Five-year Actively Controlled Clinical Trial in New Onset Juvenile Dermatomyositis

Study Overview
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Brief Summary
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This is a 5-year project, involving 185 partners from 46 countries ((110 in 21 European Union (EU) States and 75 in 25 extra-EU States)), with a randomised clinical trials (RCT) in juvenile dermatomyositis (JDM): 5-year phase III single-blind, RCT in children with newly diagnosed JDM: prednisone (PDN) versus PDN plus methotrexate (MTX) versus PDN plus Cyclosporine A. The trial is aimed to find out the treatment regimen associated with the lowest occurrence of flare and the lowest drug related toxicity

Detailed Description
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Scientific objectives: The proposed project is aimed to improve treatment approaches for rare, severe and disabling paediatric rheumatic diseases (PRD). This goal will be achieved by the Paediatric Rheumatology International Trials Organisation (PRINTO) an international network whose main function is to provide a scientific base for current PRD treatments for which no evidence based data exist in the literature, and for drugs for which there is no support from industries. This is a 5-year project, involving 46 countries (110 in 21 EU States and 75 in 25 extra-EU States), with a randomised clinical trials (RCT) in juvenile dermatomyositis (JDM): 5-year phase III single-blind, RCT in children with newly diagnosed JDM: prednisone (PDN) versus PDN plus methotrexate (MTX) versus PDN plus Cyclosporine A (CsA). The trial is aimed to find out the treatment regimen associated with the lowest occurrence of flare and the lowest drug related toxicity. The retention on treatment will be used as main measure of effectiveness. Methodology: The present protocol is the natural follow up of previous work conducted by PRINTO. In particular the RCT foreseen in this protocol is modelled after the successful completion of an early phase trial with MTX in juvenile idiopathic arthritis, and will use validated JDM outcome measures for the evaluation of response to therapy. It is the basic premise of this protocol that, without i) the involvement of the international paediatric rheumatology community, ii) the innovative type of mechanism described herein, these studies would never be conducted. Objectives. The goals of the current protocol is therefore the natural follow-up of the objectives achieved with the previous grants and, in particular, of projects designed to discern new models for the successful conduct of clinical trials in children with rare diseases, and to develop standardized and validated measures for the evaluation of response to therapy in JDM. The proposed trial in JDM (prednisone [PDN] versus PDN plus methotrexate [MTX] versus PDN plus cyclosporine [CsA]), should serve as a model for the successful running of early phase clinical trials for severe and disabling rare diseases of childhood. The ultimate aim of these trials is to provide evidence-based information about the clinical utility of drugs in the management of rare paediatric conditions.

Official Title
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Five-year Single-blind, Phase III Effectiveness Randomised Actively Controlled Clinical Trial in New Onset Juvenile Dermatomyositis: Prednisone Versus Prednisone Plus Cyclosporine a Versus Prednisone Plus Methotrexate

Conditions
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Juvenile Dermatomyositis

Intervention / Treatment
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* Drug: 3 MPDN pulse + PDN
* Drug: 3 MPDN pulse + PDN + CSA
* Drug: 3 MPDN pulse + PDN + MTX


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria. Each patient must meet all the following criteria in order to participate in this trial: Newly diagnosed and untreated children (only treatment with 1 NSAID is allowed and/or prednisone >1 mg/kg/day for no more than 1 month from diagnosis) with probable or definite diagnosis of JDM according to published (12;13). If a muscle biopsy will be performed (optional) it will be read by the pathologists of the participating centres (light and immunofluorescence). Slides of paraffin-embedded sections from all patients will be re-viewed by a blinded myopathologist at PRINTO. Age at enrolment ≤ 18 years. Female of child-bearing potential must have a negative pregnancy test at the beginning of the trial, and then every 3 months. If sexually active, they must agree to use adequate contraception, throughout study participation, and must have no intention of conceiving during the course of the study. Post-pubertal males must have no plans to father a child during the study and agree to use adequate birth control methods if sexually active. Ability to comply with the entire study procedures, ability to communicate meaningfully with the investigational staff, competence to give written informed consent; to be applied to the parents and/or patients, as appropriate Duly executed, written, informed consent obtained from the parents/patient. Exclusion Criteria. Any of the following will exclude a patient from this trial: Neutrophil count <1,500/mm3 and/or platelet count <50,000/mm3 Demonstration of cutaneous or gastrointestinal ulceration of JDM related pulmonary disease or cardiomyopathy at the time of diagnosis. History of poor compliance. Evidence of current use of alcohol or illicit drugs abuse. Live vaccines not allowed during the entire duration of the trial. Dropout Criteria. Patients will be considered treatment failures, and dropped from the trial but included in efficacy analysis, if any of the following will occur during the active period of the trial. Non compliance with study medication administration Enrolment in other therapeutic trials.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Methylprednisolone pulse (MPDN)+PDN+CSA<br>MPDN= methylprednisolone pulse PDN= prednisone or equivalent CSA= cyclosporine A | Drug: 3 MPDN pulse + PDN + CSA<br>* 3 methylprednisolone pulses followed (30 mg/kg/pulse max 1 gram) followed by prednisone 2 mg/Kg/day to be tapered to 0.2 mg/kg/day in 6 months and then discontinued in 2 years; Cyclosporine 5 mg/Kg/day in 2 oral doses<br>|
| Active Comparator: MPDN+PDN+MTX<br>MPDN= methylprednisolone pulse PDN= prednisone or equivalent MTX= methotrexate | Drug: 3 MPDN pulse + PDN + MTX<br>* 3 methylprednisolone pulses followed (30 mg/kg/pulse max 1 gram) followed by prednisone 2 mg/Kg/day to be tapered to 0.2 mg/kg/day in 6 months and then discontinued in 2 years; Methotrexate 15-20 mg/m2 once per week. Patients treated with MTX will receive concomitant folic or folinic acid according to the attending physician decision.<br>|
| Active Comparator: MPDN+PDN<br>MPDN= methylprednisolone PDN= prednisone or equivalent | Drug: 3 MPDN pulse + PDN<br>* 3 methylprednisolone pulses followed (30 mg/kg/pulse max 1 gram) followed by prednisone 2 mg/Kg/day to be tapered to 0.2 mg/kg/day in 6 months and then discontinued in 2 years.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Responder Status Defined as 20% Improvement in at Least 3 Core Set Variables With no More Than 1 of the Remaining Variables, (Muscle Strength Excluded), Worsened by > 30%. | The PRINTO Juvenile Dermatomyositis (JDM) core set variables are: muscle strength by the mean of the Childhood Myositis Assessment Scale (CMAS); physician's global assessment of disease activity on a 10 cm Visual Analogue Scale (VAS); global disease activity assessment by the mean of the Disease Activity Index (DAS); parent's/patient's global assessment of overall well-being on a 10 cm VAS; functional ability assessment by the mean of the Childhood Health Assessment Questionnaire (CHAQ) health-related quality of life assessment. | 6 months | 
| Time to Clinical Remission | Clinical remission is defined as the status of inactive disease for at least 6 continuous months defined as normal muscle strength (CMAS equal to 52) and physician global assessment of disease activity equal to 0. | 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Major Therapeutic Changes | Time to major therapeutic changes is defined as the addition of CSA or MTX or any other disease-modifying antirheumatic drug (DMARS) in any of the 3 groups or discontinuation of assigned therapy for any reason including adverse events. Retention on treatment was used as main measure of effectiveness. | 60 months | 
| Time to Prednisone, or Equivalent, Discontinuation | Prednisone or equivalent glucocorticoid discontinuation is defined as the complete discontinuation of glucocorticoids | 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Juvenile dermatomyositis, randomised actively controlled clinical trial, prednisone, cyclosporine, methotrexate, effectiveness