Juvenile Dermatomyositis
Conditions
Keywords
Juvenile dermatomyositis, randomised actively controlled clinical trial, prednisone, cyclosporine, methotrexate, effectiveness
Brief summary
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
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.
Interventions
DRUG3 MPDN pulse + PDN
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.
DRUG3 MPDN pulse + PDN + CSA
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
DRUG3 MPDN pulse + PDN + MTX
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.
Sponsors
Pediatric Rheumatology International Trials Organization
Istituto Giannina Gaslini
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
. Each patient must meet all the following criteria in order to participate in this trial: 1. 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. 2. Age at enrolment ≤ 18 years. 3. 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. 4. 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 5. Duly executed, written, informed consent obtained from the parents/patient.
Exclusion criteria
. Any of the following will exclude a patient from this trial: 1. Neutrophil count \<1,500/mm3 and/or platelet count \<50,000/mm3 2. Demonstration of cutaneous or gastrointestinal ulceration of JDM related pulmonary disease or cardiomyopathy at the time of diagnosis. 3. History of poor compliance. 4. Evidence of current use of alcohol or illicit drugs abuse. 5. 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. 1. Non compliance with study medication administration 2. Enrolment in other therapeutic trials.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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%. | 6 months | The PRINTO Juvenile Dermatomyositis (JDM) core set variables are: 1. muscle strength by the mean of the Childhood Myositis Assessment Scale (CMAS); 2. physician's global assessment of disease activity on a 10 cm Visual Analogue Scale (VAS); 3. global disease activity assessment by the mean of the Disease Activity Index (DAS); 4. parent's/patient's global assessment of overall well-being on a 10 cm VAS; 5. functional ability assessment by the mean of the Childhood Health Assessment Questionnaire (CHAQ) 6. health-related quality of life assessment. |
| Time to Clinical Remission | 60 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Major Therapeutic Changes | 60 months | 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. |
| Time to Prednisone, or Equivalent, Discontinuation | 60 months | Prednisone or equivalent glucocorticoid discontinuation is defined as the complete discontinuation of glucocorticoids |
Countries
Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MPDN+PDN MPDN+PDN MPDN= methylprednisolone PDN= prednisone or equivalent
3 MPDN pulse + PDN: 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. | 47 |
| MPDN+PDN+CSA MPDN= methylprednisolone pulse PDN= prednisone or equivalent CSA= cyclosporine A
3 MPDN pulse + PDN + CSA: 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 | 46 |
| MPDN+PDN+MTX MPDN= methylprednisolone pulse PDN= prednisone or equivalent MTX= methotrexate
3 MPDN pulse + PDN + MTX: 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. | 46 |
| Total | 139 |
Baseline characteristics
| Characteristic | MPDN+PDN+CSA | MPDN+PDN | MPDN+PDN+MTX | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 46 Participants | 47 Participants | 46 Participants | 139 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 8.9 years | 7.2 years | 7.1 years | 7.5 years |
| disease duration | 2.7 months | 2.6 months | 2.8 months | 2.8 months |
| Region of Enrollment Algeria | 0 participants | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Argentina | 2 participants | 11 participants | 2 participants | 15 participants |
| Region of Enrollment Austria | 0 participants | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Belgium | 0 participants | 3 participants | 3 participants | 6 participants |
| Region of Enrollment Brazil | 6 participants | 4 participants | 3 participants | 13 participants |
| Region of Enrollment Colombia | 0 participants | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Czech Republic | 1 participants | 1 participants | 0 participants | 2 participants |
| Region of Enrollment Denmark | 2 participants | 0 participants | 0 participants | 2 participants |
| Region of Enrollment France | 10 participants | 3 participants | 11 participants | 24 participants |
| Region of Enrollment Germany | 0 participants | 2 participants | 1 participants | 3 participants |
| Region of Enrollment Greece | 1 participants | 0 participants | 1 participants | 2 participants |
| Region of Enrollment Israel | 0 participants | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Italy | 13 participants | 11 participants | 10 participants | 34 participants |
| Region of Enrollment Latvia | 0 participants | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Mexico | 3 participants | 0 participants | 3 participants | 6 participants |
| Region of Enrollment Netherlands | 1 participants | 1 participants | 2 participants | 4 participants |
| Region of Enrollment Norway | 0 participants | 2 participants | 0 participants | 2 participants |
| Region of Enrollment Serbia | 0 participants | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Slovakia | 2 participants | 0 participants | 0 participants | 2 participants |
| Region of Enrollment Slovenia | 2 participants | 1 participants | 1 participants | 4 participants |
| Region of Enrollment Spain | 1 participants | 0 participants | 0 participants | 1 participants |
| Region of Enrollment Sweden | 1 participants | 2 participants | 2 participants | 5 participants |
| Region of Enrollment United Kingdom | 0 participants | 1 participants | 1 participants | 2 participants |
| Region of Enrollment United States | 0 participants | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Venezuela | 1 participants | 1 participants | 3 participants | 5 participants |
| Sex: Female, Male Female | 26 Participants | 26 Participants | 30 Participants | 82 Participants |
| Sex: Female, Male Male | 20 Participants | 21 Participants | 16 Participants | 57 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 29 / 47 | 35 / 46 | 29 / 46 |
| serious Total, serious adverse events | 1 / 47 | 5 / 46 | 2 / 46 |
Outcome results
Primary
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: 1. muscle strength by the mean of the Childhood Myositis Assessment Scale (CMAS); 2. physician's global assessment of disease activity on a 10 cm Visual Analogue Scale (VAS); 3. global disease activity assessment by the mean of the Disease Activity Index (DAS); 4. parent's/patient's global assessment of overall well-being on a 10 cm VAS; 5. functional ability assessment by the mean of the Childhood Health Assessment Questionnaire (CHAQ) 6. health-related quality of life assessment.
