Pediatr Radiol DOI 10.1007/s00247-016-3599-6 ORIGINAL ARTICLE Safety of gadobutrol in more than 1,000 pediatric patients: subanalysis of the GARDIAN study, a global multicenter prospective non-interventional study Katja Glutig1 & Ravi Bhargava2 & Gabriele Hahn3 & Wolfgang Hirsch4 & Christian Kunze5 & Hans-Joachim Mentzel6 & Jürgen F. Schaefer7 & Winfried Willinek8 & Petra Palkowitsch9 & on behalf of the GARDIAN study group Received: 5 October 2015 /Revised: 1 February 2016 /Accepted: 25 February 2016 # The Author(s) 2016. This article is published with open access at Springerlink.com Abstract Objective This subanalysis of data from the GARDIAN study Background Gadobutrol is a gadolinium-based contrast evaluated the safety and use of gadobutrol in pediatric patients agent, uniquely formulated at 1.0 mmol/ml. Although there (age <18 years). is extensive safety evidence on the use of gadobutrol in adults, Materials and methods The GARDIAN study was a large few studies have addressed the safety and tolerability of gad- phase IV non-interventional prospective multicenter post- obutrol in pediatric patients. authorization safety study performed in Europe, Asia, North America and Africa. A total of 23,708 patients were included who were scheduled to undergo cranial * Katja Glutig or spinal MRI, liver or kidney MRI, or MR angiography [email protected] with gadobutrol enhancement. The primary study end- on behalf of the GARDIAN study group point was the overall incidence of adverse drug reactions (ADRs) and serious adverse events (SAEs) following 1 Children’s Center Dresden-Friedrichstadt, gadobutrol administration. Fachärztin für Radiologie und Kinderradiologie, Results The GARDIAN study included 1,142 children Überörtliche Radiologische Gemeinschaftspraxis (age <18 years) who received gadobutrol at a mean Dresden-Loschwitz, dose of 0.13 (range 0.04–0.50) mmol/kg body weight. Standort Kinderzentrum Dresden-Friedrichstadt, Friedrichstr. 32, 01067 Dresden, Germany Gadobutrol was well tolerated in these children, with low rates of ADRs (0.5%) and no SAEs, consistent with 2 Stollery Children’s Hospital, University of Alberta, Edmonton, AB, Canada results in adults enrolled in the GARDIAN study. Rates of adverse events and ADRs were unrelated to pediatric 3 Pediatric Radiology, University Hospital Carl Gustav Carus Dresden, Dresden, Germany age or gadobutrol weight-adjusted dose. There were no symptoms suggestive of nephrogenic systemic fibrosis. 4 Pediatric Radiology, University Hospital Leipzig, Leipzig, Germany Investigators rated the contrast quality of gadobutrol- enhanced images as good or excellent in 97.8% of pe- 5 Pediatric Radiology, Martin-Luther-University Hospital Halle/Wittenberg, diatric patients, similar to the main study population. Halle, Germany Conclusion Gadobutrol is very well tolerated and provides 6 Pediatric Radiology, University Hospital Jena, excellent contrast quality at the recommended weight- Jena, Germany adjusted dose in children (age <18 years), similar to the profile 7 Division of Radiology, University Hospital Tuebingen, in adults. Tuebingen, Germany 8 Radiology, University Hospital Bonn, Bonn, Germany Keywords Children . Gadobutrol . Gadolinium-based . 9 Medical & Clinical Affairs Radiology, Bayer Pharma, contrast agent Magnetic resonance imaging Magnetic Berlin, Germany resonance angiography Pediatr Radiol Introduction serious adverse events (SAEs) in this population. The contrast quality of gadobutrol was also assessed by the study Gadobutrol (Gd-DO3A-butrol, Gadovist®, Gadavist®; Bayer investigators. Pharma, Leverkusen, Germany) is a second-generation gado- linium-based contrast agent (GBCA) used to enhance tissue contrast in MRI for a range of approved indications in adults Materials and methods and children of all ages [1]. Gadobutrol recently (January 2015) received approval from the U.S. Food and Drug GARDIAN was a phase IV non-interventional prospec- Administration (FDA) for use in MRI of the central nervous tive multicenter post-authorization safety study [17]. In system in children younger than 2 years, and gadobutrol is this post-approval commitment, data were planned to be approved in many other countries, including those in the collected on at least 20,000 patients in total, including European Union (EU), for whole-body MRI in this age group at least 600 children younger than 18 years and 100 [2]. children younger than 8 years. Bayer Pharma provided Gadobutrol is an extracellular non-ionic macrocyclic para- funding for the study design, data collection, data man- magnetic contrast agent that is uniquely formulated at agement and data evaluation of the GARDIAN study 1.0 mmol/ml, i.e. twice the gadolinium concentration of other and the current study subanalysis. currently