Multi-dose Oral Ondansetron for Pediatric Gastroenteritis: study Protocol for the multi-DOSE oral ondansetron for pediatric Acute GastroEnteritis (DOSE-AGE) pragmatic randomized controlled trial

Stephen B Freedman, Sarah Williamson-Urquhart, Anna Heath, Petros Pechlivanoglou, Gareth Hopkin, Serge Gouin, Amy C Plint, Andrew Dixon, Darcy Beer, Gary Joubert, Christopher McCabe, Yaron Finkelstein, Terry P Klassen, KidsCAN-Pediatric Emergency Research Canada (PERC) Innovative Pediatric Clinical Trials DOSE-AGE Study Group, Stephen B Freedman, Sarah Williamson-Urquhart, Anna Heath, Petros Pechlivanoglou, Gareth Hopkin, Serge Gouin, Amy C Plint, Andrew Dixon, Darcy Beer, Gary Joubert, Christopher McCabe, Yaron Finkelstein, Terry P Klassen, KidsCAN-Pediatric Emergency Research Canada (PERC) Innovative Pediatric Clinical Trials DOSE-AGE Study Group

Abstract

Background: There are limited treatment options that clinicians can provide to children presenting to emergency departments with vomiting secondary to acute gastroenteritis. Based on evidence of effectiveness and safety, clinicians now routinely administer ondansetron in the emergency department to promote oral rehydration therapy success. However, clinicians are also increasingly providing multiple doses of ondansetron for home use, creating unquantified cost and health system resource use implications without any evidence to support this expanding practice.

Methods/design: DOSE-AGE is a randomized, placebo-controlled, double-blinded, six-center, pragmatic clinical trial being conducted in six Canadian pediatric emergency departments (EDs). In September 2019 the study began recruiting children aged 6 months to 18 years with a minimum of three episodes of vomiting in the 24 h preceding enrollment, <72 h of gastroenteritis symptoms and who were administered a dose of ondansetron during their ED visit. We are recruiting 1030 children (1:1 allocation via an internet-based, third-party, randomization service) to receive a 48-h supply (i.e., six doses) of ondansetron oral solution or placebo, administered on an as-needed basis. All participants, caregivers and outcome assessors will be blinded to group assignment. Outcome data will be collected by surveys administered to caregivers 24, 48 and 168 h following enrollment. The primary outcome is the development of moderate-to-severe gastroenteritis in the 7 days following the ED visit as measured by a validated clinical score (the Modified Vesikari Scale). Secondary outcomes include duration and frequency of vomiting and diarrhea, proportions of children experiencing unscheduled health care visits and intravenous rehydration, caregiver satisfaction with treatment and safety. A preplanned economic evaluation will be conducted alongside the trial.

Discussion: Definitive data are lacking to guide the clinical use of post-ED visit multidose ondansetron in children with acute gastroenteritis. Usage is increasing, despite the absence of supportive evidence. The incumbent additional costs associated with use, and potential side effects such as diarrhea and repeat visits, create an urgent need to evaluate the effect and safety of multiple doses of ondansetron in children focusing on post-emergency department visit and patient-centered outcomes.

Trial registration: ClinicalTrials.gov: NCT03851835. Registered on 22 February 2019.

Keywords: Child; Dehydration; Emergency service, hospital; Gastroenteritis; Ondansetron; Randomized controlled trial; Vomiting.

Conflict of interest statement

SBF has received in-kind (study drug and placebo) support from GlaxoSmithKline and Novartis for the conduct of previous research evaluating the use of ondansetron; no support has been provided for the current study. SBF is also providing consulting services to RedHill Biopharm Ltd. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Schedule of activities. ED emergency department, HR heart rate, RR respiratory rate

