Juvenile Idiopathic ArthritisOPT-JIANCT04169828
The Ondansetron Premedication Trial in Juvenile Idiopathic Arthritis
A study testing Methotrexate, Ondansetron and Folic/folinic acid in people with Juvenile Idiopathic Arthritis, run by University of British Columbia at 11 sites in Canada.
Trial 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. Read more about this study
- Who is it for?
- Ages 4 to 16 years
- Conditions the study is for
- Juvenile Idiopathic Arthritis
- What is being tested?
- Methotrexate, Ondansetron and Folic/folinic acid
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 52 participants
- Where
- 11 sitesCanada
- Study dates
- 2 Aug 2019to 17 Jan 2025
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 4 to 16 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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
Who cannot join
- 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:
Show all 9Show fewer
- 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
Trial locations and contacts
11 sites in 1 country.
11 sites in 1 country
Canada11 sites
University of Calgary / Alberta Children's Hospital
Calgary, Alberta
University of Alberta
Edmonton, Alberta
McMaster University/McMaster Children's Hospital
Hamilton, Ontario
London Health Sciences Centre
London, Ontario
McGill University Health Centre
Montreal, Quebec
Université de Montréal
Montreal, Quebec
CHU de Quebec - Universite Laval
Québec, Quebec, G1V 4G2
Royal University Hospital
Saskatoon, Saskatchewan
Hospital for Sick Children
Toronto, Ontario
BC Children's Hospital
Vancouver, British Columbia
University of Manitoba/Children's hospital research institute
Winnipeg, Manitoba
About this study
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.
Read the detailed description
- Purpose: To evaluate if routine pre-medication with the anti-emetic ondansetron reduces methotrexate intolerance and increases the proportion of children with JIA able to continue taking methotrexate, resulting in a better quality of life and more cost-effective medication use.
- Hypothesis: Prophylactic prescription of ondansetron with methotrexate will increase the proportion of children that remain on methotrexate and intolerance free one year after starting methotrexate, relative to prescription of ondansetron after intolerance symptoms develop.
- Justification: Methotrexate intolerance is thought to be largely the result of Pavlovian conditioning secondary to previous exposure and symptoms can be triggered by associated stimuli, such as a yellow liquid similar in color to methotrexate or the smell of alcohol cleansing swabs. This intolerance leads to poor adherence to optimal dosing or to stopping the medication altogether. Children who cannot adhere to optimal dosing or stop methotrexate may require expensive biologic medications to control their JIA. Methotrexate intolerance often leads to use of anti-emetic medications which, unfortunately, rarely reverse conditioned responses. In oncology anti-emetics are used prophylactically as premedication in all subjects receiving chemotherapy to prevent the establishment of conditioned intolerance. By conducting a registry-based pragmatic adaptive superiority randomized clinical trial the investigators will include most subjects in whom the treatment may be used 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. More so, a registry-based pragmatic RCT can also be much cheaper than a traditional RCT.
- Objectives:
The investigators will assign patients starting low-dose methotrexate for JIA 1:1 online using the CAPRI Registry and block randomization by Canadian region and patient weight to one of two groups:
Intervention: Routine premedication with oral ondansetron (2, 4 or 8 mg for patient weights <15Kg, 15-30Kg, >30 Kg; 3 doses a week).
Control: Oral ondansetron at the same dosing, prescribed only to those patients who develop methotrexate-induced nausea/vomiting during usual care.
The investigators will compare:
- The proportions of patients remaining on methotrexate with no intolerance between the two groups one year after starting methotrexate (primary objective).
- Safety and tolerability
- The cumulative incidence of:
- methotrexate intolerance
- attainment of inactive disease
- biologic medication initiation
- The mean quality of life scores and methotrexate intolerance severity scores between the two groups 4-8 months after starting methotrexate. The investigators will also collect information on impacts on quality of life and medication utilization that will enable a future cost-effectiveness analysis.
- Research Design: The investigators will conduct a CAPRI JIA Registry-based pragmatic adaptive superiority RCT as per the following methods. Registry-based: The trial will use infrastructure already in place for the CAPRI JIA Registry. Pragmatic: Broad inclusion criteria and simple outcome assessments compatible with usual care. Adaptive: This is a Planned Sample-Size Re-Estimation Adaptive Trial as described by Bhatt \& Metha [34]. Superiority: Designed to test superiority (as opposed to non-inferiority) of ondansetron premedication. RCT: Treatments assigned by block randomization and analyses adjusted for post-randomization imbalances
- Statistical Analysis:
The primary outcome statistic is the ratio of two proportions (relative risk, RR), the proportion of children remaining on methotrexate with no intolerance in the intervention group divided by the same in the control group. This choice allows flexibility for the frequency of follow-up visits to be set-up as per clinical need, obviating the need for study-specific visits, increasing feasibility and decreasing costs. It is also not impacted by the times at which methotrexate intolerance or discontinuation occur which leads to simplicity in interpretation and analysis.
The sample size calculation is based on expressing the RR in the log scale and using established formulas for standard errors. With p<0.05, power of 90% and expected methotrexate continuation with no intolerance of 50% in the control group and 75% in the intervention group the result is 79 evaluable subjects per group. The investigators will aim to recruit 176 subjects total to allow for up to a 10% dropout rate, although they expect a dropout rate of <5% based on previous CAPRI studies.
A preliminary analysis after recruitment of 90 subjects will consist of a two-sided confidence interval (CI) for the RR of continuing on methotrexate with no intolerance, where the confidence level is adjusted for information accrual as per Schoenfeld.
The Data and Safety Committee will assess preliminary results according to the following guidance:
If the CI is entirely below a relative risk of 1.2, the study will be stopped for futility.
If the CI is entirely above a relative risk of 1.2, the study will be stopped and superiority will be claimed.
If the CI includes a relative risk of 1.2, the trial will continue until the re-calculated full target sample is attained.
The RR of 1.2 has been selected on clinical grounds. In a prospective study of 142 children with JIA starting methotrexate followed for one year, Van Dijkhuizen et al reported that 59 patients developed intolerance and 11 discontinued methotrexate for other reasons, for a total of 72 (50.7%) remaining on methotrexate with no intolerance. An increase in this proportion to <60% is deemed too small to justify the additional costs and risks of adding prophylactic ondansetron.
The final analysis will be an intention to treat analysis conducted after the final sample size is achieved or at the time the study is stopped. All subjects enrolled in the study at that time will complete a one-year follow-up and will be included in the final analysis. Logistic regression models will be used to adjust effect estimates for post-randomization imbalances in the two groups (intervention, control). A secondary per-protocol analysis will be conducted on those subjects who received the assigned intervention for at least 3 months.
- Conditions
- Juvenile Idiopathic Arthritis
- Being tested
- Methotrexate, Ondansetron, Folic/folinic acid
- Keywords
- Arthritis, Arthritis, Juvenile, Joint Diseases, Rheumatic diseases, Pragmatic Trials, Ondansetron, Methotrexate, Nausea
- Medical subject headings
- Arthritis, Juvenile, Arthritis, Joint Diseases, Rheumatic Diseases, Nausea
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MethotrexateDrug
Also called Trexall
Children in both the intervention and control group will receive Methotrexate dosed as prescribed by the attending rheumatologist
OndansetronDrug
Also called Zofran
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
Folic/folinic acidDrug
Also called Leucovorin
Children in both intervention and control group will receive folic acid or folinic acid dosed as prescribed by the attending rheumatologist.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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 Receives: Drug: Methotrexate; Drug: Ondansetron; Drug: Folic/folinic acid |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: One year after starting methotrexate.
Secondary outcomes (6)
Frequency and cumulative incidence of adverse events (safety and tolerability)
Frequency and cumulative incidence of adverse events, and any suspected unexpected serious adverse drug reactions (SUSARs).
