E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Juvenile Idiopathic Arthritis |
Juveniele Idiopathische Artritis |
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E.1.1.1 | Medical condition in easily understood language |
Juvenile Arthritis |
Jeugdreuma |
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E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Psychological processes [F02] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
This study’s objective is to reduce MTX related side effects with pharmacotherapeutic conditioning, by using variable reinforcement principles in patients with JIA. Pharmacotherapeutic conditioning enables to alternate standard MTX dosing with lower MTX doses, by utilizing learning effects (conditioning). By this, children with JIA will be less affected by MTX related side effects, without compromising for its therapeutic efficacy. A reduction in side effects will be assessed by intolerance percentages as defined by a cutoff score of ≥ 6 on the Methotrexate Intolerance Severity Score (MISS) questionnaire. |
Het doel van deze studie is om bijwerkingen te verminderen door middel van farmacotherapeutisch conditioneren bij patiënten met JIA. Farmacotherapeutisch conditioneren biedt de mogelijkheid om MTX doseringen af te wisselen met lagere doseringen. Door het afwisselend doseren wordt gebruik gemaakt van de leereffecten van het medicijn (conditioneren). Hierdoor zullen mogelijk minder kinderen last hebben van bijwerkingen doordat lagere MTX doseringen gebruikt kunnen worden voor de behandeling van JIA, zonder dat dit ten koste zal gaan van de ziekteactiviteit. Een verlaging in bijwerkingen zal gemeten worden aan de hand intolerantie percentages op basis van de Methotrexate Intolerance Severity Score (MISS) van 6 of hoger. |
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E.2.2 | Secondary objectives of the trial |
Secondary outcome measures are achieving low disease activity as measured by the Juvenile Arthritis Disease Activity Score (JADAS < 3), side effects as determined by liver function and gastrointestinal bleeding, laboratory assessments (e.g., cytokine levels and myeloid-related proteins and MTX polyglutamates), and self-report outcomes as assessed by validated scales about pain and burden of disease. |
Secundaire uitkomstmaten zijn het behalen van lage ziekteactiviteit, gemeten met de Juvenile Arthritis Disease Activity Score (JADAS < 3), bijwerkingen gemeten aan de hand van lever- en nierfuncties, laboratorium onderzoek (cytokine, myeloid-related proteines (MRP 8, 14) en MTX polyglutamaten gemeten uit rode bloedcellen) en standaard gevalideerde vragenlijsten voor klinisch gebruik waarin pijn en kwaliteit van leven worden gemeten. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age between 4 to 17 years (at the time of JIA diagnosis); - Diagnosed with JIA by their physician as defined by the ILAR-classification; - Able to speak or understand Dutch; - Patients (or parents/guardians of the patient under the age of 12) are able to give informed consent; - Achieve a good MTX response based on the JADAS (Juvenile Arthritis Disease Activity Score) assessing inactive disease scores at 6 months after MTX onset, with a score of 3 or lower or based on the pediatric rheumatologist's opinion. |
- Leeftijd van 4 tot 17 jaar (op het moment dat diagnose JIA is gesteld); - JIA diagnose door behandelend arts op basis van ILAR-classificatie; - Vermogen om Nederlands te spreken of te begrijpen; - De patiënt (of diens ouders/voogd tot 12 jaar) is in staat om geïnformeerd toestemming te geven; - Goede respons op MTX behandeling na 6 maanden op basis van de JADAS (Juvenile Arthritis Disease Activity Score) met een score van 3 of lager (lage ziekte activiteit) of naar inzicht van de kinderreumatoloog. |
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E.4 | Principal exclusion criteria |
- DMARD use at the moment of inclusion; or MTX experience previously - Alternative route of MTX administration than oral (e.g. subcutaneous) - Concomitant treatment with an experimental drug or procedure interfering with this study purposes - Systemic JIA - Development of uveitis which needs to be treated with a DMARD - Elevated hepatic enzyme levels (serum aspartate transaminase [AST], serum alanine transaminase [ALT] > 2 times normal value) - Bone marrow suppression as lymphocyte count <0.9×109/L, granulocyte count <1.5×109/L and/or thrombocyte count <20 × 109/L.39 - Serum creatinine levels > 150 umol/l or estimated creatinine clearance of < 75% - Biologicals |
- Gebruik van DMARD op het moment van inclusie; of eerdere ervaring met MTX - Alternatieve wijze van MTX toediening dan oraal (bv. subcutaan) - Gelijktijdige behandeling van een experimenteel medicijn of procedure welke interfereert met doel van het huidige onderzoek - Systemische JIA - Uveitis waarvoor DMARD benodigd is - Verhoogde lever-enzym waarden (serum aspartate transaminase [AST], serum alanine transaminase [ALT] > 2 keer normale waarde) - Beenmerg onderdrukking op basis van lymphocyte aantal <0.9×109/L, granulocyte aantal <1.5×109/L and/or thrombocyte aantal <20 × 109/L.39 - Serum creatinine waarden > 150 umol/l of geschatte creatinine klaring van < 75% - Medicatiebehandeling met biologicals |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome parameter is the difference in percentage of patients who experience MTX intolerance as defined by the Methotrexate Intolerance Severity Score (MISS) with a cut-off score of ≥ 6 between the control and intervention (conditioning) groups, after 9 months of interventon. The primary outcome measure MISS will be measured at month 15. The study will close with an end-of-study visit at month 18 where early flare-ups and side effects will be monitored. |
De primaire uitkomstmaat is het percentage in MTX intolerantie na 9 maanden interventie, gemeten met de Methotrexate Intolerance Severity Score (MISS) met een cut-off score ≥ 6, vergeleken tussen de controle- en interventiegroep. De primaire uitkomstmaat MISS wordt op maand 15 gemeten. De studie zal sluiten met een end-of-study visit waarin wordt gekeken naar (vroege) flare-ups en ervaren bijwerkingen |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Month 15: Primary outcome measure, MISS
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Month 15: Primaire uitkomstmaat, MISS
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E.5.2 | Secondary end point(s) |
Month 15: Secondary outcome measures: side effects as determined by liver function and gastrointestinal bleeding, laboratory assessments (e.g., cytokine levels and myeloid-related proteins and MTX polyglutamates), and self-report outcomes as assessed by validated scales about pain and burden of disease.
Month 18: Follow-up |
Maand 15: Secundiare uitkomstmaten: JADAS, bijwerkingen gemeten aan de hand van lever- en nierfuncties, laboratorium onderzoek (cytokine, myeloid-related proteines (MRP 8, 14), MTX polyglutamaten gemeten uit rode bloedcellen) en standaard gevalideerde vragenlijsten voor klinisch gebruik waarin pijn en kwaliteit van leven worden gemeten.
Month 18: Follow-up |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Month 15 and 18 |
Month 15 and 18 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Pharmacotherapeutic approach will be used to reduce side effects |
Farmacothereapeutische behandeling zal ingezet worden om bijwerkingen te verminderen. |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
standaard behandeling |
care as usual |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |