Browsing by Author "Male, Christoph"

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    Clinical characteristics, treatment, and outcomes of provoked acute cerebral sinovenous thrombosis in patients <21 years old: findings from the Kids-DOTT Multinational Trial
    (Elsevier, 2024-10-23) Woods, Gary M.; Miller, Alexandra; Mosha, Maua; Male, Christoph; Verma, Anupam; Kucine, Nicole; Sabapathy, Christine; Beg, Kisha; Ahuja, Sanjay; Raybagkar, Deepti; Hege, Kerry; Lo, Clara; Bhat, Rukhmi; Abshire, Thomas; Goldenberg, Neil A.; Pediatrics, School of Medicine
    Background: Prospective multicenter data on the treatment and outcomes of children with cerebral sinovenous thrombosis (CSVT) are limited. We aimed to describe the clinical characteristics, treatment strategies, and outcomes of patients with a first-episode of provoked acute CSVT enrolled in the Kids-DOTT trial and compare these features with those of participants with non-CSVT venous thromboembolism (VTE). Methods: This was a subgroup analysis from the Kids-DOTT trial, a multinational randomized clinical trial on duration of anticoagulation for provoked acute VTE in patients younger than 21 years. Patient and thrombus characteristics, treatments, and outcomes of patients diagnosed with CSVT were compared with those of patients with non-CSVT VTE. Results: CSVT was diagnosed in 75 of the 532 (14%), 25 of whom received 6 weeks of anticoagulant treatment and 50 received 3 or more months. When compared with non-CSVT VTE, CSVT was more likely to occur in neonates and young children, associated with infection in general and acute head/neck infection in particular, and less likely to be related to central venous catheter. No patient in either group developed symptomatic recurrent VTE or clinically relevant bleeding, and there was no significant difference in rates of complete thrombus resolution between the 2 treatment durations. Conclusion: CSVT is most common in neonates and young children and those with acute head and neck infections. A 6-week anticoagulation treatment course appears to be safe (no clinically relevant bleeding) and effective (no difference in symptomatic recurrent VTE) for provoked acute pediatric CSVT. Nevertheless, given the nature of a subpopulation analysis, these findings should be interpreted with caution.
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    A Multi-National Trial of a Direct Oral Anticoagulant in Children with Cardiac Disease: Design and Rationale of the SAXOPHONE Study
    (Elsevier, 2019-11) Payne, R. Mark; Burns, Kristin M.; Glatz, Andrew C.; Li, Danshi; Li, Xiaodong; Monagle, Paul; Newburger, Jane W.; Swan, Elizabeth A.; Wheaton, Olivia; Male, Christoph; Pediatrics, School of Medicine
    Anticoagulation in children is problematic for multiple reasons. Currently used anticoagulants have significant disadvantages and may negatively affect quality of life (QOL). This manuscript describes the design, rationale, and methods of a prospective, randomized, open label phase II multi-national clinical trial of a direct oral anticoagulant (DOAC), apixaban, in children and infants with congenital and acquired heart disease. This trial is designed to gather preliminary safety and pharmacokinetics (PK) data, as well as generate data on QOL of individuals taking apixaban compared to the standard of care (SOC) anticoagulants vitamin K antagonists (VKA) or low molecular weight heparin (LMWH). A key issue this trial seeks to address is the practice of using therapeutics tested in adult trials in the pediatric population without robust pediatric safety or efficacy data. Pediatric heart diseases are not common, and specific diagnoses often meet the criteria of a rare disease; thus, statistical efficacy may be difficult to achieve. This trial will provide valuable PK and safety data intended to inform clinical practice for anticoagulation in pediatric heart diseases, a setting in which a fully powered phase III clinical trial is not feasible. A second consideration this trial addresses is that metrics besides efficacy, such as QOL, have not been traditionally used as endpoints in regulated anticoagulation studies yet may add substantial weight to the clinical decision for use of a DOAC in place of VKA or LMWH. This study examines QOL related to both heart disease and anticoagulation among children randomized to either SOC or apixaban. There are considerable strengths and benefits to conducting a clinical trial in pediatric rare disease populations via an industry-academic collaboration. The SAXOPHONE study represents a collaboration between Bristol-Myers Squibb (BMS)/Pfizer Alliance, and the National Heart, Lung, and Blood Institute's (NHLBI) Pediatric Heart Network (PHN) and may be an attractive model for future pediatric drug trials.
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    Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial
    (Elsevier, 2020-01) Male, Christoph; Lensing, Anthonie W. A.; Palumbo, Joseph S.; Kumar, Riten; Nurmeev, Ildar; Hege, Kerry; Bonnet, Damien; Connor, Philip; Hooimeijer, Hélène L.; Torres, Marcela; Chan, Anthony K. C.; Kenet, Gili; Holzhauer, Susanne; Santamaría, Amparo; Amedro, Pascal; Chalmers, Elizabeth; Simioni, Paolo; Bhat, Rukhmi V.; Yee, Donald L.; Lvova, Olga; Beyer-Westendorf, Jan; Biss, Tina T.; Martinelli, Ida; Saracco, Paola; Peters, Marjolein; Kállay, Krisztián; Gauger, Cynthia A.; Massicotte, M. Patricia; Young, Guy; Pap, Akos F.; Majumder, Madhurima; Smith, William T.; Heubach, Jürgen F.; Berkowitz, Scott D.; Thelen, Kirstin; Kubitza, Dagmar; Crowther, Mark; Prins, Martin H.; Monagle, Paul; EINSTEIN-Jr Phase 3 Investigators; Pediatrics, School of Medicine
    Background Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. Methods In a multicentre, parallel-group, open-label, randomised study, children (aged 0–17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children <2 years of age with catheter-related venous thromboembolism). The primary efficacy outcome, symptomatic recurrent venous thromboembolism (assessed by intention-to-treat), and the principal safety outcome, major or clinically relevant non-major bleeding (assessed in participants who received ≥1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed. Findings From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87–95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29–35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0·40, 95% CI 0·11–1·41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0·012). Major or clinically relevant non-major bleeding in participants who received ≥1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1·58, 95% CI 0·51–6·27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths. Interpretation In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants.