The Ondansetron Premedication Trial in Juvenile Idiopathic Arthritis

NCT04169828 | Completed DMC

• 1 other identifier: H18-03176
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 11

Brief Summary

Far too many kids and families live in dread over the weekly nausea and vomiting caused by methotrexate - a medicine that controls joint swelling in Juvenile Arthritis patients. If methotrexate is not tolerated, expensive alternative biological medications may be started. This registry-based pragmatic randomized controlled trial will evaluate if routine premedication with the anti-emetic drug Ondansetron, reduces nausea and vomiting and increases the proportion of children able to continue methotrexate. By preventing nausea before it starts, the investigators hope to give kids and families a better quality of life and see a more cost-effective use of medication.

Conditions

Juvenile Idiopathic Arthritis

Keywords

Arthritis; Arthritis, Juvenile; Joint Diseases; Rheumatic diseases; Pragmatic Trials; Ondansetron; Methotrexate; Nausea

Outcome Measures

Primary Outcomes (1)

• Proportion of subjects that remain on methotrexate with no intolerance

  Intolerance will be defined as ≥6 points in the English or French versions of the validated Methotrexate Intolerance Severity Score, MISS \[10, 36\]. Scores in the MISS questionaire go from 0 (no signs of intolerance) to a maximum of 36 (all signs of intolerance are severe). The MISS questionnaire takes less than 2 minutes to complete (see Appendix). It will be added to the Registry questionnaires completed by families online or on paper as per the CAPRI Centre usual Registry procedures.

  One year after starting methotrexate.

Secondary Outcomes (6)

• Frequency and cumulative incidence of adverse events (safety and tolerability)

  Within one year

• Methotrexate intolerance

  Within one year

• Attainment of inactive disease

  Within one year

• Starting a biologic medication

  Within one year

• Quality of My Life scale

  4-8 months after starting methotrexate

Study Arms (2)

Ondansetron premedication

EXPERIMENTAL

Methotrexate and folic/folinic acid as prescribed by physician. Ondansetron: 2 mg if \<15Kg, 4 mg if 15-30Kg, 8 mg if \>30Kg to be taken by mouth one hour before each weekly methotrexate dose, followed by two additional doses every 6-8 hours if awake. To be started from the very first dose of methotrexate.

Drug: Methotrexate; Drug: Ondansetron; Drug: Folic/folinic acid

Ondansetron as needed

ACTIVE COMPARATOR

Methotrexate and folic/folinic acid as prescribed by physician. ONLY children who report nausea/vomiting during regular care will be prescribed ondansetron at the same dose as in experimental group (2 mg if \<15Kg, 4 mg if 15-30Kg, 8 mg if \>30Kg to be taken by mouth one hour before each weekly methotrexate dose, followed by two additional doses every 6-8 hours if awake), as per the attending rheumatologist's discretion

Drug: Methotrexate; Drug: Ondansetron; Drug: Folic/folinic acid

Interventions

Methotrexate DRUG

Children in both the intervention and control group will receive Methotrexate dosed as prescribed by the attending rheumatologist

Also known as: Trexall

Ondansetron as needed; Ondansetron premedication

Ondansetron DRUG

Children in the intervention group will be prescribed premedication with oral ondansetron. Children in the control group will be prescribed ondansetron ONLY if the child reports nausea/vomiting during regular treatment care with Methotrexate

Also known as: Zofran

Ondansetron as needed; Ondansetron premedication

Folic/folinic acid DRUG

Children in both intervention and control group will receive folic acid or folinic acid dosed as prescribed by the attending rheumatologist.

Also known as: Leucovorin

Ondansetron as needed; Ondansetron premedication

Eligibility Criteria

• Age: 4 Years - 16 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Ages 4-16 years
• Diagnosis of JIA as per ILAR criteria \[1\], irrespective of JIA category
• Followed at a CAPRI centre in Canada
• Starting methotrexate to control JIA manifestations (arthritis, uveitis, psoriasis). (Female subjects of child bearing potential who are taking methotrexate for JIA cannot be pregnant, breastfeeding, or planning a pregnancy while on the drug and females of childbearing potential who are sexually active must use highly effective medically acceptable contraception. Subjects who stop methotrexate during the study will also discontinue ondansetron.)
• Informed written consent to participate
• Participating in the CAPRI JIA Registry

