Intravenous magnesium for pediatric sickle cell vaso‐occlusive crisis: Methodological issues of a randomized controlled trial

Abstract

Background Multiple recent Sickle Cell Disease studies have been terminated due to poor enrollment. We developed methods to overcome past barriers and utilized these to study the efficacy and safety of intravenous magnesium for vaso-occlusive crisis (VOC). We describe the methods of the Intravenous Magnesium in Sickle Vaso-occlusive Crisis (MAGiC) trial and discuss methods used to overcome past barriers. Procedure MAGiC was a multicenter randomized double-blind placebo-controlled trial of intravenous magnesium versus normal saline for treatment of VOC. The study was a collaboration between Pediatric Hematologists and Emergency Physicians in the Pediatric Emergency Care Applied Research Network (PECARN). Eligible patients were randomized within 12 hours of receiving intravenous opioids in the emergency department (ED) and administered study medication every eight hours. The primary outcome was hospital length of stay. Associated plasma studies elucidated magnesium’s mechanism of action and the pathophysiology of VOC. Health-related quality of life was measured. Site-, protocol- and patient-related barriers to prior studies were identified and addressed. Results Limited study staff availability, lack of collaboration with the ED, and difficulty obtaining consent were previously identified barriers. Leveraging PECARN resources, forging close collaborations between Sickle Cell Centers and EDs of participating sites, and approaching eligible patients for prior consent helped overcome these barriers. Conclusion Participation in the PECARN network and establishment of collaborative arrangements between Sickle Cell Centers and their affiliated EDs are major innovative features of the MAGiC study that allowed improved subject capture. These methods could serve as a model for future studies of VOCs.

A multicenter randomized controlled trial of intravenous magnesium for sickle cell pain crisis in children

“…25 The MAGiC study was a multicenter, randomized, parallel, double-blind, placebo-controlled trial of IV magnesium vs normal saline in addition to standard therapy for the treatment of pediatric sickle cell pain crisis. Participating centers included 8 sites (see "Acknowledgments") within the Pediatric Emergency Care Applied Research Network (PECARN).…”

“…Inclusion and exclusion criteria are described in full detail elsewhere. 25 The genotype was reported by the parent and confirmed by either review of original electrophoresis or past hematology note. Race/ethnicity data and hydroxyurea status were obtained by parent/self-report, chosen from a standard National Institutes of Health listing of racial/ethnic categories; other demographic characteristics and past history were obtained by medical record review.…”

“…All opioid doses, whether IV or oral, were recorded and converted to IV morphine equivalents. 25,28 The PedsQL generic core scales and the PedsQL multidimensional fatigue scales, which are valid and reliable for use in patients with sickle cell disease, were used to assess HRQL with the resultant total HRQL scores. 29,30 The PedsQL sickle cell disease module, the only valid and reliable disease-specific measure for children with sickle cell disease, was also used.…”

Challenges Enrolling Children Into Traumatic Brain Injury Trials: An Observational Study

“…5,17 The Pediatric Emergency Care Applied Research Network (PECARN) was established to overcome the barriers of conducting research pertaining to acutely ill and injured children during all phases of emergency care and has a history of successful completion of large multicenter clinical trials. [18][19][20][21][22][23][24][25] Due to the promising preclinical and phase II studies for the use of progesterone for adult TBI, PECARN investigators were funded to conduct feasibility planning for a clinical trial of progesterone and other promising agents for TBI in children. 26 In this article we report a prospective observational feasibility study of children with moderate-to-severe TBI presenting to 16 pediatric EDs across the United States.…”

Orphan drugs for sickle vaso-occlusion: dawn of a new era of targeted treatment

“…90,91 Magnesium was well tolerated, but had no effect on hospital duration, pain scores, or cumulative analgesia use in either study. However, a number of important future feasibility issues were successfully addressed in these studies, including recruitment and initial administration of study drug in the Emergency Department setting.…”