Measured: Within one year
Methotrexate intolerance
The cumulative incidence of methotrexate intolerance
Measured: Within one year
Attainment of inactive disease
The cumulative incidence of attainment of inactive disease, defined by Wallace criteria
Measured: Within one year
Starting a biologic medication
The cumulative incidence of starting a biologic medication
Measured: Within one year
Quality of My Life scale
Mean quality of life scores in the Quality of My Life scale. The scale has a minimum value of zero (WORST quality of life) and a maximum value of 10 (BEST quality of life).
Measured: 4-8 months after starting methotrexate
MISS questionnaire
Mean scores in the Methotrexate Intolerance Severity Score (MISS) questionnaire. Scores in the MISS questionnaire go from 0 (no signs of intolerance) to a maximum of 36 (all signs of intolerance are severe).
Measured: 4-8 months after starting methotrexate
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Nov 2019
- Study start2 Aug 2019
- Primary completion17 Jan 2025
- Study completion17 Jan 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (32)Papers the sponsor has linked to this study.
- Other trials for Juvenile Idiopathic ArthritisStudies of the same condition, open and under way.
- More trials run by University of British ColumbiaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 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.
- Masking
- None (open label)
- Enrolment
- 52 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of British Columbia
- Sponsor type
- University, hospital or other
- Collaborators
- The Arthritis Society, Canada, University of Calgary, The Hospital for Sick Children, McGill University Health Centre/Research Institute of the McGill University Health Centre, London Health Sciences Centre, University of Manitoba, Alberta Children's Hospital, McMaster University, McMaster Children's Hospital, Université de Montréal
- Responsible party
- Principal investigator, Jaime Guzman, University of British Columbia
- Investigators
- Jaime Guzman, MD, FRCPC, Principal investigator, University of British Columbia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04169828
- Sponsor's protocol ID
- H18-03176
- Acronym
- OPT-JIA
- Status last verified
- Jun 2025
- First submitted
- 18 Nov 2019
- Last updated
- 29 Jun 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: If the ethics boards at all participating centres approve individual participant data sharing we will upload to clinicaltrials.gob a data sharing plan at that time.
Publications
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.
PubMed 14760812Shiff 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.
PubMed 25257764ANSELL 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.
PubMed 14145024Giannini 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.
PubMed 1549149Beukelman 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.
PubMed 21452260Guzman 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.
PubMed 24842571Falvey 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.
PubMed 28629458Bulatovic 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.
PubMed 21437879Dupont-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.
PubMed 28107279Mulligan 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.
PubMed 26653415van 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.
PubMed 25745368Bechard 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.
PubMed 25584042Klotsche 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.
PubMed 29453217Scheuern 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.
PubMed 28122960Schoemaker 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.
PubMed 29448947
Study at a glance
From the registry record, last updated by the sponsor on 29 Jun 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Ondansetron Premedication Trial in Juvenile Idiopathic Arthritis
- ClinicalTrials.gov ID
- NCT04169828
- Acronym / sponsor ID
- OPT-JIA / H18-03176
- Conditions
- Juvenile Idiopathic Arthritis
- Keywords
- Arthritis, Arthritis, Juvenile, Joint Diseases, Rheumatic diseases, Pragmatic Trials, Ondansetron, Methotrexate, Nausea
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 52 participants (actual)
- Lead sponsor
- University of British ColumbiaUniversity, hospital or other
- Collaborators
- The Arthritis Society, Canada, University of Calgary, The Hospital for Sick Children, McGill University Health Centre/Research Institute of the McGill University Health Centre, London Health Sciences Centre, University of Manitoba, Alberta Children's Hospital, McMaster University, McMaster Children's Hospital, Université de Montréal
- Study start
- 2 Aug 2019 (actual)
- Primary completion
- 17 Jan 2025 (actual)
- Study completion
- 17 Jan 2025 (actual)
- First posted
- 20 Nov 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
- Purpose: To evaluate if routine pre-medication with the anti-emetic ondansetron reduces methotrexate intolerance and increases the proportion of children with JIA able to continue taking methotrexate, resulting in a better quality of life and more cost-effective medication use.