You may not qualify if:

• Previous use of methotrexate
• Known hypersensitivity to ondansetron or any components of its formulations
• Known hypersensitivity to other 5-HT3 antagonists
• Known congenital Long-QT syndrome
• Patients taking other medicinal products that lead to either QT prolongation or electrolyte abnormalities
• Because the serotonin syndrome may occur when ondansetron is combined with other agents that may affect the serotonergic neurotransmitter system, patients receiving any of the serotonergic and/or neuroleptic drugs listed below will be excluded:
• Triptans, SSRIs, SNRIs, lithium, sibutramine, fentanyl and its analogues, dextromethorphan, tramadol, tapendalol, meperidine, methadone, pentazocine or St. John's Wort (Hypericum perforatum), MAOIs, linezolid, methylene blue.
• Patients who are pregnant or breastfeeding, or are sexually active and unwilling to practice an acceptable method of birth control.
• Family unable to complete questionnaires in English or French

Sponsors & Collaborators

• University of British Columbia: lead
• The Arthritis Society, Canada: collaborator
• University of Calgary: collaborator
• The Hospital for Sick Children: collaborator
• McGill University Health Centre/Research Institute of the McGill University Health Centre: collaborator
• London Health Sciences Centre: collaborator
• University of Manitoba: collaborator
• Alberta Children's Hospital: collaborator
• McMaster University: collaborator
• McMaster Children's Hospital: collaborator
• Université de Montréal: collaborator

Study Sites (11)

University of Calgary / Alberta Children's Hospital

Calgary, Alberta, Canada

Location

University of Alberta

Edmonton, Alberta, Canada

Location

BC Children's Hospital

Vancouver, British Columbia, Canada

Location

University of Manitoba/Children's hospital research institute

Winnipeg, Manitoba, Canada

Location

McMaster University/McMaster Children's Hospital

Hamilton, Ontario, Canada

Location

London Health Sciences Centre

London, Ontario, Canada

Location

Hospital for Sick Children

Toronto, Ontario, Canada

Location

McGill University Health Centre

Montreal, Quebec, Canada

Location

Université de Montréal

Montreal, Quebec, Canada

Location

CHU de Quebec - Universite Laval

Québec, Quebec, G1V 4G2, Canada

Location

Royal University Hospital

Saskatoon, Saskatchewan, Canada

Location

Related Publications (32)

• Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, He X, Maldonado-Cocco J, Orozco-Alcala J, Prieur AM, Suarez-Almazor ME, Woo P; International League of Associations for Rheumatology. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004 Feb;31(2):390-2. No abstract available.

  PMID: 14760812 BACKGROUND

• Shiff NJ, Lix LM, Joseph L, Duffy C, Tucker LB, Svenson LW, Belisle P, Bernatsky S. The prevalence of systemic autoimmune rheumatic diseases in Canadian pediatric populations: administrative database estimates. Rheumatol Int. 2015 Mar;35(3):569-73. doi: 10.1007/s00296-014-3136-6. Epub 2014 Sep 26.

  PMID: 25257764 BACKGROUND

• ANSELL BM, BYWATERS EG. RHEUMATOID ARTHRITIS (STILL'S DISEASE). Pediatr Clin North Am. 1963 Nov;10:921-39. doi: 10.1016/s0031-3955(16)31475-4. No abstract available.

  PMID: 14145024 BACKGROUND

• Giannini EH, Brewer EJ, Kuzmina N, Shaikov A, Maximov A, Vorontsov I, Fink CW, Newman AJ, Cassidy JT, Zemel LS. Methotrexate in resistant juvenile rheumatoid arthritis. Results of the U.S.A.-U.S.S.R. double-blind, placebo-controlled trial. The Pediatric Rheumatology Collaborative Study Group and The Cooperative Children's Study Group. N Engl J Med. 1992 Apr 16;326(16):1043-9. doi: 10.1056/NEJM199204163261602.

  PMID: 1549149 BACKGROUND

• Beukelman T, Patkar NM, Saag KG, Tolleson-Rinehart S, Cron RQ, DeWitt EM, Ilowite NT, Kimura Y, Laxer RM, Lovell DJ, Martini A, Rabinovich CE, Ruperto N. 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res (Hoboken). 2011 Apr;63(4):465-82. doi: 10.1002/acr.20460.