Time frame: 6 months
Population: Comparison between group 2 (PDN+CSA) and 3 (PDN+MTX) combined versus group 1 (PDN)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1 (MPDN+PDN) | 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%. | 24 Participants |
| Group 2 (MPDN+PDN+CSA) | 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%. | 32 Participants |
| Group 3 (MPDN+PDN+MTX) | 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%. | 33 Participants |
Comparison: We calculated that a sample size of 40 patients would be needed in each study group (total 120 patients) to have 80% power for comparison of combination treatments (prednisone plus methotrexate or prednisone plus ciclosporin) with the reference treatment (prednisone alone).p-value: 0.0228Chi-squared
Primary
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.
Time frame: 60 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 (MPDN+PDN) | Time to Clinical Remission | 5.99 events per 1000 persons-time |
| Group 2 (MPDN+PDN+CSA) | Time to Clinical Remission | 4.95 events per 1000 persons-time |
| Group 3 (MPDN+PDN+MTX) | Time to Clinical Remission | 13.39 events per 1000 persons-time |
Comparison: We used the Kaplan-Meier method to produce survival curves (groups 1 and 2 versus group 3) and compared them with the Log-Rank test. We judged a p value less than 0·05 significant. We reported in the table the incidence rates with 95% confidence intervals of the 3 groups.p-value: 0.01295% CI: [1.2, 5]Log Rank
Secondary
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.
Time frame: 60 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 (MPDN+PDN) | Time to Major Therapeutic Changes | 30.52 events per 1000 persons-time |
| Group 2 (MPDN+PDN+CSA) | Time to Major Therapeutic Changes | 17.52 events per 1000 persons-time |
| Group 3 (MPDN+PDN+MTX) | Time to Major Therapeutic Changes | 13.92 events per 1000 persons-time |
Comparison: We used the Kaplan-Meier method to produce survival curves (group 1 versus groups 2 and 3) and compared them with the Log-Rank test. We judged a p value less than 0·05 significant. We reported in the table the incidence rates with 95% confidence intervals of the 3 groups.p-value: 0.00995% CI: [1.2, 3.15]Log Rank
Secondary
Time to Prednisone, or Equivalent, Discontinuation
Prednisone or equivalent glucocorticoid discontinuation is defined as the complete discontinuation of glucocorticoids
Time frame: 60 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 (MPDN+PDN) | Time to Prednisone, or Equivalent, Discontinuation | 15.91 events per 1000 persons-time |
| Group 2 (MPDN+PDN+CSA) | Time to Prednisone, or Equivalent, Discontinuation | 27.82 events per 1000 persons-time |
| Group 3 (MPDN+PDN+MTX) | Time to Prednisone, or Equivalent, Discontinuation | 24.42 events per 1000 persons-time |
Comparison: We used the Kaplan-Meier method to produce survival curves (groups 2 and 3 versus group 1) and compared them with the Log-Rank test. We judged a p value less than 0·05 significant. We reported in the table the incidence rates with 95% confidence intervals of the 3 groups.p-value: 0.00295% CI: [1.24, 2.14]Log Rank
Comparison: We used the Kaplan-Meier method to produce survival curves (groups 1 versus groups 2 and 3) and compared them with the Log-Rank test. We judged a p value less than 0·05 significant. We reported in the table the incidence rates with 95% confidence intervals of the 3 groups.p-value: 0.00295% CI: [1.24, 2.14]Log Rank