Five year single blind effectiveness randomised actively controlled Phase III Clinical Trial in New Onset Juvenile Dermatomyositis: Steroids Treatment versus Steroids plus Cyclosporine Treatment versus Steroids plus Methotrexate Treatment

Juvenile dermatomyositis (JDM) is a multisystem disease characterised by acute
and chronic non-suppurative inflammation of striated muscles and skin. The
disease is marked early in its course by the presence of a vasculopathy of
varying severity that can be widespread and sometime also fatal, and late by
the development of dystrophic calcinosis (that is more frequent in children
than in adults) . Although JDM is a rare disease, it is the most common of the
pediatric inflammatory myopathies, with an incidence of 3.2 cases/1 million
children/year fulfilling the diagnostic criteria of Bohan and Peter. Disease
duration in JDM ranges from <1.0 year to persistent disease beginning during
childhood but lasting well into adulthood . Death has been reported to occur in
up to 39% of children with JDM with most studies reporting mortality rates
between 3-18%.
However, even for those surviving the illness, there are often chronic
complications and long-lasting disability. In one long-term study that followed
childhood onset JDM patients into adulthood, 33% still demonstrated weakness,
39% still had dermatologic manifestations, 22% had persistent contractures, and
39% had subcutaneous calcinosis. In another study of childhood onset JDM
patients evaluated at a mean age of 18.8 years, 33% reported limitations in
ability to do daily activities, 78% still had dermatologic manifestations, 58%
had additional
nondermatologic abnormalities on physical exam, and 50% had evidence of muscle
scarring by ultrasound evaluation .
Current available treatments in children: the treatment of JDM, is
unsatisfactory, and corticosteroids are the only agents currently approved by
the US Food and Drug Administration for myositis. Prednisone therapy is
frequently required for long periods with a mean duration ranging from 25 to 54
months. In some series, over 40% of the JDM subjects remain on prednisone for
more than 7 years . Many of JDM patients fail to respond adequately to
corticosteroids and require additional immunosuppressive medications, none of
which have been tested in controlled trials in this conditions. Indeed no
randomised clinical trial with immunosuppressive agents are available for
children with JDM, and most of the studies involve single referral centres
reporting retrospectively on small numbers of patients followed for relatively
brief periods of time. Few examples are reported in the following paragraphs.
The duration of prednisone treatment was studied retrospectively in children
with JDM treated by two different methods, PDN alone versus MTX and PDN. The
authors concluded that in this short-term comparison, early use of MTX allowed
for acceptable clinical outcomes with much shorter duration of prednisone
treatment. This study suggests a significant prednisone sparing effect with the
early introduction of MTX in the treatment of JDM. Similar conclusions were
reported by others.
In other 2 studies cyclosporine A (CsA) has been used to treat patients with
refractory JDM. the Authors concluded that CsA represents a promising agent for
the treatment JDM.
Although suggestive, these trials have significant design limitations, small
sample size, they lack standardised measures to evaluate the outcome, and they
do not have a standardised protocols for prednisone tapering. As a conclusion
it can be stated that current treatment for JDM has failed to eliminate
significant morbidity and mortality and that although several publications
describe experience with second line agents no prospective randomized trial has
ever been performed
in children with JDM.

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.

Trial Objective. To assess the effectiveness (efficacy, safety, tolerability
and compliance to treatment) of the 3 treatment approaches for the treatment of
children with JDM. THE OVERALL HYPOTHESIS TO BE TESTED IN THIS TRIAL is that
the early introduction of combination therapy of corticosteroids and either MTX
or CsA will prove more effective and safe than corticosteroids alone in the
treatment of JDM.

Trial Design and Duration. Two-year single-blind (assessor blinded to treatment
arm of subject), randomised, actively controlled, multi-centre, international
prospective, non inferiority trial of different combination of drugs. Patients
will be then followed for up to 5 years for the evaluation of long term
morbidity and mortality.
Dose Regimen: 3 daily pulses of intravenous (iv) methylprednisolone (30
mg/kg/pulse max 1 g/pulse) followed by randomisation into one of these 3 groups.

Group 1 prednisone or equivalent (PDN): PDN 2 mg/kg/day;
Group 2 PDN+cyclosporine A (CsA): PDN 2 mg/kg/day + CsA 5 mg/kg/day in 2 oral
doses.;
Group 3 PDN + methotrexate (MTX): PDN 2 mg/kg/day + MTX 15-20 mg/m2 once per
week. Patients treated with MTX will receive concomitant folic or folinic acid
according to the attending physician decision.

Long term follow up after month 24 until month 60. All patients will be
followed for a total of 5 years for the assessment of long term morbidity and
mortality rate. After month 24 treatment will be left open to the physician
decision based on the clinical status of the patient.

none

fully compliant with current medical care, i.e. there is no significant burden.
Potential benefit is early remission with reduced toxicity and disease damage.