  PMID: 21452260 BACKGROUND

• Guzman J, Oen K, Tucker LB, Huber AM, Shiff N, Boire G, Scuccimarri R, Berard R, Tse SM, Morishita K, Stringer E, Johnson N, Levy DM, Duffy KW, Cabral DA, Rosenberg AM, Larche M, Dancey P, Petty RE, Laxer RM, Silverman E, Miettunen P, Chetaille AL, Haddad E, Houghton K, Spiegel L, Turvey SE, Schmeling H, Lang B, Ellsworth J, Ramsey S, Bruns A, Campillo S, Benseler S, Chedeville G, Schneider R, Yeung R, Duffy CM; ReACCh-Out investigators. The outcomes of juvenile idiopathic arthritis in children managed with contemporary treatments: results from the ReACCh-Out cohort. Ann Rheum Dis. 2015 Oct;74(10):1854-60. doi: 10.1136/annrheumdis-2014-205372. Epub 2014 May 19.

  PMID: 24842571 BACKGROUND

• Falvey S, Shipman L, Ilowite N, Beukelman T. Methotrexate-induced nausea in the treatment of juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2017 Jun 19;15(1):52. doi: 10.1186/s12969-017-0180-2.

  PMID: 28629458 BACKGROUND

• Bulatovic M, Heijstek MW, Verkaaik M, van Dijkhuizen EH, Armbrust W, Hoppenreijs EP, Kamphuis S, Kuis W, Egberts TC, Sinnema G, Rademaker CM, Wulffraat NM. High prevalence of methotrexate intolerance in juvenile idiopathic arthritis: development and validation of a methotrexate intolerance severity score. Arthritis Rheum. 2011 Jul;63(7):2007-13. doi: 10.1002/art.30367.

  PMID: 21437879 BACKGROUND

• Dupont-Lucas C, Grandjean-Blanchet C, Leduc B, Tripcovici M, Larocque C, Gervais F, Jantchou P, Amre D, Deslandres C. Prevalence and Risk Factors for Symptoms of Methotrexate Intolerance in Pediatric Inflammatory Bowel Disease. Inflamm Bowel Dis. 2017 Feb;23(2):298-303. doi: 10.1097/MIB.0000000000001014.

  PMID: 28107279 BACKGROUND

• Mulligan K, Wedderburn LR, Newman S. The experience of taking methotrexate for juvenile idiopathic arthritis: results of a cross-sectional survey with children and young people. Pediatr Rheumatol Online J. 2015 Dec 12;13:58. doi: 10.1186/s12969-015-0052-6.

  PMID: 26653415 BACKGROUND

• van Dijkhuizen EH, Bulatovic Calasan M, Pluijm SM, de Rotte MC, Vastert SJ, Kamphuis S, de Jonge R, Wulffraat NM. Prediction of methotrexate intolerance in juvenile idiopathic arthritis: a prospective, observational cohort study. Pediatr Rheumatol Online J. 2015 Feb 18;13:5. doi: 10.1186/s12969-015-0002-3. eCollection 2015.

  PMID: 25745368 BACKGROUND

• Bechard MA, Lemieux JR, Roth J, Watanabe Duffy K, Duffy CM, Aglipay MO, Jurencak R. Procedural pain and patient-reported side effects with weekly injections of subcutaneous methotrexate in children with rheumatic disorders. Pediatr Rheumatol Online J. 2014 Dec 19;12:54. doi: 10.1186/1546-0096-12-54. eCollection 2014.

  PMID: 25584042 BACKGROUND

• Klotsche J, Minden K, Niewerth M, Horneff G. Time spent in inactive disease before MTX withdrawal is relevant with regard to the flare risk in patients with JIA. Ann Rheum Dis. 2018 Jul;77(7):996-1002. doi: 10.1136/annrheumdis-2017-211968. Epub 2018 Feb 16.

  PMID: 29453217 BACKGROUND

• Scheuern A, Tyrrell PN, Haas JP, Hugle B. Countermeasures against methotrexate intolerance in juvenile idiopathic arthritis instituted by parents show no effect. Rheumatology (Oxford). 2017 Jun 1;56(6):901-906. doi: 10.1093/rheumatology/kew507.

