%) children received at least one dose of study treatment and were evaluable for the primary endpoints. None of the children had a major bleed, and four (4%, 95% CI 1·2–10·6) of these children had a clinically relevant non-major bleed (three children aged 12–17 years with menorrhagia and one child aged 6–11 years with gingival bleeding). We found no symptomatic recurrent venous thromboembolism in any patients (0%, 0·0–3·9). 24 (32%) of 75 patients with repeat imaging had their thrombotic burden resolved, 43 (57%) patients improved, and eight (11%) patients were unchanged. No patient deteriorated. We confirmed therapeutic rivaroxaban exposures with once-daily dosing in children with bodyweights of at least 30 kg and with twice-daily dosing in children with bodyweights of at least 20 kg and less than 30 kg. Children with low bodyweights (<20 kg, particularly <12 kg) showed low exposures so, for future studies, rivaroxaban dosages were revised for these weight categories, to match the target adult exposure range. 61 (66%) of 93 children had adverse events during the study. Pyrexia was the most common adverse event (ten [11%] events), and anaemia and neutropenia or febrile neutropenia were the most frequent grade 3 or worse events (four [4%] events each). No children died or were discontinued from rivaroxaban because of adverse events. Interpretation: Treatment with bodyweight-adjusted rivaroxaban appears to be safe in children. The treatment regimens that we confirmed in children with bodyweights of at least 20 kg and the revised treatment regimens that we predicted in those with bodyweights less than 20 kg will be evaluated in the EINSTEIN-Jr phase 3 trial in children with acute venous thromboembolism. Funding: Bayer AG, Janssen Research and Development.

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