Combined Treatment of Methotrexate + Glucocorticoids Versus Glucocorticoids Alone in Patients With PM and DM
Condition: Polymyositis; Dermatomyositis
MeSH terms: Dermatomyositis; Polymyositis
Intervention: Prednisone; Methotrexate
Intervention description: Prednisone will be administered orally, initially at 1.0 mg/kg/day dosage and then tapered gradually equally in the two arms; MTX will be administered orally (in case of oral intolerance intramusculary (i.m.)), once weekly for 48 weeks. There will be a clinically oriented dose escalation starting from 10 up to 20-25 mg of MTX. Five to ten mg of folic acid will be given 24 hours after each methotrexate dose.
Intervention MeSH terms: Prednisone; Prednisolone; Methotrexate
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Enrollment: 31.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Polymyositis; Dermatomyositis; Glucocorticoids; Methotrexate

Summary:

      Therapeutical trial in patients with idiopathic polymyositis (PM) and dermatomyositis (DM) is
      proposed. The study will investigate the safety and efficacy of combined methotrexate (MTX) +
      glucocorticoids (GC) treatment compared with GC alone.

      This will be a randomised, open-label, assessor-blind, international multicenter trial,
      performed in several European centres interested in research on inflammatory myopathies
      (IIM).

      A total number of 50 patients with PM/DM will be randomised into two groups (1: MTX+ GC and
      2: GC only). Patients will be equally distributed between the two groups providing 25
      patients per treatment arm. The randomisation will be based on random numbers generated by a
      computer program. After being enrolled in the study, the patients will receive 12 months of
      therapy followed by a 12-month follow-up period.

      The primary endpoint is the total dose of GC ( in mg/kg weight), which will be administered
      for 12 months between baseline and the end of treatment.

      There are several of secondary objectives, which will be pursued during and after the trial.
      Disease activity and damage will be prospectively assessed by tools for myositis disease
      activity (MYOACT and MITAX) and for myositis damage (MYODAM and MDI), global assessment of
      activity and damage by patients and by physician, muscle endurance, muscle strength by manual
      muscle testing, enzyme levels, GC related side effects, functional ability measured by HAQ,
      quality of life by SF-36, and number of patients with treatment failures. The other aims will
      also include (i) search for reliable prognostic parameters in the further prognosis of
      patients with PM/DM and (ii) studies on the pathogenic aspects of IIM. The investigations of
      serum, lymphocytes, muscle tissue and MRI will be organized. DNA and RNA will be stored for
      future genetic studies.

      Patients with definite or probable PM or DM diagnosed according to diagnostic criteria will
      be enrolled. They will have disease activity that according to physician's own judgement
      requires high dose immunosuppressive treatment (based on clinical assessment of weakness,
      elevation of muscle enzymes and, if available, on magnetic resonance imaging findings).
      Patients should be previously untreated with the exception of GC treatment up to 8 weeks.

      Patients with other than primary idiopathic PM or DM, such as drug-induced myositis, myositis
      in association with other connective tissue disease, inclusion body myositis, malignancy
      related myositis, and juvenile DM will be excluded.

      All patients will start with prednisone 1 mg/kg/day and the dose will be tapered if patients
      meet definition of improvement, which has been proposed by IMACS group. MTX will be
      administered orally, once weekly, with a starting dose 10 mg. This will be increased
      gradually to 25 mg/week if tolerated by week 5. Patients will be first assessed after 2 weeks
      and than monthly for a period of 48 weeks. There will be a follow-up after a further 1 year
      in order to find out the impact of the early treatment on the long-term disease outcome.

      All efficacy analyses will be performed using intention-to-treat population (ITT). In
      addition, the primary and secondary variables will be analysed using the per-protocol
      population, which will contain all patients in the ITT population, who also reached Week 48
      without any major protocol violations. The safety population, which will contain any patient
      who received at least one dose of study drug, will be used for all safety analyses.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age between 18 - 80 years.

          2. Patients with definite or probable polymyositis or dermatomyositis diagnosed according
             to diagnostic criteria (9, 10) (Appendix 1)

          3. Physician's own judgment of the disease activity that requires high dose
             immunosuppressive treatment (based on clinical assessment of weakness, elevation of
             muscle enzymes and, if available, on magnetic resonance imaging findings).

          4. Previously untreated patients with the exception of glucocorticoid treatment up to 8
             weeks

          5. Signed informed consent.

        Exclusion Criteria:

          1. Treatment with any immunosuppressive drug prior the study start.

          2. Treatment with glucocorticoids (> 20 mg of Prednisone or equivalent) more than 8 weeks
             prior to study start.

          3. Drug induced myositis.

          4. Polymyositis and dermatomyositis in association with other connective tissue disease.

          5. Inclusion body myositis.

          6. Patients with immunodeficiency syndrome.

          7. Pregnancy and lactation.

          8. Fertile women not using adequate contraception during the study, women planning to
             have children during the study course or 12 months after the end of the study.

          9. Malignancy.

         10. Juvenile dermatomyositis.

         11. Uncontrolled, clinically significant hematological, cardiovascular, pulmonary,
             endocrine, metabolic, gastrointestinal, hepatic or renal disease, which according to
             physician's consideration would interfere with high dose glucocorticoid and
             immunosuppressive treatment or would prevent to follow the treatment protocol.

         12. Severe infection.

         13. History of drug or alcohol abuse within the previous 6 months.

         14. Patients known to be HIV positive.

         15. Known hypersensitivity to methotrexate.