The Ondansetron Premedication Trial in Juvenile Idiopathic Arthritis

Juvenile Idiopathic Arthritis Clinical Trial

— OPT-JIA  

Official title:

The Ondansetron Premedication Trial in Juvenile Idiopathic Arthritis

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04169828
• Other study ID #: H18-03176
• Status: Active, not recruiting
• Phase: N/A
• Start date: August 2, 2019
• Est. completion date: March 1, 2025

Study information

• Verified date: January 2024
• Source: University of British Columbia
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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.

Description:

1. 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.

2. 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.

3. 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.

4. 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:

1. The proportions of patients remaining on methotrexate with no intolerance between the two groups one year after starting methotrexate (primary objective).

2. Safety and tolerability

3. The cumulative incidence of:

1. methotrexate intolerance

2. attainment of inactive disease

3. biologic medication initiation

4. 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.

5. 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

6. 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 52
• Est. completion date: March 1, 2025
• Est. primary completion date: October 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 4 Years to 16 Years

Eligibility

Inclusion Criteria:

1. Ages 4-16 years

2. Diagnosis of JIA as per ILAR criteria [1], irrespective of JIA category

3. Followed at a CAPRI centre in Canada

4. 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.)

5. Informed written consent to participate

6. Participating in the CAPRI JIA Registry

Exclusion Criteria:

1. Previous use of methotrexate

2. Known hypersensitivity to ondansetron or any components of its formulations

3. Known hypersensitivity to other 5-HT3 antagonists

4. Known congenital Long-QT syndrome

5. Patients taking other medicinal products that lead to either QT prolongation or electrolyte abnormalities

6. 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.

7. Patients who are pregnant or breastfeeding, or are sexually active and unwilling to practice an acceptable method of birth control.

8. Family unable to complete questionnaires in English or French

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Juvenile
• Juvenile Idiopathic Arthritis

Intervention

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

Locations

Country	Name	City	State
Canada	University of Calgary / Alberta Children's Hospital	Calgary	Alberta
Canada	University of Alberta	Edmonton	Alberta
Canada	McMaster University/McMaster Children's Hospital	Hamilton	Ontario
Canada	London Health Sciences Centre	London	Ontario
Canada	McGill University Health Centre	Montréal	Quebec
Canada	Université de Montréal	Montréal	Quebec
Canada	CHU de Quebec - Universite Laval	Québec	Quebec
Canada	Royal University Hospital	Saskatoon	Saskatchewan
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	BC Children's Hospital	Vancouver	British Columbia
Canada	University of Manitoba/Children's hospital research institute	Winnipeg	Manitoba

Sponsors (11)

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

Country where clinical trial is conducted

Canada, 

References & Publications (32)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 32 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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).	Within one year
Secondary	Methotrexate intolerance	The cumulative incidence of methotrexate intolerance	Within one year
Secondary	Attainment of inactive disease	The cumulative incidence of attainment of inactive disease, defined by Wallace criteria	Within one year
Secondary	Starting a biologic medication	The cumulative incidence of starting a biologic medication	Within one year
Secondary	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).	4-8 months after starting methotrexate
Secondary	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).	4-8 months after starting methotrexate

External Links

•   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 methotrexate.
•   Health Canada prescribing information for ondansetron
•   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).
•   Ontario Drug Benefit Formulary