References

    1. Scallan E, Griffin PM, Angulo FJ, Tauxe RV, Hoekstra RM. Foodborne illness acquired in the United States—unspecified agents. Emerg Infect Dis. 2011;17:16–22. doi: 10.3201/eid1701.P21101.
    1. Ozuah PO, Avner JR, Stein RE. Oral rehydration, emergency physicians, and practice parameters: a national survey. Pediatrics. 2002;109:259–261. doi: 10.1542/peds.109.2.259.
    1. Tomasik E, Ziolkowska E, Kolodziej M, Szajewska H. Systematic review with meta-analysis: ondansetron for vomiting in children with acute gastroenteritis. Aliment Pharmacol Ther. 2016;44:438–446. doi: 10.1111/apt.13728.
    1. Nunez J, Liu DR, Nager AL. Dehydration treatment practices among pediatrics-trained and non-pediatrics trained emergency physicians. Pediatr Emerg Care. 2012;28:322–328. doi: 10.1097/PEC.0b013e31824d8b26.
    1. Freedman SB, Ali S, Oleszczuk M, Gouin S, Hartling L. Treatment of acute gastroenteritis in children: an overview of systematic reviews of interventions commonly used in developed countries. Evid Based Child Health. 2013;8:1123–1137. doi: 10.1002/ebch.1932.
    1. Ramsook C, Sahagun-Carreon I, Kozinetz CA, Moro-Sutherland D. A randomized clinical trial comparing oral ondansetron with placebo in children with vomiting from acute gastroenteritis. Ann Emerg Med. 2002;39:397–403. doi: 10.1067/mem.2002.122706.
    1. Yilmaz HL, Yildizdas RD, Sertdemir Y. Clinical trial: oral ondansetron for reducing vomiting secondary to acute gastroenteritis in children—a double-blind randomized study. Aliment Pharmacol Ther. 2010;31:82–91. doi: 10.1111/j.1365-2036.2009.04145.x.
    1. McLaren SH, Yim RB, Fleegler EW. Impact of ondansetron prescription on return emergency department visits among children with acute gastroenteritis. Pediatr Emerg Care. 2019. 10.1097/PEC.0000000000001907.
    1. Gray James M., Maewal Jaya D., Lunos Scott A., Furnival Ronald A., Hendrickson Marissa A. Ondansetron Prescription for Home Use in a Pediatric Emergency Department. Pediatric Emergency Care. 2020;36(3):e120–e124. doi: 10.1097/PEC.0000000000001343.
    1. Freedman SB, Powell EC, Nava-Ocampo AA, Finkelstein Y. Ondansetron dosing in pediatric gastroenteritis: a prospective cohort, dose-response study. Paediatric Drugs. 2010;12:405–410. doi: 10.2165/11537770-000000000-00000.
    1. Freedman SB, Williamson-Urquhart S, Schuh S, Sherman PM, Farion KJ, et al. Impact of emergency department probiotic treatment of pediatric gastroenteritis: study protocol for the PROGUT (Probiotic Regimen for Outpatient Gastroenteritis Utility of Treatment) randomized controlled trial. Trials. 2014;15:170. doi: 10.1186/1745-6215-15-170.
    1. Roden DM. Clinical practice. Long-QT syndrome. N Engl J Med. 2008;358:169–176. doi: 10.1056/NEJMcp0706513.
    1. Novartis Pharmaceuticals Canada Inc. Zofran tablets, oral solution and injection—product monograph Available at: . Accessed 9 Dec 2019.
    1. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42:377–381. doi: 10.1016/j.jbi.2008.08.010.
    1. Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, et al. The REDCap consortium: building an international community of software platform partners. J Biomed Inform. 2019;95:103208. doi: 10.1016/j.jbi.2019.103208.
    1. Schnadower D, Tarr PI, Gorelick MH, O'Connell K, Roskind CG, et al. Validation of the modified Vesikari score in children with gastroenteritis in 5 US emergency departments. J Pediatr Gastroenterol Nutr. 2013;57:514–519. doi: 10.1097/MPG.0b013e31829ae5a3.
    1. Freedman SB, Eltorky M, Gorelick M, Pediatric Emergency Research Canada Gastroenteritis Study Group Evaluation of a gastroenteritis severity score for use in outpatient settings. Pediatrics. 2010;125:e1278–e1285. doi: 10.1542/peds.2009-3270.
    1. Alpern ER, Henretig FM. Fever. In: Fleisher GR, Ludwig S, editors. Textbook of pediatric emergency medicine. 6. Philadelphia: Lippincott Williams & Wilkins; 2010. pp. 266–275.
    1. Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, Abate H, Breuer T, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med. 2006;354:11–22. doi: 10.1056/NEJMoa052434.
