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The Ondansetron Premedication Trial in Juvenile Idiopathic Arthritis (OPT-JIA)

Primary Purpose

Juvenile Idiopathic Arthritis

Status
Recruiting
Phase
Not Applicable
Locations
Canada
Study Type
Interventional
Intervention
Methotrexate
Ondansetron
Folic/folinic acid
Sponsored by
University of British Columbia
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Juvenile Idiopathic Arthritis focused on measuring Arthritis, Arthritis, Juvenile, Joint Diseases, Rheumatic diseases, Pragmatic Trials, Ondansetron, Methotrexate, Nausea

Eligibility Criteria

4 Years - 16 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Calgary / Alberta Children's HospitalRecruiting
  • University of Alberta
  • BC Children's HospitalRecruiting
  • University of Manitoba/Children's hospital research institute
  • Memorial University/Janeway Childrens Health and Rehabilitation Centre
  • IWK Health Centre
  • McMaster University/McMaster Children's HospitalRecruiting
  • London Health Sciences CentreRecruiting
  • Hospital for Sick ChildrenRecruiting
  • McGill University Health CentreRecruiting
  • Université de MontréalRecruiting
  • CHU de Quebec - Universite LavalRecruiting
  • University of Sherbrooke
  • Royal University Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Ondansetron premedication

Ondansetron as needed

Arm Description

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.

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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).
Methotrexate intolerance
The cumulative incidence of methotrexate intolerance
Attainment of inactive disease
The cumulative incidence of attainment of inactive disease, defined by Wallace criteria
Starting a biologic medication
The cumulative incidence of starting a biologic medication
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).
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).

Full Information

First Posted
November 18, 2019
Last Updated
August 11, 2023
Sponsor
University of British Columbia
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
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1. Study Identification

Unique Protocol Identification Number
NCT04169828
Brief Title
The Ondansetron Premedication Trial in Juvenile Idiopathic Arthritis
Acronym
OPT-JIA
Official Title
The Ondansetron Premedication Trial in Juvenile Idiopathic Arthritis
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 2, 2019 (Actual)
Primary Completion Date
September 1, 2024 (Anticipated)
Study Completion Date
January 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of British Columbia
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

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Juvenile Idiopathic Arthritis
Keywords
Arthritis, Arthritis, Juvenile, Joint Diseases, Rheumatic diseases, Pragmatic Trials, Ondansetron, Methotrexate, Nausea

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
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)
Allocation
Randomized
Enrollment
176 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Ondansetron premedication
Arm Type
Experimental
Arm Description
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.
Arm Title
Ondansetron as needed
Arm Type
Active Comparator
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Other Intervention Name(s)
Trexall
Intervention Description
Children in both the intervention and control group will receive Methotrexate dosed as prescribed by the attending rheumatologist
Intervention Type
Drug
Intervention Name(s)
Ondansetron
Other Intervention Name(s)
Zofran
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Folic/folinic acid
Other Intervention Name(s)
Leucovorin
Intervention Description
Children in both intervention and control group will receive folic acid or folinic acid dosed as prescribed by the attending rheumatologist.
Primary Outcome Measure Information:
Title
Proportion of subjects that remain on methotrexate with no intolerance
Description
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.
Time Frame
One year after starting methotrexate.
Secondary Outcome Measure Information:
Title
Frequency and cumulative incidence of adverse events (safety and tolerability)
Description
Frequency and cumulative incidence of adverse events, and any suspected unexpected serious adverse drug reactions (SUSARs).
Time Frame
Within one year
Title
Methotrexate intolerance
Description
The cumulative incidence of methotrexate intolerance
Time Frame
Within one year
Title
Attainment of inactive disease
Description
The cumulative incidence of attainment of inactive disease, defined by Wallace criteria
Time Frame
Within one year
Title
Starting a biologic medication
Description
The cumulative incidence of starting a biologic medication
Time Frame
Within one year
Title
Quality of My Life scale
Description
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).
Time Frame
4-8 months after starting methotrexate
Title
MISS questionnaire
Description
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).
Time Frame
4-8 months after starting methotrexate

10. Eligibility

Sex
All
Minimum Age & Unit of Time
4 Years
Maximum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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 Exclusion Criteria: 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jaime Guzman, MD, FRCPC
Phone
604-875-2437
Email
jguzman@cw.bc.ca
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jaime Guzman, MD, FRCPC
Organizational Affiliation
University of British Columbia
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Calgary / Alberta Children's Hospital
City
Calgary
State/Province
Alberta
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Heinrike Schmeling, MD
Facility Name
University of Alberta
City
Edmonton
State/Province
Alberta
Country
Canada
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dax Rumsey, MD
Facility Name
BC Children's Hospital
City
Vancouver
State/Province
British Columbia
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jaime Guzman, MD, FRCPC
Facility Name
University of Manitoba/Children's hospital research institute
City
Winnipeg
State/Province
Manitoba
Country
Canada
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lily SH Lim, MD, PhD
Facility Name
Memorial University/Janeway Childrens Health and Rehabilitation Centre
City
St. John's
State/Province
Newfoundland and Labrador
Country
Canada
Individual Site Status
Withdrawn
Facility Name
IWK Health Centre
City
Halifax
State/Province
Nova Scotia
Country
Canada
Individual Site Status
Withdrawn
Facility Name
McMaster University/McMaster Children's Hospital
City
Hamilton
State/Province
Ontario
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michelle Batthish, MD, FRCPC
Facility Name
London Health Sciences Centre
City
London
State/Province
Ontario
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Roberta Berard, MD
Facility Name
Hospital for Sick Children
City
Toronto
State/Province
Ontario
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Brian Feldman, MD, MSc
Facility Name
McGill University Health Centre
City
Montréal
State/Province
Quebec
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gaëlle Chédeville, MD
Facility Name
Université de Montréal
City
Montréal
State/Province
Quebec
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jean Jacques De Bruycker, MD
Facility Name
CHU de Quebec - Universite Laval
City
Québec
State/Province
Quebec
ZIP/Postal Code
G1V 4G2
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jean-Philippe Proulx-Gauthier, MD
Facility Name
University of Sherbrooke
City
Sherbrooke
State/Province
Quebec
Country
Canada
Individual Site Status
Withdrawn
Facility Name
Royal University Hospital
City
Saskatoon
State/Province
Saskatchewan
Country
Canada
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alan Rosenberg, MD

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
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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Links:
URL
https://pdf.hres.ca/dpd_pm/00053618.PDF
Description
Health Canada prescribing information for methotrexate.
URL
http://acrabstracts.org/abstract/perceptions-of-methotrexate-intolerance-in-school-aged-children-with-juvenile-idiopathic-arthritis/.
Description
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).
URL
http://www.ped-rheum.com/content/12/S1/P199
Description
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)
URL
https://pdf.hres.ca/dpd_pm/00058412.PDF
Description
Health Canada prescribing information for ondansetron
URL
https://www.formulary.health.gov.on.ca/formulary/
Description
Ontario Drug Benefit Formulary

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The Ondansetron Premedication Trial in Juvenile Idiopathic Arthritis

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