  PMID: 28122960 BACKGROUND

• Schoemaker CG, van Dijkhuizen EHP, Vastert SJ. Contradictory and weak evidence on the effectiveness of anti-emetics for MTX-intolerance in JIA-patients. Pediatr Rheumatol Online J. 2018 Feb 15;16(1):13. doi: 10.1186/s12969-018-0229-x. No abstract available.

  PMID: 29448947 BACKGROUND

• Phillips RS, Friend AJ, Gibson F, Houghton E, Gopaul S, Craig JV, Pizer B. Antiemetic medication for prevention and treatment of chemotherapy-induced nausea and vomiting in childhood. Cochrane Database Syst Rev. 2016 Feb 2;2(2):CD007786. doi: 10.1002/14651858.CD007786.pub3.

  PMID: 26836199 BACKGROUND

• Cubeddu LX, Hoffmann IS, Fuenmayor NT, Finn AL. Efficacy of ondansetron (GR 38032F) and the role of serotonin in cisplatin-induced nausea and vomiting. N Engl J Med. 1990 Mar 22;322(12):810-6. doi: 10.1056/NEJM199003223221204.

  PMID: 1689807 BACKGROUND

• De Mulder PH, Seynaeve C, Vermorken JB, van Liessum PA, Mols-Jevdevic S, Allman EL, Beranek P, Verweij J. Ondansetron compared with high-dose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting. A multicenter, randomized, double-blind, crossover study. Ann Intern Med. 1990 Dec 1;113(11):834-40. doi: 10.7326/0003-4819-113-11-834.

  PMID: 2146911 BACKGROUND

• Dick GS, Meller ST, Pinkerton CR. Randomised comparison of ondansetron and metoclopramide plus dexamethasone for chemotherapy induced emesis. Arch Dis Child. 1995 Sep;73(3):243-5. doi: 10.1136/adc.73.3.243.

  PMID: 7492164 BACKGROUND

• Kempinska A, Benchimol EI, Mack A, Barkey J, Boland M, Mack DR. Short-course ondansetron for the prevention of methotrexate-induced nausea in children with Crohn disease. J Pediatr Gastroenterol Nutr. 2011 Oct;53(4):389-93. doi: 10.1097/MPG.0b013e31822855e7.

  PMID: 21681112 BACKGROUND

• Blanco R, Gonzalez-Gay MA, Garcia-Porrua C, Ibanez D, Garcia-Pais MJ, Sanchez-Andrade A, Vazquez-Caruncho M. Ondansetron prevents refractory and severe methotrexate-induced nausea in rheumatoid arthritis. Br J Rheumatol. 1998 May;37(5):590-2. doi: 10.1093/rheumatology/37.5.590. No abstract available.

  PMID: 9651100 BACKGROUND

• Cubeddu LX, Pendergrass K, Ryan T, York M, Burton G, Meshad M, Galvin D, Ciociola AA. Efficacy of oral ondansetron, a selective antagonist of 5-HT3 receptors, in the treatment of nausea and vomiting associated with cyclophosphamide-based chemotherapies. Ondansetron Study Group. Am J Clin Oncol. 1994 Apr;17(2):137-46. doi: 10.1097/00000421-199404000-00010.

  PMID: 8141105 BACKGROUND

• Silverman E, Mouy R, Spiegel L, Jung LK, Saurenmann RK, Lahdenne P, Horneff G, Calvo I, Szer IS, Simpson K, Stewart JA, Strand V; Leflunomide in Juvenile Rheumatoid Arthritis (JRA) Investigator Group. Leflunomide or methotrexate for juvenile rheumatoid arthritis. N Engl J Med. 2005 Apr 21;352(16):1655-66. doi: 10.1056/NEJMoa041810.

  PMID: 15843668 BACKGROUND

• Ford I, Norrie J. Pragmatic Trials. N Engl J Med. 2016 Aug 4;375(5):454-63. doi: 10.1056/NEJMra1510059. No abstract available.

  PMID: 27518663 BACKGROUND

• 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 Apr;42(2):377-81. doi: 10.1016/j.jbi.2008.08.010. Epub 2008 Sep 30.