licensed GBCAs. Combined with its high relaxivity, gadobutrol provides the highest T1-shortening effect per mil- Ethical approval liliter compared with conventional GBCAs, which contributes to an increase in signal intensity [3, 4]. The more compact Local ethics committee/institutional review board approval bolus shape permitted by the higher (1 M) gadolinium con- was obtained at each study site. Prior to study enrollment each centration is associated with enhanced image quality in faster child or guardian provided written informed consent for the imaging techniques [5, 6]. The macrocyclic structure of gad- child’s data to be used for scientific purposes, consistent with obutrol provides greater stability of the chelate and reduced the ethical principles of the Declaration of Helsinki and the release of gadolinium ions compared with linear GBCAs [7]. International Conference of Harmonisation guidelines, Good Release of gadolinium ions has been associated with the de- Clinical Practice (ICH-GCP). The study additionally adhered velopment of nephrogenic systemic fibrosis (NSF) in people to guidelines of the EMA, the FDA and local laws and with impaired renal function [8, 9]. In view of these charac- regulations. teristics, gadobutrol has been placed by the American College of Radiology, European Medicines Agency (EMA), and the Participants European Society of Urogenital Radiology in the lowest risk category for development of NSF [10–12]. Between August 2010 and April 2013, boys and girls The recommended standard dose of gadobutrol for intrave- younger than 18 years who were scheduled to undergo nous injection is 0.1 mmol/kg body weight, with doses up to approved use of gadobutrol in cranial or spinal MRI, 0.3 mmol/kg body weight approved for specific indications in liver or kidney MRI, or MR angiography were recruited adults. At these doses, the efficacy and safety of gadobutrol from 272 study centers in 17 countries across Europe, have been demonstrated in numerous clinical studies in adults Asia, North America and Africa (Table 1). Gadobutrol [1, 13, 14]. By contrast, there have been few studies of gado- was administered according to usual clinical practice, butrol in pediatric patients [1, 15]. In the absence of direct with no additional diagnostic or monitoring processes evidence, strategies for use of contrast agents in the pediatric for study purposes. Children with contraindications as population [16] are typically extrapolated from adult studies. stated in the Summary of Product Characteristics for GARDIAN (Gadovist® in Routine Diagnostic MRI – Gadovist (e.g., hypersensitivity to the active substance Administration in Non-selected Patients; NCT01095081) or to any of the excipients) were excluded. Children with was a prospective large-scale multicenter non-interventional moderate or severe renal impairment (estimated glomer- study initiated at the request of the German authority, when ular filtration rate [GFR]: 30–59 or <30 ml/min/1.73 m2, the label in the EU was extended to use in pediatric patients. respectively) were scheduled for follow-up investigation The study was designed to evaluate the safety and tolerability after 3 months in accordance with routine practice, at the of gadobutrol use in approved indications in people requiring discretion of the treating physician. routine contrast-enhanced MRI [17]. The main study results from GARDIAN, excluding the pediatric data, are reported Outcome measures elsewhere [17]. The current subanalysis focuses on children (<18 years), with the primary aim to investigate the incidence Patient data (demographics, medical data, safety param- of adverse events (AEs), adverse drug reactions (ADRs) and eters, treatment signs and symptoms) were documented Pediatr Radiol Table 1 Number of pediatric patients per country (safety population) Statistical analyses Country Total number of pediatric patients (n, % by region) Descriptive analyses were performed on non-missing contin- uous (median, mean, standard deviation, maxima and minima, Asia 425 (37.2) upper and lower quartiles) and categorical data (frequency China 156 (36.7) tables). Kazakhstan & Kyrgyzstan 144 (33.9) Event rates for AEs and ADRs in children were calculated Korea 108 (25.4) as a proportion of the pediatric study population. All enrolled Taiwan 16 (3.8) subjects who were administered at least 1 dose of gadobutrol Thailand 1 (0.2) were included in the safety population. Only patients who Europe 650 (56.9) underwent an MRI/MR angiography scan were included in Bosnia & Herzegovina 28 (4.3) the efficacy population. Statistical analyses were performed Czech Republic 6 (0.9) using SAS version 9.2 (SAS Institute, Cary, NC). France 9 (1.4) Germany 465 (71.5) Greece 8 (1.2) Hungary 2 (0.3) Results Italy 17 (2.6)