- Hypothesis: Prophylactic prescription of ondansetron with methotrexate will increase the proportion of children that remain on methotrexate and intolerance free one year after starting methotrexate, relative to prescription of ondansetron after intolerance symptoms develop.
- Justification: Methotrexate intolerance is thought to be largely the result of Pavlovian conditioning secondary to previous exposure and symptoms can be triggered by associated stimuli, such as a yellow liquid similar in color to methotrexate or the smell of alcohol cleansing swabs. This intolerance leads to poor adherence to optimal dosing or to stopping the medication altogether. Children who cannot adhere to optimal dosing or stop methotrexate may require expensive biologic medications to control their JIA. Methotrexate intolerance often leads to use of anti-emetic medications which, unfortunately, rarely reverse conditioned responses. In oncology anti-emetics are used prophylactically as premedication in all subjects receiving chemotherapy to prevent the establishment of conditioned intolerance. By conducting a registry-based pragmatic adaptive superiority randomized clinical trial the investigators will include most subjects in whom the treatment may be used 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. More so, a registry-based pragmatic RCT can also be much cheaper than a traditional RCT.
- Objectives:
The investigators will assign patients starting low-dose methotrexate for JIA 1:1 online using the CAPRI Registry and block randomization by Canadian region and patient weight to one of two groups:
Intervention: Routine premedication with oral ondansetron (2, 4 or 8 mg for patient weights <15Kg, 15-30Kg, >30 Kg; 3 doses a week).
Control: Oral ondansetron at the same dosing, prescribed only to those patients who develop methotrexate-induced nausea/vomiting during usual care.
The investigators will compare:
- The proportions of patients remaining on methotrexate with no intolerance between the two groups one year after starting methotrexate (primary objective).
- Safety and tolerability
- The cumulative incidence of:
- methotrexate intolerance
- attainment of inactive disease
- biologic medication initiation
- The mean quality of life scores and methotrexate intolerance severity scores between the two groups 4-8 months after starting methotrexate. The investigators will also collect information on impacts on quality of life and medication utilization that will enable a future cost-effectiveness analysis.
- Research Design: The investigators will conduct a CAPRI JIA Registry-based pragmatic adaptive superiority RCT as per the following methods. Registry-based: The trial will use infrastructure already in place for the CAPRI JIA Registry. Pragmatic: Broad inclusion criteria and simple outcome assessments compatible with usual care. Adaptive: This is a Planned Sample-Size Re-Estimation Adaptive Trial as described by Bhatt \& Metha [34]. Superiority: Designed to test superiority (as opposed to non-inferiority) of ondansetron premedication. RCT: Treatments assigned by block randomization and analyses adjusted for post-randomization imbalances
- Statistical Analysis:
The primary outcome statistic is the ratio of two proportions (relative risk, RR), the proportion of children remaining on methotrexate with no intolerance in the intervention group divided by the same in the control group. This choice allows flexibility for the frequency of follow-up visits to be set-up as per clinical need, obviating the need for study-specific visits, increasing feasibility and decreasing costs. It is also not impacted by the times at which methotrexate intolerance or discontinuation occur which leads to simplicity in interpretation and analysis.
The sample size calculation is based on expressing the RR in the log scale and using established formulas for standard errors. With p<0.05, power of 90% and expected methotrexate continuation with no intolerance of 50% in the control group and 75% in the intervention group the result is 79 evaluable subjects per group. The investigators will aim to recruit 176 subjects total to allow for up to a 10% dropout rate, although they expect a dropout rate of <5% based on previous CAPRI studies.
A preliminary analysis after recruitment of 90 subjects will consist of a two-sided confidence interval (CI) for the RR of continuing on methotrexate with no intolerance, where the confidence level is adjusted for information accrual as per Schoenfeld.
The Data and Safety Committee will assess preliminary results according to the following guidance:
If the CI is entirely below a relative risk of 1.2, the study will be stopped for futility.
