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| ID | Type | Description | Link |
|---|---|---|---|
| AIFA | Other Grant/Funding Number | Agenzia Italiana del Farmaco (no FARMJWPZ) | |
| Myositis Association | Other Grant/Funding Number | Myositis Association |
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| Name | Class |
|---|---|
| Pediatric Rheumatology International Trials Organization | OTHER |
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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
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Methylprednisolone pulse (MPDN)+PDN+CSA | Active Comparator | MPDN= methylprednisolone pulse PDN= prednisone or equivalent CSA= cyclosporine A |
|
| MPDN+PDN+MTX | Active Comparator | MPDN= methylprednisolone pulse PDN= prednisone or equivalent MTX= methotrexate |
|
| MPDN+PDN | Active Comparator | MPDN= methylprednisolone PDN= prednisone or equivalent |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 3 MPDN pulse + PDN | Drug | 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. |
| 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:
| 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 |
| 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 |
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Inclusion Criteria. Each patient must meet all the following criteria in order to participate in this trial:
Exclusion Criteria. Any of the following will exclude a patient from this 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.
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| Name | Affiliation | Role |
|---|---|---|
| Nicolino Ruperto, MD, MPH | Istituto Giannina Gaslini _ PRINTO Senior Scientist | Principal Investigator |
| Alberto Martini, MD, Prof. | Istituto Giannina Gaslini_PRINTO Chairman | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Istituto Giannina Gaslini | Genoa | 16147 | Italy |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 1418005 | Background | Miller LC, Sisson BA, Tucker LB, DeNardo BA, Schaller JG. Methotrexate treatment of recalcitrant childhood dermatomyositis. Arthritis Rheum. 1992 Oct;35(10):1143-9. doi: 10.1002/art.1780351006. | |
| 10791626 | Background | Al-Mayouf S, Al-Mazyed A, Bahabri S. Efficacy of early treatment of severe juvenile dermatomyositis with intravenous methylprednisolone and methotrexate. Clin Rheumatol. 2000;19(2):138-41. doi: 10.1007/s100670050032. |
| Label | URL |
|---|---|
| Web site of the international network who is conducting the trial | View source |
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Data will be provided upon request to the Paediatric Rheumatology InterNational Trials Organisation (PRINTO) network as per its bylaws
Data will be available upon request
Request to the Paediatric Rheumatology International Trials Organisation (PRINTO) international coordinating centre: PRINTO@gaslini.org
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| ID | Title | Description |
|---|---|---|
| FG000 | Methylprednisolone Pulse+Prednisone | Group 1 received 3 pulses of methylprednisolone and has been randomized to prednisone or equivalent |
| FG001 | Methylprednisolone Pulse+Prednisone+Cyclosporine A | Group 2 received 3 pulses of methylprednisolone and has been randomized to prednisone or equivalent plus cyclosporine A |
| FG002 | Methylprednisolone Pulses+Prednisone+Methotrexate | Group 3 received 3 pulses of methylprednisolone and has been randomized to prednisone or equivalent plus methotrexate |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | MPDN+PDN+CSA |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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:
| Comparison between group 2 (PDN+CSA) and 3 (PDN+MTX) combined versus group 1 (PDN) | Posted | Count of Participants | Participants | 6 months |
|
5 years
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Subcutaneous abscess | Skin and subcutaneous tissue disorders | MedDRA (Unspecified) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypertrichosis | Skin and subcutaneous tissue disorders | MedDRA (Unspecified) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Nicolino Ruperto | IRCCS Istituto Giannina Gaslini | +39-010-382854 | nicolaruperto@gaslini.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Feb 23, 2007 | Mar 24, 2023 | Prot_000.pdf |
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| ID | Term |
|---|---|
| D003882 | Dermatomyositis |
| ID | Term |
|---|---|
| D017285 | Polymyositis |
| D009220 | Myositis |
| D009135 | Muscular Diseases |
| D009140 | Musculoskeletal Diseases |
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| 3 MPDN pulse + PDN + CSA | Drug | 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 |
|
| 3 MPDN pulse + PDN + MTX | Drug | 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. |
|
| Time to Prednisone, or Equivalent, Discontinuation | Prednisone or equivalent glucocorticoid discontinuation is defined as the complete discontinuation of glucocorticoids | 60 months |
| 2566009 | Background | Heckmatt J, Hasson N, Saunders C, Thompson N, Peters AM, Cambridge G, Rose M, Hyde SA, Dubowitz V. Cyclosporin in juvenile dermatomyositis. Lancet. 1989 May 13;1(8646):1063-6. doi: 10.1016/s0140-6736(89)92456-2. |
| 8508564 | Background | Pistoia V, Buoncompagni A, Scribanis R, Fasce L, Alpigiani G, Cordone G, Ferrarini M, Borrone C, Cottafava F. Cyclosporin A in the treatment of juvenile chronic arthritis and childhood polymyositis-dermatomyositis. Results of a preliminary study. Clin Exp Rheumatol. 1993 Mar-Apr;11(2):203-8. |
