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

Sponsor:	Istituto Giannina Gaslini
Collaborator:	Pediatric Rheumatology International Trials Organization
Information provided by:	Istituto Giannina Gaslini
ClinicalTrials.gov Identifier:	NCT00323960

Purpose

This is a 5-year project, involving 185 partners from 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. The trial is aimed to find out the treatment regimen associated with the lowest occurrence of flare and the lowest drug related toxicity

Condition	Intervention	Phase
Juvenile Dermatomyositis	Drug: 3 MPDN pulse + PDN Drug: 3 MPDN pulse + PDN + CSA Drug: 3 MPDN pulse + PDN + MTX	Phase III

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
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

Resource links provided by NLM:

Genetics Home Reference related topics: idiopathic inflammatory myopathy

Drug Information available for: Prednisolone Prednisolone acetate Prednisone Depo-medrol Methotrexate Cyclosporine Medrol veriderm Cyclosporin Methylprednisolone Prednisolone sodium phosphate Prednisolone Sodium Succinate Methylprednisolone Sodium Succinate Methylprednisolone hemisuccinate 6-Methylprednisolone

U.S. FDA Resources

Further study details as provided by Istituto Giannina Gaslini:

Primary Outcome Measures:

20% improvement in at least 3 core set variables with no more than 1 of the remaining variables, (muscle strength excluded), worsened by > 30%. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
The PRINTO 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 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.
Primary Outcome Measures after 24 months of treatment [ Time Frame: 24 months ] [ Designated as safety issue: No ]
a) time to clinical remission on medication defined as normal muscle strength and physician global assessment of disease activity equal to 0; b) time to flare of the disease defined as at least 20%, worsening from the previous evaluation value in 2 of any 6 JDM core set measures with no more than 1 of the remaining improved by more than 30% (muscle strength excluded).
Effectiveness [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
the rate of retention on treatment will be used as main measure of effectiveness

Secondary Outcome Measures:

Change over time in the individual components of the JDM core set of variables; a) time to muscle enzymes normalisation; b) frequency of drop-out of suggested steroids use; c) frequency of drop-out for inefficacy of treatment. [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
Safety parameters [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
1. Incidence of adverse events (AE):
  1. Number of patients discontinuing trial due to on-therapy conditions and AE possibly, probably, or definitely related to the experimental therapy, and listing of AE that cause discontinuation.
  2. Number of patients for whom the dosage was lowered, or withheld temporarily, due to AE, and listing of the specific AE that caused such action.
  3. Complete list of AE by system.
2. Incidence of clinically significant changes in laboratory parameters.
3. Drop out rate due to toxicity

Estimated Enrollment:	120
Study Start Date:	May 2006
Estimated Study Completion Date:	May 2011
Primary Completion Date:	December 2006 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: MPDN+PDN+CSA MPDN= methylprednisolone pulse PDN= prednisone or equivalent CSA= cyclosporine A	Drug: 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
Active Comparator: MPDN+PDN+MTX MPDN= methylprednisolone pulse PDN= prednisone or equivalent MTX= methotrexate	Drug: 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.
Active Comparator: MPDN+PDN MPDN+PDN MPDN= methylprednisolone PDN= prednisone or equivalent	Drug: 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.

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. 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

Ages Eligible for Study:	1 Year to 18 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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 the Bohan and Peter criteria (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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00323960

Contacts

Contact: Nicolino Ruperto, MD, MPH	0039-010-382854	nicolaruperto@ospedale-gaslini.ge.it
Contact: Simona Angioloni, B.A.	0039-010-393425	simonaangioloni@ospedale-gaslini.ge.it

Locations

Italy
Istituto Giannina Gaslini	Recruiting
Genoa, Italy, 16147

Sponsors and Collaborators

Istituto Giannina Gaslini

Pediatric Rheumatology International Trials Organization

Investigators

Principal Investigator:	Nicolino Ruperto, MD, MPH	Istituto Giannina Gaslini _ PRINTO Senior Scientist
Study Chair:	Alberto Martini, MD, Prof.	Istituto Giannina Gaslini_PRINTO Chairman

More Information

Additional Information:

Web site of the international network who is conducting the trial This link exits the ClinicalTrials.gov site

Web site for families in 50 different languages with information about the pediatric rheumatic diseases This link exits the ClinicalTrials.gov site

Publications:

Miller LC, Sisson BA, Tucker LB, DeNardo BA, Schaller JG. Methotrexate treatment of recalcitrant childhood dermatomyositis. Arthritis Rheum. 1992 Oct;35(10):1143-9.

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.

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.

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.

Responsible Party:	Nicolino Ruperto, MD, MPH, Paediatric Rheumatology International Trials Organization (PRINTO)
ClinicalTrials.gov Identifier:	NCT00323960 History of Changes
Other Study ID Numbers:	IGG-PRINTO-002, AIFA, Myositis Association
Study First Received:	May 9, 2006
Last Updated:	February 16, 2011
Health Authority:	Italy: Ministry of Health

Keywords provided by Istituto Giannina Gaslini:

Juvenile dermatomyositis
randomised actively controlled clinical trial
prednisone

cyclosporine
methotrexate
effectiveness

Additional relevant MeSH terms:

Dermatomyositis
Myositis
Muscular Diseases
Musculoskeletal Diseases
Polymyositis
Neuromuscular Diseases
Nervous System Diseases
Connective Tissue Diseases
Skin Diseases
Cyclosporins
Cyclosporine
Methotrexate
Methylprednisolone Hemisuccinate
Prednisolone
Prednisone

Methylprednisolone acetate
Prednisolone acetate
Methylprednisolone
Prednisolone phosphate
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Dermatologic Agents
Antirheumatic Agents

ClinicalTrials.gov processed this record on February 09, 2012