Clinical trial NCT00323960: Five-year Actively Controlled Clinical Trial in New Onset Juvenile Dermatomyositis
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Juvenile Dermatomyositis
Keywords: Juvenile dermatomyositis
randomised actively controlled clinical trial
prednisone
cyclosporine
methotrexate
effectiveness
Lead sponsor: Istituto Giannina Gaslini
Sponsor class: OTHER
Collaborators: name: Pediatric Rheumatology International Trials Organization
First posted: 2006-05-10
Enrollment: 139
Sex: ALL
Minimum age (years): 1
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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%.
timeFrame: 6 months
measure: Time to Clinical Remission
timeFrame: 60 months
Secondary outcomes:
measure: Time to Major Therapeutic Changes
timeFrame: 60 months
measure: Time to Prednisone, or Equivalent, Discontinuation
timeFrame: 60 months
Other outcomes:
Locations:
city: Genoa
country: Italy
facility: Istituto Giannina Gaslini
Study officials:
affiliation: Istituto Giannina Gaslini _ PRINTO Senior Scientist
name: Nicolino Ruperto, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Istituto Giannina Gaslini_PRINTO Chairman
name: Alberto Martini, MD, Prof.
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.