If the CI is entirely above a relative risk of 1.2, the study will be stopped and superiority will be claimed.
If the CI includes a relative risk of 1.2, the trial will continue until the re-calculated full target sample is attained.
The RR of 1.2 has been selected on clinical grounds. In a prospective study of 142 children with JIA starting methotrexate followed for one year, Van Dijkhuizen et al reported that 59 patients developed intolerance and 11 discontinued methotrexate for other reasons, for a total of 72 (50.7%) remaining on methotrexate with no intolerance. An increase in this proportion to <60% is deemed too small to justify the additional costs and risks of adding prophylactic ondansetron.
The final analysis will be an intention to treat analysis conducted after the final sample size is achieved or at the time the study is stopped. All subjects enrolled in the study at that time will complete a one-year follow-up and will be included in the final analysis. Logistic regression models will be used to adjust effect estimates for post-randomization imbalances in the two groups (intervention, control). A secondary per-protocol analysis will be conducted on those subjects who received the assigned intervention for at least 3 months.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| Ondansetron premedication | Experimental | Drug: Methotrexate, Drug: Ondansetron, Drug: Folic/folinic acidMethotrexate 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. |
| Ondansetron as needed | Active comparator | Drug: Methotrexate, Drug: Ondansetron, Drug: Folic/folinic acidMethotrexate 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 |
Who may qualify
- Ages
- 4 to 16 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (9 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MethotrexateAlso: TrexallChildren in both the intervention and control group will receive Methotrexate dosed as prescribed by the attending rheumatologist | Drug | Ondansetron as needed, Ondansetron premedication |
| OndansetronAlso: ZofranChildren 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 | Drug | Ondansetron as needed, Ondansetron premedication |
| Folic/folinic acidAlso: LeucovorinChildren in both intervention and control group will receive folic acid or folinic acid dosed as prescribed by the attending rheumatologist. | Drug | Ondansetron as needed, Ondansetron premedication |
Primary outcome
Proportion of subjects that remain on methotrexate with no intolerance
Time frame: One year after starting methotrexate.
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.
6 secondary outcomes
Frequency and cumulative incidence of adverse events (safety and tolerability)
Time frame: Within one year
Methotrexate intolerance
Time frame: Within one year
Attainment of inactive disease
Time frame: Within one year
Starting a biologic medication
Time frame: Within one year
Quality of My Life scale
Time frame: 4-8 months after starting methotrexate
MISS questionnaire
Time frame: 4-8 months after starting methotrexate
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Jun 2025.
- Background: PubMed 14760812Petty 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.
- Background: PubMed 25257764Shiff 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.
- Background: PubMed 14145024ANSELL 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.
- Background: PubMed 1549149Giannini 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.
- Background: PubMed 21452260Beukelman 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.
- Background: PubMed 24842571Guzman 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.
- Background: PubMed 28629458Falvey 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.
- Background: PubMed 21437879Bulatovic 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.
- Background: PubMed 28107279Dupont-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.
- Background: PubMed 26653415Mulligan 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.
- Background: PubMed 25745368van 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.
- Background: PubMed 25584042Bechard 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.
- Health Canada prescribing information for methotrexate.Link provided by the sponsor.
- 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).Link provided by the sponsor.
- 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)Link provided by the sponsor.
- Health Canada prescribing information for ondansetronLink provided by the sponsor.
- Ontario Drug Benefit FormularyLink provided by the sponsor.
- Individual participant dataSharing planned: No. If the ethics boards at all participating centres approve individual participant data sharing we will upload to clinicaltrials.gob a data sharing plan at that time.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jaime Guzman, MD, FRCPC principal investigator
University of British Columbia
11 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Methotrexate, Ondansetron and Folic/folinic acid in people with Juvenile Idiopathic Arthritis, run by University of British Columbia at 11 sites in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Jun 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 11 sites in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportion of subjects that remain on methotrexate with no intolerance (time frame: One year after starting methotrexate.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04169828, which also lists 32 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Jun 2025.