  PMID: 18929686 BACKGROUND

• Bhatt DL, Mehta C. Adaptive Designs for Clinical Trials. N Engl J Med. 2016 Jul 7;375(1):65-74. doi: 10.1056/NEJMra1510061. No abstract available.

  PMID: 27406349 BACKGROUND

• Efird J. Blocked randomization with randomly selected block sizes. Int J Environ Res Public Health. 2011 Jan;8(1):15-20. doi: 10.3390/ijerph8010015. Epub 2010 Dec 23.

  PMID: 21318011 BACKGROUND

• Chausset A, Fargeix T, Pereira B, Echaubard S, Duquesne A, Desjonqueres M, Freychet C, Belot A, Merlin E. MISS questionnaire in French version: a good tool for children and parents to assess methotrexate intolerance. Clin Rheumatol. 2017 Jun;36(6):1281-1288. doi: 10.1007/s10067-017-3638-1. Epub 2017 May 5.

  PMID: 28477218 BACKGROUND

• Wallace CA, Giannini EH, Huang B, Itert L, Ruperto N; Childhood Arthritis Rheumatology Research Alliance; Pediatric Rheumatology Collaborative Study Group; Paediatric Rheumatology International Trials Organisation. American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2011 Jul;63(7):929-36. doi: 10.1002/acr.20497.

  PMID: 21717596 BACKGROUND

• Feldman BM, Grundland B, McCullough L, Wright V. Distinction of quality of life, health related quality of life, and health status in children referred for rheumatologic care. J Rheumatol. 2000 Jan;27(1):226-33.

  PMID: 10648043 BACKGROUND

• Otto C, Barthel D, Klasen F, Nolte S, Rose M, Meyrose AK, Klein M, Thyen U, Ravens-Sieberer U. Predictors of self-reported health-related quality of life according to the EQ-5D-Y in chronically ill children and adolescents with asthma, diabetes, and juvenile arthritis: longitudinal results. Qual Life Res. 2018 Apr;27(4):879-890. doi: 10.1007/s11136-017-1753-8. Epub 2017 Nov 30.

  PMID: 29189988 BACKGROUND

• Schoenfeld DA. A simple algorithm for designing group sequential clinical trials. Biometrics. 2001 Sep;57(3):972-4. doi: 10.1111/j.0006-341x.2001.00972.x.

  PMID: 11550952 BACKGROUND

Related Links

• Health Canada prescribing information for methotrexate.
• Hopper C, Khan S, Mancini J, Rennick J. Perceptions of Methotrexate Intolerance in School-aged Children With Juvenile Idiopathic Arthritis \[abstract\].Arthritis Rheumatol. 2017; 69 (suppl 4).
• Da Silva C, Farias A, Sinicato N, Veloso R, Marini R, Appenseller S. Reasons for stopping methotrexate treatment in patients with juvenile idiopathic arthritisPediatric Rheumatology 2014, 12(Suppl 1):P199 (abstract)
• Health Canada prescribing information for ondansetron
• Ontario Drug Benefit Formulary

MeSH Terms

Conditions

Arthritis, Juvenile; Arthritis; Joint Diseases; Rheumatic Diseases; Nausea

Interventions

Methotrexate; Ondansetron; Leucovorin

Condition Hierarchy (Ancestors)

Musculoskeletal Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Signs and Symptoms, Digestive; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Carbazoles; Indoles; Heterocyclic Compounds, 3-Ring; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Coenzymes; Enzymes and Coenzymes

Study Officials

• Jaime Guzman, MD, FRCPC

  University of British Columbia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principle Investigator

Model Details: Pragmatic RCTs use alternative designs to establish effectiveness of a treatment strategy in usual care. Pragmatic trials aim to include all subjects in whom the treatment may be used and are conducted under the usual conditions of practice to demonstrate effectiveness under real word circumstances. Patients enrolled in a pragmatic trial are more representative because eligibility criteria are less strict.

Study Record Dates

• First Submitted: November 18, 2019
• First Posted: November 20, 2019
• Study Start: August 2, 2019
• Primary Completion: January 17, 2025
• Study Completion: January 17, 2025
• Last Updated: June 29, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

CA (11)