    1. Madhi SA, Cunliffe NA, Steele D, Witte D, Kirsten M, et al. Effect of human rotavirus vaccine on severe diarrhea in African infants. N Engl J Med. 2010;362:289–298. doi: 10.1056/NEJMoa0904797.
    1. Huppertz HI, Forster J, Heininger U, Roos R, Neumann HU, Hammerschmidt T. The parental appraisal of the morbidity of diarrhea in infants and toddlers (PAMODI) survey. Clin Pediatr (Phila) 2008;47:363–371. doi: 10.1177/0009922807310933.
    1. Diez-Domingo J, Patrzalek M, Cantarutti L, Arnould B, Meunier J, et al. The impact of childhood acute rotavirus gastroenteritis on the parents’ quality of life: prospective observational study in European primary care medical practices. BMC Pediatr. 2012;12:58. doi: 10.1186/1471-2431-12-58.
    1. Freedman SB, Williamson-Urquhart S, Farion KJ, Gouin S, Willan AR, et al. Multicenter trial of a combination probiotic for children with gastroenteritis. N Engl J Med. 2018;379:2015–2026. doi: 10.1056/NEJMoa1802597.
    1. Schnadower D, Tarr PI, Casper TC, Gorelick MH, Dean JM, et al. Lactobacillus rhamnosus GG versus placebo for acute gastroenteritis in children. N Engl J Med. 2018;379:2002–2014. doi: 10.1056/NEJMoa1802598.
    1. Freedman SB, Adler M, Seshadri R, Powell EC. Oral ondansetron for gastroenteritis in a pediatric emergency department. N Engl J Med. 2006;354:1698–1705. doi: 10.1056/NEJMoa055119.
    1. Freedman SB, Willan AR, Boutis K, Schuh S. Effect of dilute apple juice and preferred fluids vs electrolyte maintenance solution on treatment failure among children with mild gastroenteritis: a randomized clinical trial. JAMA. 2016;315:1966–1974. doi: 10.1001/jama.2016.5352.
    1. Vanderkooi OG, Xie J, Lee BE, Pang XL, Chui L, et al. A prospective comparative study of children with gastroenteritis: emergency department compared with symptomatic care at home. Eur J Clin Microbiol Infect Dis. 2019;38:2371–2379. doi: 10.1007/s10096-019-03688-8.
    1. Xie J, Nettel-Aguirre A, Lee BE, Chui L, Pang XL, et al. Relationship between enteric pathogens and acute gastroenteritis disease severity: a prospective cohort study. Clin Microbiol Infect. 2019;25:454–461. doi: 10.1016/j.cmi.2018.06.016.
    1. Fleiss J. Statistical methods for rates and proportions. 2. New York: Wiley; 1981.
    1. Plint AC, Johnson DW, Patel H, Wiebe N, Correll R, et al. Epinephrine and dexamethasone in children with bronchiolitis. N Engl J Med. 2009;360:2079–2089. doi: 10.1056/NEJMoa0900544.
    1. Bjornson CL, Klassen TP, Williamson J, Brant R, Mitton C, et al. A randomized trial of a single dose of oral dexamethasone for mild croup. N Engl J Med. 2004;351:1306–1313. doi: 10.1056/NEJMoa033534.
    1. Holm S. A simple sequentially rejective multiple test procedure. Scand J Stat. 1979;6:65–70.
    1. Montori VM, Devereaux PJ, Adhikari NK, Burns KE, Eggert CH, et al. Randomized trials stopped early for benefit: a systematic review. JAMA. 2005;294:2203–2209. doi: 10.1001/jama.294.17.2203.
    1. Bassler D, Briel M, Montori VM, Lane M, Glasziou P, et al. Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis. JAMA. 2010;303:1180–1187. doi: 10.1001/jama.2010.310.
    1. Brown EG, Wood L, Wood S. The medical dictionary for regulatory activities (MedDRA) Drug Saf. 1999;20:109–117. doi: 10.2165/00002018-199920020-00002.
    1. Guidelines for the economic evaluation of health technologies: Canada—4th edition. Ottawa: CADTH; 2017 March. Available at: . Accessed 2 Mar 2020.
    1. Ryan M, Gerard K, Amaya-Amaya M. Discrete choice experiments in a nutshell. In: Ryan M, Gerard K, Amaya-Amaya M, editors. Using discrete choice experiments to value health and health care the economics of non-market goods and resources. Dordrecht: Springer; 2008.
    1. Freedman SB, Lee BE, Louie M, Pang XL, Ali S, et al. Alberta Provincial Pediatric EnTeric Infection TEam (APPETITE): epidemiology, emerging organisms, and economics. BMC Pediatr. 2015;15:89. doi: 10.1186/s12887-015-0407-7.
    1. Kelly LE, Richer L, Ali S, Plint AC, Poonai N, et al. Innovative approaches to investigator-initiated, multicentre paediatric clinical trials in Canada. BMJ Open. 2019;9:e029024. doi: 10.1136/bmjopen-2019-029024.

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