| 27353819 | Derived | Ruperto N, Pistorio A, Ravelli A, Angioloni S, Martini A; Paediatric Rheumatology International Trials Organisation (PRINTO). The PRINTO juvenile dermatomyositis trial - Authors' reply. Lancet. 2016 Jun 25;387(10038):2601. doi: 10.1016/S0140-6736(16)30671-7. No abstract available. |
| 27353816 | Derived | Dale A, Milosevic I, Goldacre B; COMPare project team. The PRINTO juvenile dermatomyositis trial. Lancet. 2016 Jun 25;387(10038):2600-2601. doi: 10.1016/S0140-6736(16)30845-5. No abstract available. |
| 26645190 | Derived | Ruperto N, Pistorio A, Oliveira S, Zulian F, Cuttica R, Ravelli A, Fischbach M, Magnusson B, Sterba G, Avcin T, Brochard K, Corona F, Dressler F, Gerloni V, Apaz MT, Bracaglia C, Cespedes-Cruz A, Cimaz R, Couillault G, Joos R, Quartier P, Russo R, Tardieu M, Wulffraat N, Bica B, Dolezalova P, Ferriani V, Flato B, Bernard-Medina AG, Herlin T, Trachana M, Meini A, Allain-Launay E, Pilkington C, Vargova V, Wouters C, Angioloni S, Martini A; Paediatric Rheumatology International Trials Organisation (PRINTO). Prednisone versus prednisone plus ciclosporin versus prednisone plus methotrexate in new-onset juvenile dermatomyositis: a randomised trial. Lancet. 2016 Feb 13;387(10019):671-678. doi: 10.1016/S0140-6736(15)01021-1. Epub 2015 Nov 30. |
| Web site for families in 50 different languages with information about the pediatric rheumatic diseases | View source |
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 |
| BG002 | 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. |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | For age it is intended age at first observation | Median | Inter-Quartile Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| disease duration | Median | Inter-Quartile Range | months |
|
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.
| OG001 | Group 2 (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 |
| OG002 | Group 3 (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. |
|
|
|
| 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. | Posted | Number | 95% Confidence Interval | events per 1000 persons-time | 60 months |
|
|
|
|
| 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. | Posted | Number | 95% Confidence Interval | events per 1000 persons-time | 60 months |
|
|
|
|
| Secondary | Time to Prednisone, or Equivalent, Discontinuation | Prednisone or equivalent glucocorticoid discontinuation is defined as the complete discontinuation of glucocorticoids | Posted | Number | 95% Confidence Interval | events per 1000 persons-time | 60 months |
|
|
|
|
| 1 |
| 47 |
| 29 |
| 47 |
| EG001 | 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 | 5 | 46 | 35 | 46 |
| EG002 | 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. | 2 | 46 | 29 | 46 |
| Posterior reversible encephalopathy | Nervous system disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Convulsion | Nervous system disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Deep vein thrombosis | Vascular disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Appendicitis | Gastrointestinal disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Sepsis | Infections and infestations | MedDRA (Unspecified) | Systematic Assessment |
|
| Paronychia | Skin and subcutaneous tissue disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Dermo-hypodermitis | Skin and subcutaneous tissue disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Hirsutism | Skin and subcutaneous tissue disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Alopecia | Skin and subcutaneous tissue disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Infection and infestations | Infections and infestations | MedDRA (Unspecified) | Systematic Assessment |
|
| Cushing syndrome | Endocrine disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Weight gain | Metabolism and nutrition disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Increases in serum creatinine | Investigations | MedDRA (Unspecified) | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| General disorders and administration site conditions | Injury, poisoning and procedural complications | MedDRA (Unspecified) | Systematic Assessment |
|
| Musculoskeletal disorders | Musculoskeletal and connective tissue disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Psychiatric disorders | Psychiatric disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Metabolic disorders | Metabolism and nutrition disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Vascular disorders | Vascular disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Tachycardia | Cardiac disorders | MedDRA (Unspecified) | Systematic Assessment |
|
| Eye disorders | Eye disorders | MedDRA (Unspecified) | Systematic Assessment |
|
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| D009468 |
| Neuromuscular Diseases |
| D009422 | Nervous System Diseases |
| D003240 | Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D012871 | Skin Diseases |
| 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 0ยท05 significant. We reported in the table the incidence rates with 95% confidence intervals of the 3 groups. | Log Rank | 0.002 | Relative risk | 1.65 | 2-Sided | 95 | 1.24 | 2.14 | RR related to prednisone alone (group 1) versus prednisone plus ciclosporin (group 2) and prednisone plus methotrexate arm (group 3). | Superiority |